integrated clinical trial report (final version) a...

B. Braun Melsungen AG BBMDE-0312 Page: 1 of 92

INTEGRATED CLINICAL TRIAL REPORT

(FINAL VERSION)

A comparison of venous tolerability and injection pain of

Propofol diluted in a lipid emulsion and standard Propofol

in the induction of anesthesia in children

Study number: BBMDE-0312

C o n f i d e n t i a l

The information in this CLINICAL TRIAL REPORT is property of the company B. Braun Melsungen AG. It is provided confidentially and should only be disclosed to those persons responsible for execution and

organization of the trial and on condition that all such persons agree upon no further dissemination.

INTEGRATED CLINICAL TRIAL REPORT BBMDE-0312, Final Version IAS 1/28.03.2006/BBM0201-09 B. Braun Melsungen AG, Carl-Braun-Straße 1, 34212 Melsungen, Germany


0. SIGNATURE DOCUMENT

0.1 STATEMENT OF THE SPONSOR

The undersigned declare that they have read this report and confirm that to the best of their knowledge it accurately describes the conduct and results of the study BBMDE-0312.

Responsibility Name Date Signature

Project coordinator Dr. med. U. Brauer B. Braun Melsungen AG Hospital Care Division Research and Development Clinical Development Carl-Braun-Straße 1 34212 Melsungen, Germany

Study coordinator T. Dehnhardt B. Braun Melsungen AG Hospital Care Division Research and Development Clinical Development Carl-Braun-Straße 1 34212 Melsungen, Germany

Biometrician Dr. rer. nat. Jörg Schnitker Institut für angewandte Statistik GmbH Artur-Ladebeck-Straße 155 33647 Bielefeld, Germany

0.2 STATEMENT OF THE PRINCIPAL INVESTIGATOR

I, the undersigned, declare that I have read this report and confirm that to the best of my knowledge it accurately describes the conduct and results of the study BBMDE-0312.

Responsibility Name Date Signature

Principal investigator pursuant to § 40 AMG

PD Dr. med. G. Molter Klinik für Anästhesie und operative Intensivmedizin Klinikum Leverkusen gGmbH Akademisches Lehrkrankenhaus der Universität zu Köln Dhünnberg 60 51375 Leverkusen, Germany

This study was performed in compliance with ICH Good Clinical Practice (CPMP/ICH/135/95).



1. TITLE PAGE

Study title A comparison of venous tolerability and injection pain of Propofol diluted in a lipid emulsion and standard Propofol in the induction of anesthesia in children

Name of test drug / investigational product Propofol

Indication studied Anesthesia

Study design Prospective, parallel group, controlled, randomized, single-blind and, regarding the primary endpoint, double-blind ('observer blind') monocenter study

Sponsor B. Braun Melsungen AG Hospital Care Division Research and Development Carl-Braun-Straße 1 34212 Melsungen, Germany

Study number BBMDE-0312

Development phase of study Phase III

Study initiation date 15.08.2003

Study completion date 09.02.2005

Principal investigator (Leiter der klinischen Prüfung according to German Drug Law) PD Dr. med. G. Molter

Klinik für Anästhesie und operative Intensivmedizin Klinikum Leverkusen gGmbH Akademisches Lehrkrankenhaus der Universität zu Köln Dhünnberg 60 51375 Leverkusen, Germany

Study coordinator T. Dehnhardt B. Braun Melsungen AG Hospital Care Division Research and Development Clinical Development Carl-Braun-Straße 1 34212 Melsungen, Germany

GCP This study was performed in compliance with ICH Good Clinical Practice (CPMP/ICH/135/95).

Date of the report 28.03.2006.



2. SYNOPSIS

Name of the finished product Propofol-®Lipuro

Name of the active ingredient Propofol MCT / LCT

Title of the study A comparison of venous tolerability and injection pain of Propofol diluted in alipid emulsion and standard Propofol in the induction of anesthesia in children.

Investigators • PD Dr. med. G. Molter Klinik für Anästhesie und operative Intensivmedizin Klinikum Leverkusen gGmbH Akademisches Lehrkrankenhaus der Universität zu Köln Dhünnberg 60, 51375 Leverkusen, Germany

• Dr. med. S. Soltész Oberarzt der Klinik für Anästhesie und operative Intensivmedizin Klinikum Leverkusen gGmbH Dhünnberg 60, 51375 Leverkusen, Germany

Study center Klinikum Leverkusen gGmbH Klinik für Anästhesie und operative Intensivmedizin Akademisches Lehrkrankenhaus der Universität zu Köln Dhünnberg 60, 51375 Leverkusen, Germany

Publication (reference) –

Study period Date of first patient enrolled : 15.08.2003 Date of last patient completed : 09.02.2005

Phase of development III

Objectives To compare anesthesia induction by means of Propofol-®Lipuro 0.5% and Propofol-®Lipuro 1.0% with regard to venous tolerability and injection pain inchildren.

Methodology Prospective, monocenter, parallel group, controlled, randomized, single-blind and, regarding the primary endpoint, double-blind ('observer blind') clinical phase III study.

Number of patients • planned for enrollment : 64 (32 per group) • enrolled and randomized : 64 (32 per group) • screening failures, not treated : 4 ( 2 / 2)* • safety population : 60 (30 / 30)* • intention-to-treat set : 60 (30 / 30)* • per protocol set : 60 (30 / 30)*

[*: Propofol 0.5% / Propofol 1.0%].

Diagnosis and main criteria for inclusion

Children aged ≥ 2 and < 6 years undergoing elective surgery under general anesthesia: • ASA I – III • Venous access for induction of anesthesia situated on the dorsum of the

hand.

Test product Propofol MCT / LCT 0.5% (Propofol-®Lipuro 0.5%) Dose Bolus 3 mg/kg i.v.; in addition by steps up to 1 mg/kg until absence of winking

reflex, as required Mode of administration I.v. boli fractionized over approximately 30 sec each Batch no. 3151A131



Duration of treatment 0.5 – 5.5 min, approx. 2 min at average

Reference therapy Propofol MCT / LCT 1.0% (Propofol-®Lipuro 1.0%) Dose Bolus 3 mg/kg i.v.; in addition by steps up to 1 mg/kg until absence of winking

reflex, as required Mode of administration I.v. boli fractionized over approximately 30 sec each Batch no. 3054C33, 4475C34

Criteria for evaluation

Efficacy • Need of Propofol • Time until absence of winking reflex.

Safety • Spontaneous expression of pain during injection • Intensity of spontaneous expression of pain • Child's attempt to draw back the arm • Anesthesist's statement whether he / she needed to keep the hand or arm in

position during the injection • Anesthesist's assessment of injection pain (VAS) • Events during anesthesia until end of observation period • Local reactions • Triglycerides (subgroup) • Blood pressure, heart rate • Oxygen saturation.

Statistical methods • Fisher's exact test • χ2 test • U test • t-test • Significance level α=0.05 two-tailed • Analysis of covariance for the repeated measurement design.

Efficacy results

Time to absence of winking reflex (U test: p=0.3050) • Propofol 0.5% : 1.47 ± 0.94 min • Propofol 1.0% : 1.67 ± 0.88 min.

Propofol required until absence of winking reflex (U test: p=0.6463) • Propofol 0.5% : 80.0 ± 22.9 mg • Propofol 1.0% : 75.2 ± 18.9 mg.

Further Propofol boli after absence of winking reflex • Propofol 0.5% : N=7 • Propofol 1.0% : N=7.




Propofol required during induction of anesthesia (U test: p=0.6412) • Propofol 0.5% : 85.6 ± 26.9 mg • Propofol 1.0% : 80.1 ± 18.4 mg.

Serious adverse events • Propofol 0.5% : N=– • Propofol 1.0% : N=1 (recurrent vomiting, hospitalization).

Safety results

Incidence of spontaneous expression of injection pain (Fisher's exact test: p=0.1028) • Propofol 0.5% : N=1 ( 3.3%) • Propofol 1.0% : N=6 (20.0%).

Intensity of spontaneous expression of injection pain (U test: p=0.0424) • Propofol 0.5% no pain : N=29 (96.7%)

grimacing : N= 1 ( 3.3%) crying : N= – screaming : N= –

• Propofol 1.0% no pain : N=24 (80.0%) grimacing : N= 2 ( 6.7%) crying : N= 4 (13.3%) screaming : N= –.

Drawing back of the arm (Fisher's exact test: p=0.0006) • Propofol 0.5% : N= 7 (23.3%) • Propofol 1.0% : N=21 (70.0%).

Need to hold the arm tightly (Fisher's exact test: p=0.0033) • Propofol 0.5% : N= 6 (20.0%) • Propofol 1.0% : N=18 (60.0%).

Anesthesist's VAS of injection pain (U test: p<0.0001) • Propofol 0.5% : 2.6 ± 5.2 mm • Propofol 1.0% : 18.6 ± 18.6 mm.


Other adverse events (N = number of patients showing adverse events, all in all 13 adverse events were documented) • Propofol 0.5% : N=5 (16.7%) • Propofol 1.0% : N=6 (20.0%).

Besides injection pain, a relationship to study drug was ruled out except for the cases of 2 patients who experienced erythemas after administration of Propofol 1.0%

Triglyceride levels A significantly higher increase of triglycerides was seen after administration of Propofol 0.5%. The adjusted mean levels (± SEM) showed no relevant differences already 20 min after end of Propofol administration:

Propofol 0.5% Propofol 1.0% Time of measurement adj. mean SEM adj. mean SEM

t-test

Before anesthesia induction 58.0 58.0

End of anesthesia induction + 3 min 240.9 17.0 158.6 16.2 p=0.0021 End of anesthesia induction + 20 min 124.7 17.0 85.3 16.2 p=0.1139 .

Blood pressure and heart rate At absence of winking reflex, a stronger decrease of BP and HR was seen after Propofol 0.5% as compared to Propofol 1.0%.

Correlation of changes in blood pressure and occurrence of injection pain The different courses of blood pressure and heart rate in both dosage groups suggested a causal relationship between injection pain and decrease of blood pressure. The lesser injection pain upon Propofol 0.5% possibly causes a reduced endogenous catecholamine production followed by a pronounced Propofol-induced depression of blood pressure. This would imply a direct effect of injection pain on blood pressure which was not verified in the study. The lack of BP decrease in the Propofol 1.0% group seemed to be caused by some outliers and by a lower BP level at baseline. Therefore, this was a more incidental finding.

Oxygen saturation No statistically significant differences between the trial groups were detected in respect to the oxygen saturation.



Conclusions

As to efficacy, need of Propofol is similar in both treatment groups. Concerning time until absence of winking reflex, similar Propofol dosages in the two groups were required. A comparable number of additional boli of Propofol in order to achieve anesthesia was needed, and dosage per bolus was also comparable in both treatment groups. The analysis of the use of further surgery-induced medication reveals no medically relevant differences. The two different concentrations of Propofol do not trigger different comedication schemes during or after anesthesia.

Injection pain as the primary endpoint in this study was differently distributed in both trial groups with clear advantages for Propofol 0.5%. The rate of spontaneous expression of injection pain was much lower in the Propofol 0.5% group. The intensity of the spontaneously expressed pain revealed statistically significant and medically relevant differences between both treatment groups with stronger pain reactions following Propofol 1.0%.

Fewer patients (23.3%) treated with Propofol 0.5% compared to those treated with Propofol 1.0% (70%) tried to draw back the arm (p=0.0006), the effect being even more pronounced when the intensity of the attempt was considered (p=0.0002). Significant differences in the judgment of injection pain intensity by the anesthesist (p<0.0001) were also recorded.

No statistically significant differences between both trial groups were determined with regard to adverse events during anesthesia until end of observation. Erythema / exanthema and nausea / vomiting were reported in the Propofol 1.0% group only (6.7% patients each). A relationship to study drug was ruled out except for the 2 patients who experienced erythemas after administration of Propofol 1.0%. A serious adverse event was reported in one patient treated with Propofol 1.0%. The child (male, 5 years) developed a moderate recurrent vomiting after administration of Nubain® i.v. (nalbuphin) and was hospitalized as a measure of precaution. According to the physician, causal relationship with Propofol was not likely. No death occurred throughout the entire study.

Based upon these results, Propofol 0.5% is a valuable alternative to Propofol 1.0% to be used in children aged 2 – 6 years for induction of anesthesia. Pain under Propofol 0.5% is less frequent and particularly intensity of pain is lower. What is more, during the entire study fewer adverse events were reported under Propofol 0.5%.



3. TABLE OF CONTENTS

0. SIGNATURE DOCUMENT............................................................................................ 2 0.1 STATEMENT OF THE SPONSOR........................................................................... 2 0.2 STATEMENT OF THE PRINCIPAL INVESTIGATOR .................................................... 2

1. TITLE PAGE ............................................................................................................. 3 2. SYNOPSIS ............................................................................................................... 4 3. TABLE OF CONTENTS ............................................................................................... 9 4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................14 5. ETHICS ..................................................................................................................15

5.1 ETHICS COMMITTEE.........................................................................................15 5.2 ETHICAL CONDUCT OF THE STUDY.....................................................................15 5.3 PATIENT INFORMATION AND CONSENT ...............................................................16

6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .........................................17 7. INTRODUCTION .......................................................................................................19 8. STUDY OBJECTIVES ................................................................................................20 9. INVESTIGATIONAL PLAN ...........................................................................................20

9.1 OVERALL STUDY DESIGN AND PLAN – DESCRIPTION.............................................20 9.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS.....21 9.3 SELECTION OF STUDY POPULATION...................................................................22

9.3.1 Inclusion criteria ...............................................................................................22 9.3.2 Exclusion criteria ..............................................................................................22 9.3.3 Removal of patients from therapy or assessment............................................22

9.4 TREATMENTS..................................................................................................23 9.4.1 Treatments administered..................................................................................23 9.4.2 Identity of investigational product.....................................................................23 9.4.3 Method of assigning patients to treatment groups ...........................................23 9.4.4 Selection of doses in the study ........................................................................24 9.4.5 Selection and timing of dose for each patient ..................................................24 9.4.6 Blinding.............................................................................................................24 9.4.7 Prior and concomitant therapy .........................................................................24 9.4.8 Treatment compliance......................................................................................24



9.5 EFFICACY AND SAFETY VARIABLES ....................................................................25 9.5.1 Efficacy and safety measurements assessed and flow chart ..........................25 9.5.1.1 Parameter related to efficacy ...........................................................................25 9.5.1.2 Injection pain measurement .............................................................................25 9.5.1.3 Events during anesthesia until end of observation period ...............................25 9.5.1.4 Local reactions .................................................................................................26 9.5.1.5 Other adverse events .......................................................................................26 9.5.1.6 Triglyceride.......................................................................................................26 9.5.1.7 Blood pressure, pulse, oxygen saturation........................................................27 9.5.1.8 Schedule of investigations and measurements ...............................................27 9.5.2 Appropriateness of measurements ..................................................................28 9.5.3 Primary variables..............................................................................................28

9.6 DATA QUALITY ASSURANCE ..............................................................................28 9.6.1 Monitoring.........................................................................................................28 9.6.2 Source Data Verification / Audit .......................................................................28 9.6.3 Data management............................................................................................29

9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION OF SAMPLE SIZE ..................................................................................................30 9.7.1 Statistical and analytical plans .........................................................................30 9.7.2 Determination of sample size...........................................................................30

9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES......................30 10. STUDY PATIENTS ....................................................................................................31

10.1 DISPOSITION OF PATIENTS ...............................................................................31 10.2 PROTOCOL DEVIATIONS ...................................................................................32

10.2.1 Violations of inclusion criteria...........................................................................32 10.2.2 Violations of exclusion criteria..........................................................................32 10.2.3 Violation of criteria related to the study conduct ..............................................33 10.2.4 Summary of protocol deviations.......................................................................33

11. EFFICACY EVALUATION............................................................................................34 11.1 DATA SETS ANALYZED......................................................................................34 11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................................34

11.2.1 Demographic data ............................................................................................34 11.2.2 Medical history .................................................................................................34 11.2.3 Baseline characteristics ...................................................................................35 11.2.4 Homogeneity check..........................................................................................35

11.3 MEASUREMENTS OF TREATMENT COMPLIANCE...................................................36



11.4 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL PATIENT DATA....................37 11.4.1 Analysis of efficacy...........................................................................................37 11.4.1.1 Course of operative procedure.........................................................................37 11.4.1.2 Propofol required..............................................................................................38 11.4.1.3 Further surgery-induced medication ................................................................51 11.4.2 Statistical / analytical issues.............................................................................53 11.4.2.1 Adjustments for covariates...............................................................................53 11.4.2.2 Handling of dropouts or missing data...............................................................53 11.4.2.3 Interim analysis and data monitoring ...............................................................53 11.4.2.4 Multicenter studies ...........................................................................................53 11.4.2.5 Multiple comparison / multiplicity......................................................................53 11.4.2.6 Use of an 'efficacy subset' of patients ..............................................................53 11.4.2.7 Active-control studies intended to show equivalence ......................................54 11.4.2.8 Examination of subgroups................................................................................54 11.4.3 Tabulation of individual response data.............................................................54 11.4.4 Drug dose, drug concentration, and relationships to response .......................54 11.4.5 Drug-drug and drug-disease interaction ..........................................................54 11.4.6 By-patient displays ...........................................................................................54 11.4.7 Efficacy conclusions .........................................................................................55

12. SAFETY EVALUATION...............................................................................................56 12.1 EXTENT OF EXPOSURE.....................................................................................56

12.1.1 Trial medication ................................................................................................56 12.1.2 Changes in concomitant medication ................................................................56

12.2 ADVERSE EVENTS ...........................................................................................57 12.2.1 Brief summary of adverse events.....................................................................57 12.2.2 Display of adverse events ................................................................................58 12.2.3 Analysis of adverse events...............................................................................59 12.2.3.1 Injection pain: Incidence of spontaneous reactions .........................................59 12.2.3.2 Injection pain: Profile of pain ............................................................................60 12.2.3.3 Events during anesthesia until end of observation ..........................................67 12.2.3.4 Injection site reactions......................................................................................67 12.2.3.5 Summary of further adverse events .................................................................67 12.2.4 Listing of adverse events by patient.................................................................68

12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS ...........................................................................................68 12.3.1 Listing of deaths, other serious adverse events and other significant

adverse events .................................................................................................68 12.3.1.1 Deaths ..............................................................................................................68 12.3.1.2 Other serious adverse events ..........................................................................68 12.3.1.3 Other significant adverse events......................................................................68 12.3.2 Narratives of deaths, other serious adverse events and certain other

significant adverse events ................................................................................69 12.3.3 Analysis and discussion of deaths, other serious adverse events and

other significant adverse events.......................................................................69



12.4 CLINICAL LABORATORY EVALUATION .................................................................69 12.4.1 Listing of individual laboratory measurements by patient (16.2.8) and

each abnormal laboratory value.......................................................................69 12.4.2 Evaluation of each laboratory parameter .........................................................69 12.4.2.1 Baseline characteristics of 21 patients selected for triglyceride

determination....................................................................................................69 12.4.2.2 Triglyceride values over time ...........................................................................69 12.4.2.3 Individual patient changes of triglycerides .......................................................71 12.4.2.4 Individual clinically significant abnormalities of the triglycerides......................72

12.5 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY..........................................................................................................73 12.5.1 Blood pressure and pulse ................................................................................73 12.5.1.1 Blood pressure and pulse rate in the all-patients-group ..................................73 12.5.1.2 Blood pressure and pulse rate related to injection pain...................................82 12.5.2 Oxygen saturation ............................................................................................88

12.6 SAFETY CONCLUSION ......................................................................................88 13. DISCUSSION AND OVERALL CONCLUSIONS ................................................................90

14. TABLES REFERRED TO BUT NOT INCLUDED IN THE TEXT 14.1 DEMOGRAPHIC DATA 14.2 EFFICACY DATA 14.3 SAFETY DATA

15. REFERENCE LIST



16. APPENDICES 16.1 STUDY INFORMATION

16.1.1 Protocol and protocol amendments 16.1.2 Sample case report form 16.1.3 List of IECs - Representative written information for patient and sample

consent forms 16.1.4 List and description of investigators and other important participants in

the study 16.1.5 Signatures of sponsor's responsible medical officers 16.1.6 Listings of patients receiving test drug(s) / investigational product(s)

from specific batches, where more than one batch was used 16.1.7 Randomization scheme and codes (patient identification and treatment

assigned) 16.1.8 Audit certificates 16.1.9 Documentation of statistical methods 16.1.9.1 Descriptive statistics 16.1.9.2 Statistical methods 16.1.9.3 References 16.1.9.4 Appendix 1: Statistischer Analyse-Plan BBMDE-0312

(IAS 1/17.05.2005/BBM0201-SAP2) 16.1.9.5 Appendix 2: Data Review Report BBMDE-0312

(IAS 1/10.05.2005/BBM0201-02) 16.1.10 Documentation of inter-laboratory standardization methods and quality

assurance procedures 16.1.11 Publications based on the study 16.1.12 Important publications referenced in the report

16.2 PATIENT DATA LISTINGS 16.2.1 Discontinued patients 16.2.2 Protocol deviations 16.2.3 Patients excluded from the efficacy analysis 16.2.4 Demographic data 16.2.5 Compliance 16.2.6 Individual efficacy response data 16.2.7 Adverse events listings (each patient) 16.2.8 Listing of individual laboratory measurements by patient

16.3 CASE REPORT FORMS (CRFs) 16.3.1 CRFs for deaths, other serious AEs and withdrawals for AE 16.3.2 Other CRFs

16.4 INDIVIDUAL PATIENT DATA LISTINGS (ARCHIVE)



4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

A0 Before anesthesia induction A1 End of anesthesia induction + 3 min A2 End of anesthesia induction + 20 min AE Adverse event AMG German Drug Law ANCOVA Analysis of covariance approx. approximately ASA American Society of Anesthesiologists ATC Anatomic(al) & Therapeutic Classification BP Blood pressure cf. confer CHD Coronary heart disease CPMP Committee for Proprietary Medicinal Products DBP Diastolic blood pressure GCP Good Clinical Practice HR Heart rate HLTs High level terms i.v. intravenous ICH International Conference on Harmonization ITT Intention-To-Treat LCT Long-chain triglycerides MAP Mean arterial pressure MedDRA Medical Dictionary for Regulatory Activities MCT Medium-chain triglycerides NEC Not elsewhere classified Pat. no. Patient number SAP Statistical analyses plan SEM Standard error of the mean SBP Systolic blood pressure SD Standard deviation SO2 Oxygen saturation SOC System Organ Class VAS Visual analogue scale Times T0 baseline T1 immediately following initial bolus T2 absence of winking reflex T3 intubation + 1 min T4 intubation + 3 min T5 intubation + 5 min T6 intubation + 10 min T7 intubation + 20 min T8 immediately upon end of anesthetics administration



5. ETHICS

The clinical trial is subject to the relevant laws (e.g. AMG §§ 40 – 42) in their respective current version.

The clinical trial will be performed according to the recommendations on "Good Clinical Practice" (GCP) of the "International Conference on Harmonization" (ICH) and shall comply with the "Declaration of Helsinki" in the respective current version.

Prior to study start a favorable opinion of an Ethics Committee responsible according to Federal Law must be obtained.

5.1 ETHICS COMMITTEE

Ethik-Kommission der Medizinischen Fakultät der Universität zu Köln, Melatengürtel 60-62 50823 Köln, Germany

Meeting attendees: Prof. Dr. med. H.H. Hilger, em. Direktor der Klinik III für Innere Medizin / OStA'in L. Kaufmann-Fund, Staatsanwaltschaft Köln / Prof. Dr. med. W. Klaus, Direktor des Instituts für Pharmakologie / Prof. Dr. rer. nat. W. Lehmacher, Direktor des Instituts für Medizinische Statistik, Informatik und Epidemiologie / Prof. Dr. P. Mallmann, Direktor der Klinik und Poliklinik für Frauenheilkunde / Prof. Dr. D. Michalk, Direktor der Klinik und Poliklinik für Allgemeine Kinderheilkunde / Prof. Dr. med. H. Schicha, Direktor der Klinik und Poliklinik für Nuklearmedizin / Prof. Dr. med. E.R. de Vivie, Direktor der Klinik und Poliklinik für Herz- und Thoraxchirurgie / Prof. Dr. med. H. Staak, em. Direktor des Instituts für Rechtsmedizin / Dr. med. Dr. jur. F. Pluisch, Geschäftsführer der Ethik-Kommission

5.2 ETHICAL CONDUCT OF THE STUDY

This study was performed and monitored in accordance with the principles of Good Clinical Practice (GCP) in compliance with the Declaration of Helsinki in the version of Somerset West (1996). The investigators followed the recommendations set forth in the International Conference on Harmonization (ICH) GCP Guidelines CPMP/ICH/135/95.

On June 04, 2003 the Ethics Committee granted final approval.



5.3 PATIENT INFORMATION AND CONSENT

The treating physician informed the parents prior to inclusion in the study of the nature, significance and consequence of the clinical trial and written informed consent for participation in the study was obtained by at least one parent.

The parents were informed in verbal and written form about the investigational drug, nature, significance and consequences of the study and its possible risks. Also during the course of the study any relevant information had to be communicated to them. They had enough time to obtain details of the study and decide for or against participation. Furthermore they were informed that participation in the study is voluntary and that they may withdraw from the study at any time without giving reasons and without fear of detriment to their child.

In addition the parents were informed of the conditions and requirements of the subject insurance legally decreed. According to the insurance conditions it was among the patient's obligations during the clinical trial to undergo other medical treatment only in agreement with the investigator, not to participate in another clinical trial and report to the insurer without delay damage to health which might have occurred as a result of the clinical trial (guarantee of insurance protection).

The parents declared their agreement to the inspection of the patient's documents by monitors authorized by the study sponsor and by the responsible authorities. These inspections served to control protection of the patient and accuracy of documentation. Personal data were treated as confidential.

By signing the declaration of informed consent the parents confirmed the voluntary participation of their child and their intention to follow the study protocol and the investigating physician's instructions and to answer the questions arising in the course of the trial.

It was necessary to obtain the parents' declaration of consent to participate in the study prior to study start.



6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

Study center Klinik für Anästhesie und operative Intensivmedizin Klinikum Leverkusen gGmbH Akademisches Lehrkrankenhaus der Universität zu Köln Dhünnberg 60 51375 Leverkusen, Germany

Principal investigator pursuant to § 40 AMG PD Dr. med. G. Molter

Klinik für Anästhesie und operative Intensivmedizin Klinikum Leverkusen gGmbH Akademisches Lehrkrankenhaus der Universität zu Köln Dhünnberg 60 51375 Leverkusen, Germany Phone : ++49-(0)214-13 2146 Fax : ++49-(0)214-13 2203 e-mail : [email protected]

Investigator Dr. med. S. Soltész

Oberarzt der Klinik für Anästhesie und operative Intensivmedizin Klinikum Leverkusen gGmbH Akademisches Lehrkrankenhaus der Universität zu Köln Dhünnberg 60 51375 Leverkusen, Germany Phone : ++49-(0)214-13 2114 Fax : ++49-(0)214-13 2203 e-mail : [email protected]

Sponsor B. Braun Melsungen AG

Hospital Care Division Research and Development Carl-Braun-Straße 1 34212 Melsungen, Germany

Responsible person for the sponsor

Dr. Hans-Otto Maier Senior Vice President R & D Hospital Care Division Carl-Braun-Straße 1 34212 Melsungen, Germany Phone : ++49-(0)5661-71 1446 Fax : ++49-(0)5661-75 1446 e-mail : [email protected]



Project coordinator Dr. med. U. Brauer Carl-Braun-Straße 1 34212 Melsungen, Germany Phone : ++49-(0)5661-71 2706 Fax : ++49-(0)5661-75 2706 e-mail : [email protected]

Study coordinator + monitor T. Dehnhardt

Carl-Braun-Straße 1 34212 Melsungen, Germany Phone : ++49-(0)5661-71 2290 Fax : ++49-(0)5661-75 2290 e-mail : [email protected]

Biometrician Dr. rer. nat. Jörg Schnitker

Institut für angewandte Statistik Dr. Jörg Schnitker GmbH Artur-Ladebeck-Straße 155 33647 Bielefeld, Germany Phone : ++49-(0)521-56088-0 Fax : ++49-(0)521-56088-70 e-mail : [email protected]



7. INTRODUCTION

Propofol (2.6-Diisopropylphenol) is a short-acting intravenous general anesthetic used for induction and maintenance of a general anesthesia, for sedation of ventilated patients in intensive care treatment or for sedation of patients undergoing diagnostic or surgical procedures. Propofol may be used alone or in combination with a local or regional anesthesia. Originally, propofol had been formulated as a 1% solution in a pharmaceutical fat emulsion consisting of long-chain triglycerides (LCT-emulsion) only, being marketed by Astra Zeneca under the trade name of Disoprivan®.

Propofol-®Lipuro 1% is a pharmaceutical formulation of the same active substance using a fat emulsion that consists of medium-chain and long-chain triglycerides (MCT/LCT emulsion) and a 1% concentration of the active substance (= 10 mg of propofol/mL). The fat emulsion used for the formulation of Propofol-®Lipuro 1% has proven its value with the name of Lipofundin® MCT in years of clinical use as caloric substitution and for the supply with essential fatty acids in parenteral nutrition. In May 1999 Propofol-®Lipuro 1% has been approved in Germany with the registration number 41913.00.00.

Propofol-®Lipuro 0.5% is a new pharmaceutical formulation of the same active substance and the same fat emulsion consisting of medium- and long-chain triglycerides (MCT/LCT-emulsion), but with a 0.5% concentration of the active substance (= 5 mg of propofol/mL) only. In fact, Propofol-®Lipuro 0.5% is a dilution of Propofol-®Lipuro 1%.

Pain on injection is the most frequently reported side effect associated with the use of propofol. Depending on the size of the vein used, up to 90% of the patients complain about pain on injection of propofol dissolved in a LCT-fat emulsion (1 – 4). Various measures have been taken to reduce the pain on injection. The most frequently ones used are the administration of lidocain, fentanyl, morphine or meperidine prior to propofol administration (5 – 7) or the mixture of lidocain and propofol as well as cooling of the emulsion (8). All measures, however, involve the risk of contamination of the solution or are rather awkward. Though pain on injection had been reduced with the use of some of the methods mentioned above, they may not be regarded as a satisfactory solution of the problem (9).

In isolated cases improved vein tolerability was reported after the administration of Propofol-®Lipuro 0.5% diluted with a 10% Lipofundin MCT solution compared to Propofol-®Lipuro 1%. In these infants the frequency of pain on injection after administration of diluted 0.5% propofol was reduced by half. The current study was conducted to investigate whether this finding is reproducible in a double-blind, controlled and randomized setting.



8. STUDY OBJECTIVES

The objective of the study was to compare anesthesia induction by means of Propofol-®Lipuro 0.5% and Propofol-®Lipuro 1.0% with regard to venous tolerability and injection pain in children. The study was carried out to show superior tolerability of diluted Propofol over standard Propofol.

The primary endpoint of the study was the incidence of spontaneous expressions of pain during injection (binary parameter).

Secondary endpoints were • parameters for further specification of injection pain (intensity of reaction; intensity of the

attempt to draw back the arm; need to keep the hand or arm in position during injection; and anesthesist's VAS for assessment of injection pain)

• Propofol dosage and Propofol requirement, concomitant medication before, during, and after surgery

• hemodynamic parameters, oxygen saturation, triglycerides in a subpopulation, further adverse events

• time course of the operative procedure.

9. INVESTIGATIONAL PLAN

9.1 OVERALL STUDY DESIGN AND PLAN – DESCRIPTION

This was a prospective, monocenter, parallel group, controlled, randomized, single-blind and, regarding the primary endpoint, double-blind ('observer blind') clinical phase III study. Patients were randomly assigned to one of the following groups: • Propofol-®Lipuro 0.5% • Propofol-®Lipuro 1.0%.

The clinical trial in one patient began at the time when it had been established on the basis of the inclusion and exclusion criteria that the patient can participate in the clinical trial and that his/her parents had given their written consent to participation.

Initial examinations

• Initial examinations and recording of patient-related data and documentation of anamnesis prior to the intervention

• Verification of inclusion- and exclusion criteria • Written consent (of at least on parent) is given to participation in the study (= study start).



Day of intervention

• Randomization right before start of anesthesia induction • Preparation of study medication • Pre-medication: Administration of dormicum (0.5 mg/kg) – orally • Placement of necessary intravenous accesses (blue central venous cannula for propofol

injection, a further one for blood withdrawal for triglyceride determination in two subgroups of 10 patients each).

• Placement of the necessary ECG electrodes • Determination of safety parameters (systolic and diastolic blood pressure, heart rate,

arterial oxygen saturation). Blood pressure, heart rate and arterial oxygen saturation are measured according to the time points indicated in the schedule diagram. Measurement of blood pressure is to be made non-invasively, at the arm contralateral to the one with the intravenous access.

• Preparations for surgery • Measurement of vital parameters (baseline) • Blood withdrawal for determination of triglycerides – 0-value (subgroup) • Start of anesthetic administration by anesthesiologist • Recording of data referring to pain on injection during propofol injection • Blood withdrawal for determination of triglycerides – 3 and 20 minutes after the end of

anesthesia induction (subgroup) • Recording of propofol amount needed for anesthesia induction • Intubation: accompanying administration of 0.2 mg/kg of mivacurium for muscle relaxation • Skin incision • Measurement of vital parameters during intervention according to predefined time points • Documentation of the required data relative to the intervention, concomitant treatment and

the unexpected adverse events possibly occurring during the study • End of application of anaesthetic • Extubation • Postoperative check of injection site for inflammation.

9.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS

Aim of this study was to compare Propofol-®Lipuro 0.5% and Propofol-®Lipuro 1% with regard to vein tolerability.



9.3 SELECTION OF STUDY POPULATION

9.3.1 Inclusion criteria

• Age between ≥ 2 and < 6 years. • The parents (at least one parent) have been instructed by the investigator of the nature,

significance and extent of the clinical study previous to enrollment of their (his / her) child, and have given their (his / her) written informed consent.

• Anesthetic risk classified as ASA I – III. • Patient undergoing elective surgery under general anesthesia. • Venous access for induction of anesthesia situated on the dorsum of the hand. • Hospital care for at least 3 hrs after end of anesthesia guaranteed.

9.3.2 Exclusion criteria

• Simultaneous participation in another trial or participation during the month preceding the study on hand.

• Known hypersensitivity to Propofol, other ingredients of the emulsion, or to any other necessary co-medication.

• Patient who receives psychopharmacologic agents, tranquillizers, or centrally active analgesics as concomitant medication.

• Patient is expected to require concomitant medication not allowed in this study. • History of decompensated renal failure. • History of severe hepatic dysfunction, hepatic cirrhosis. • Angiographically confirmed CHD (coronary heart disease) or cerebral ischemia. • History of convulsive disorders. • Decompensated cardiac insufficiency. • Hypovolemia. • Increased intracranial pressure. • Lack of parents' informed consent. • Patient who receives parenteral fat emulsion, e.g. intralipid.

9.3.3 Removal of patients from therapy or assessment

When the study was terminated, the nature of termination had to be documented in the case report form (scheduled end / discontinuation with justification). In the event of discontinuation of the study, it was recorded who took the decision to discontinue (investigator / investigating physician / sponsor / patient / parents of the patient).



9.4 TREATMENTS

9.4.1 Treatments administered

• Propofol MCT / LCT 0.5% (Propofol-®Lipuro 0.5%) • Propofol MCT / LCT 1.0% (Propofol-®Lipuro 1.0%).

9.4.2 Identity of investigational product

• Name : Propofol MCT/LCT 0.5% • Composition : 5 mg of propofol per 1 mL of emulsion • Manufacturer : B. Braun Melsungen AG • Batch No. : known by the study coordinator • Expiry date : see label

Labelling

Intended for clinical trials

Propofol MCT/LCT 0.5% 50 ml emulsion for i.v. administration

Concentration of active substance 5mg/ml Store at room temperature, protect from light,

shake before use CH.-B.: Use before: B. Braun Melsungen AG D-34209 Melsungen

The investigational products merely differ in the propofol concentration, 0.5% vs. 1%.

9.4.3 Method of assigning patients to treatment groups

Patients were randomly assigned to one of the two treatment groups. The randomization schedule was provided by the Biometrics Department of B. Braun Melsungen AG and remained with the coordinating investigator. The study center was provided with sealed numbered randomization envelopes according to this schedule. Patients fulfilling the inclusion criteria whose parent(s) gave written informed consent to the study were allocated an identification number in ascending order. According to the information in the respective randomization envelope, the patients were assigned to either of the two treatment groups, Propofol-®Lipuro 0.5% or Propofol-®Lipuro 1.0%. Furthermore, it determined if a triglycerides measurement was to be conducted in this patient, which was the case with a subpopulation of 10 patients with the lowest patient numbers in each treatment group.



9.4.4 Selection of doses in the study

Bolus 3 mg/kg i.v.; in addition by steps up to 1 mg/kg until absence of winking reflex, as required for induction of anaesthesia.

9.4.5 Selection and timing of dose for each patient

• Initial bolus (3 mg/kg BW) within 30 seconds. • First repeated dose given 30 seconds after the end of the induction bolus within 10

seconds. • All further repeated doses until absence of winking reflex given 20 seconds after the

previous one also within 10 seconds.

9.4.6 Blinding

This clinical study was designed as a single-blinded study i. e. only the patient did not know what anesthetic agent was used for induction of anesthesia. Regarding the primary endpoint a double-blind setting (observer blinded setting) was used, i.e. the observer did also not know which anaesthetic was used for induction of anesthesia.

9.4.7 Prior and concomitant therapy

• Dormicum 0.5 mg/kg oral • Remifentanil 0.25 µg/kg/min for 1 min • Paracetamol 250 – 500 mg • Sevofluran 1/3 MAC.

9.4.8 Treatment compliance

Recording of compliance served to check whether each patient received the treatment scheduled for him/her.

The following measures are applied:

On each sheet of the case report form patient number and patient initials were entered. The anesthetic used for induction of anesthesia (Propofol-®Lipuro 0.5% or 1%) as well as the information whether triglyceride determination had been made or not were entered in the case report form by fixing the label of each randomization envelope onto the case report form. The measurement of treatment compliance was defined as check of faultless treatment allocation and a correct selection of patients for triglyceride determination.



9.5 EFFICACY AND SAFETY VARIABLES

9.5.1 Efficacy and safety measurements assessed and flow chart

9.5.1.1 Parameter related to efficacy

Regarding the efficacy of the trial medication, the need of Propofol and the time until absence of winking effect were analyzed.

9.5.1.2 Injection pain measurement

Any spontaneous expressions of pain during injection were recorded as primary endpoint by means of a binary scale (yes / no). Additionally, the injection pain was specified by means of the following (secondary) parameters: • Intensity of spontaneous expression during injection: grimacing / crying / screaming. • Child's attempt to draw back the arm (yes / no); if yes, intensity of the withdrawal: gentle

(ongoing single attempt to draw back the arm) / moderate (child’s arm needs to be fixed with one hand) / strong (arm needs to be kept in place with both hands or by a second person).

• Anesthetist's statement whether he / she needed to keep the hand or arm in position during the injection.

• Anesthetist’s assessment of injection pain by means of a visual analogue scale (VAS).

9.5.1.3 Events during anesthesia until end of observation period

During the whole of the observation period, the following events had to be recorded: • Myoclonia upon anesthesia induction (localization, if applicable) • Coughing (frequency: single / intermittent, if applicable) • singultus • erythema, exanthema (localization, if applicable) • nausea, vomiting • headache • spontaneous movements during operative procedure • others (specification, if applicable).



9.5.1.4 Local reactions

After surgery the venous injection site was examined: • reddening, whealing, other skin changes / disorders (yes / no / not done) • if yes, intensity (mild / moderate / severe) • description.

9.5.1.5 Other adverse events

Further adverse events were described as follows: • event description (sign and symptoms) • onset (date and time) • end (date and time, or ongoing) • severity of event (mild / moderate / severe) • frequency (single / intermittent) • action taken (none / discontinuation / withdrawal of study drug / treatment changes /

hospitalization / dose adjustment) • relationship to study drug (yes / no / unknown) • serious (yes / no; if yes, information concerning the reason for regarding the AE as

serious, changes in study and concomitant medication etc. had to be recorded on an SAE form).

• outcome (disappeared, ongoing, sequelae, unknown, death).

9.5.1.6 Triglyceride

In a subpopulation of 10 patients in each treatment group, triglyceride concentration was measured • before anesthesia induction • at end of anesthesia induction + 3 min • at end of anesthesia induction + 20 min (end of anesthesia induction = last Propofol administration).



9.5.1.7 Blood pressure, pulse, oxygen saturation

Hemodynamic and pulsoxymetric parameters: • blood pressure (SBP, DBP, MAP) • heart rate • oxygen saturation were obtained at • T0 : baseline • T1 : immediately following initial bolus • T2 : absence of winking reflex • T3 : intubation + 1 min • T4 : intubation + 3 min • T5 : intubation + 5 min • T6 : intubation + 10 min • T7 : intubation + 20 min • T8 : immediately upon end of anesthetics administration.

9.5.1.8 Schedule of investigations and measurements

Figure 9.1: Flow chart

Pre- medication Baseline Administration of anesthetic End of anesthetic

administration

Prior to intervention

Immediatelyafter induction

bolus

Absenceof winking

reflex

Intubation+ 1 min + 3 min + 5 min + 10 min + 20 min

right after the end of anesthetic

administration

Initial examination x

Verification of inclusion and exclusion criteria x

Written consent x

Randomization x

Premedication x

Triglyceride level x x x

SBP x x x x x x x x x

DBP x x x x x x x x x

HR x x x x x x x x x

SPO2 x x x x x x x x x

Propofol x

Postoperative examination of puncture site

x



9.5.2 Appropriateness of measurements

Besides routine documentation of adverse events and standard methods of patient monitoring, only the children's pain reactions were observed and pain assessments used (pain rating scale, VAS).

9.5.3 Primary variables

The primary variable used in this study was the incidence of spontaneous expression of pain during Propofol injection.

9.6 DATA QUALITY ASSURANCE

9.6.1 Monitoring

The coordinating investigator permitted an authorized, qualified representative of the B. Braun Group to visit the investigational site at regular intervals for monitoring purposes. At this, in compliance with the data protection regulations, accuracy and completeness of the CRF entries were checked. The coordinating investigator also permitted to visit hospital and laboratory facilities.

9.6.2 Source Data Verification / Audit

The coordinating investigator permitted an authorized Clinical Research Organization being independent of the responsible department within the B. Braun Group, to perform additional, superordinated inspections (audits) of the actions taken for quality assurance (monitoring). In doing so it was verified that the CRF entries are consistent with the entries in the source documents. It was determined whether the trial is conducted in accordance with the trial protocol and the guideline for good clinical practice (GCP). Moreover the facilities of hospital and laboratory were inspected. An audit certificate was issued.



9.6.3 Data management

The trial data of the case report forms were entered by two independent members of staff of IAS into two different databases generated for this study by means of SAS. An electronic data comparison and print-out of data discrepancies was effected; the necessary corrections were made and then verified independently. According to the final data management plan data plausibility checks were performed prospectively. Implausibilities were corrected according to the respective type of discrepancy: • type 1 – discrepancy : Can be clarified definitely by referring to other sections of the

case report form • type 2 – discrepancy : Cannot be definitely clarified by referring to other sections of the

case report form, clarification must be obtained on the basis of the source data available at the study center.

Corrections of type 1 – discrepancies could be performed by means of the correction lists and could be confirmed by the investigator. Alternatively it was allowed to make these corrections electronically and to attach a list of the corrections to the study documentation (data management convention). Corrections of type 2 – discrepancies had to be made by the investigator by means of the correction lists.

The data on the correction list given by the investigator were entered into the database according to the same procedure as with the primary entry. After confirmation of identity of both databases, both versions were saved under a project-oriented file name.

All inconsistencies were detected prior to final closing of the database (data base lock).

The data management (cf. Data Review Report) was performed on the basis of the trial protocol dated March 05, 2003, the amendments no. 1 dated July 10, 2003, no.2 dated September 02, 2003, no. 3 dated June 09, 2004 and no. 4 dated January 21, 2005 as well as according to the data management plan dated February 04, 2005.



9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION OF SAMPLE SIZE

9.7.1 Statistical and analytical plans

Statistical and analytical plans of this study were represented in the Statistical Analysis Plan, final version SAP2, dated 17.05.2005 (cf. Appendix 16.1.9). Standard procedures for the comparison of two parallel groups were used. These were: • Fisher's exact test for binary data, especially for the comparison of spontaneous injection

pain reactions following Propofol • χ2 test for 2xk-tables (k>2) • U test according to Wilcoxon-Mann-Whitney • t-test • analysis of covariance for repeated measures (ANCOVA).

Deviating from the SAP2, ordinal scales were analyzed by means of U test instead of χ2 test because small cell expectations occurred in the majority of the test situations.

All statistical tests were performed two-tailed with a prespecified significance level of α=0.05.

9.7.2 Determination of sample size

The sample size was determined prospectively upon the following conditions: • characteristic injection pain incidence approx. 66% following Propofol 1.0% • target outcome: to reduce the pain incidence by half to 33% • sample size needed (α=0.05 one-tailed, 1–β=0.80): N=29 per group • dropout rate: 10% • total sample size: N=64.

9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES

• 4 Amendments • Two-sided tests (level α=0.05) instead of one-sided tests (level α=0.05) (cf. ICH-E9).



10. STUDY PATIENTS

10.1 DISPOSITION OF PATIENTS

The disposition of patients is shown in Figure 10.1:

Figure 10.1: Disposition of patients

N=64 PATIENTS RANDOMIZED

N=32 Propofol 0.5%

N=32 Propofol 1%

N=2 Termination before op1 N=2 Termination before op2 • no venous access at dorsum of

the hand, no trial medication (2) • no venous access at dorsum of

the hand, no trial medication (2)

N=30 STUDY POPULATION

N=30 STUDY POPULATION

N=30 COMPLETERS

N=30 COMPLETERS

1: Pat. nos. 18, 332: Pat. nos. 49, 59 .

Four patients terminated the trial prematurely after randomization because the venous access at the dorsum of the hand was not achieved. Study drug was not administered.

The study population consisted of 60 patients, and all patients terminated the trial as 'completers'.



10.2 PROTOCOL DEVIATIONS

10.2.1 Violations of inclusion criteria

The check of inclusion criteria is represented in Table 14.1. In 6 patients the upper age limit of '< 6 years' was violated. Because all children were not older than '6 years', this was regarded as minor violation of the protocol (cf. Data Review Report, Appendix 16.1.9).

10.2.2 Violations of exclusion criteria

Violations of exclusion criteria were detected in 11 patients (Table 14.2): intraoperative medication with drugs classified N02A (opioids) or N02B (other analgesics and antipyretics) • Propofol 0.5% : N=31 • Propofol 1.0% : N=3

intraoperative medication with drugs classified N01 (anesthetics; Fentanyl) • Propofol 0.5% : N=21 • Propofol 1.0% : N=4.

All cases were classified as 'minor violations of the protocol' because the unallowed drugs were administered after the end of Propofol administration (cf. Data Review Report, Appendix 16.1.9).

1 1 double entry.



10.2.3 Violation of criteria related to the study conduct

In Table 10.1 protocol deviations concerning the study conduct are shown:

Table 10.1: Violation of criteria related to the study conduct

Criterion Propofol 0.5% Propofol 1.0% Study population

Number of patients 30 30 60

Randomization errors 2 ( 6.7%) 3 (10.0%) 5 ( 8.3%) Violation of the prespecified procedure of triglyceride determination 1 ( 3.3%) 2 ( 6.7%) 3 ( 5.0%) Delayed administration of the first Propofol bolus regarding the documented starting time of anesthesia 2 ( 6.7%) 6 (20.0%) 8 (13.3%) Deviation from the prespecified procedure of Paracetamol treatment 6 (20.0%) 10 (33.3%) 16 (26.7%)

Deviation from the prespecified procedure of Sevofluran treatment 1 ( 3.3%) – 1 ( 1.7%) .

All violations of the protocol summarized in Table 10.1 were classified as 'minor' because they did not interfere with the primary study endpoint, i.e. the assessment of injection pain (cf. Data Review Report, Appendix 16.1.9).

10.2.4 Summary of protocol deviations

Incidences of • violations of inclusion criteria • violations of exclusion criteria • violations of criteria related to the study conduct are represented in Table 10.2:

Table 10.2: Summary of protocol deviations (multiple entries)

Criterion Propofol 0.5% Propofol 1.0% Study population


Violations of inclusion criteria 4 (13.3%) 2 ( 6.7%) 6 (10.0%) Violations of exclusion criteria 4 (13.3%) 7 (23.3%) 11 (18.3%)

Violations of criteria related to the study conduct 10 (33.3%) 16 (53.3%) 26 (43.3%)

At least one violation of prespecified study criteria 15 (50.0%) 19 (63.3%) 34 (56.7%) .



11. EFFICACY EVALUATION

11.1 DATA SETS ANALYZED

In this trial, 60 patients were treated with Propofol 0.5% (N=30) or Propofol 1.0% (N=30), respectively. The Data Review revealed no major protocol violations, therefore, the study population represented the 'intention-to-treat set' as well as the 'per protocol set'.

Table 11.1: Data sets analyzed

Population Propofol 0.5% Propofol 1.0% Study population


Safety analysis, ITT 30 (100.0%) 30 (100.0%) 60 (100.0%) Major protocol violations – – –

Per protocol set = ITT 30 (100.0%) 30 (100.0%) 60 (100.0%) .

11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS

11.2.1 Demographic data

The total study population consisted of 60 patients aged between 2 and 6 years (inclusive). The mean (± SD) age was 4.4 ± 1.3 years. Nearly all patients were male (96.7%). The mean (± SD) weight and height amounted to • body weight : 17.9 ± 4.0 kg • body height : 105 ± 9 cm (Table 14.3).

11.2.2 Medical history

The main indications for surgery are specified in Table 14.4. The most frequent diagnosis was phimosis with a proportion of 80.0%. The anesthetic risk was classified ASA I in nearly all patients (98.3%).

Allergies were registered in 4 patients (drugs, food, plaster), other risk factors in further 2 cases (MedDRA HLTs): • mitral valvular disorders (1x) • vascular anomalies congenital NEC; pulmonary vascular disorders (1x).

Concomitant medication was registered in one patient only (Table 14.5).



11.2.3 Baseline characteristics

The distribution at baseline of blood pressure, heart rate, oxygen saturation, and triglycerides concentration is shown in Table 14.6. The following means, SDs and ranges were determined:

Table 11.2: Distribution of baseline characteristics

Parameter Mean SD Minimum Maximum

SBP [mmHg] 111.9 17.3 80 150

DBP [mmHg] 67.5 13.6 42 99

MAP [mmHg] 82.3 14.0 56.3 110.0

HR [bpm] 106.1 26.9 69 174

sO2 [%] 98.8 1.5 93 100

Triglycerides* [mg/dL] 58.0 34.3 31 171

[*: N=21].

11.2.4 Homogeneity check

Tests for homogeneity of the treatment group at baseline are summarized in Table 14.7. Altogether 20 exploratory tests for homogeneity were performed, 2 of which (10%) yielded p-values below 0.15. This result lay below the expected value of 15%. Therefore, the occurrence of possible inhomogeneities was consistent with chance. In other words, the randomization resulted in comparable treatment groups.

Statistically significant differences were seen for the following variables (significance level for homogeneity tests: α=0.15): • deviations from criteria related to the study conduct (p=0.1180): higher rate of deviations

in the Propofol 1.0% group (53.3% vs. 33.3% in the Propofol 0.5% group) • inguinal hernia as main indication for surgery (p=0.0384): 4 patients only in the

Propofol 1.0% trial group.



11.3 MEASUREMENTS OF TREATMENT COMPLIANCE

The 'measurement of treatment compliance' was defined as check of a faultless treatment allocation and a correct selection of patients for triglyceride determination. Regarding this, 5 randomization errors and 3 violations of the prespecified procedure of triglyceride determination were detected (cf. Table 10.1). As pointed out in Chapter 10.2, these deviations from the protocol were regarded as 'minor'.



11.4 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL PATIENT DATA

11.4.1 Analysis of efficacy

11.4.1.1 Course of operative procedure

The course of the operative procedure is characterized in Table 14.8 by means of the following variables:

type of venous access clock time Propofol injection started duration of time periods from start of anesthesia to … • absence of winking reflex (cf. Figure 11.1) • intubation • skin incision • skin suture • end of anesthetics administration • extubation duration of anesthetics administration.

No statistically significant or clinically relevant differences between both trial groups were registered.

Figure 11.1: Duration from start of anesthesia to absence of winking reflex

0102030405060708090

100

0 1 2 3 4 5Minutes since start of anesthesia

Perc

enta

ge o

f pat

ient

s

Propofol 0.5% Propofol 1.0% .



The mean (± SD) time to absence of winking reflex amounted to (U test: p=0.3050) • Propofol 0.5% : 1.47 ± 0.94 min • Propofol 1.0% : 1.67 ± 0.88 min.

11.4.1.2 Propofol required

Until absence of winking reflex, similar dosages of Propofol were required in both treatment groups:

dosages in mg (U test: p=0.6463) • Propofol 0.5% : 80.0 ± 22.9 mg • Propofol 1.0% : 75.2 ± 18.9 mg

dosages in mg/kg (U test: p=0.9621) • Propofol 0.5% : 4.40 ± 1.01 mg/kg • Propofol 1.0% : 4.31 ± 0.86 mg/kg.

In 7 patients (23.3%) of each group 1 to 2 further boli were administered resulting in a total dosage for induction of anesthesia of

dosages in mg (U test: p=0.6412) • Propofol 0.5% : 85.6 ± 26.9 mg • Propofol 1.0% : 80.1 ± 18.4 mg

dosages in mg/kg (U test: p=0.9379) • Propofol 0.5% : 4.70 ± 1.19 mg/kg • Propofol 1.0% : 4.61 ± 0.86 mg/kg.

In each case, 1 to 6 boli were administered; the individual mean dose/bolus was dosages in mg (U test: p=0.7170) • Propofol 0.5% : 34.6 ± 10.6 mg/bolus • Propofol 1.0% : 33.5 ± 10.3 mg/bolus

dosages in mg/kg (U test: p=0.6615) • Propofol 0.5% : 1.89 ± 0.43 mg/kg/bolus • Propofol 1.0% : 1.90 ± 0.37 mg/kg/bolus

(cf. Table 14.9). The Propofol treatment is visualized in 12 figures:

Number of boli • Figure 11.2 : Number of boli until absence of winking reflex • Figure 11.3 : Total number of boli



Dosage until absence of winking reflex • Figure 11.4 : Cumulative Propofol dosage over time until absence of winking reflex

[mean ± SD; mg] • Figure 11.5 : Cumulative Propofol dosage over time until absence of winking reflex

[mean ± SD; mg/kg] • Figure 11.6 : Cumulative Propofol dosage over time until absence of winking reflex

[mean ± SD; %] • Figure 11.7 : Boxplots of Propofol required until absence of winking reflex [mg] • Figure 11.8 : Distribution of Propofol required until absence of winking reflex

[mg/kg]

Total dosage • Figure 11.9 : Cumulative Propofol dosage over time [mean ± SD; mg] • Figure 11.10 : Cumulative Propofol dosage over time [mean ± SD; mg/kg] • Figure 11.11 : Cumulative Propofol dosage over time [mean ± SD; %] • Figure 11.12 : Boxplots of Propofol required [mg] • Figure 11.13 : Distribution of Propofol required [mg/kg]

Figure 11.2: Number of boli until absence of winking reflex

1 2 3 4 5 6Number of Propofol boli

Perc

enta

ge o

f pat

ient

s

Propofol 0.5% Propofol 1.0%

0

10

20

30

40

50

60

100



Figure 11.3: Total number of boli

1 2 3 4 5 6Number of Propofol boli

Perc

enta

ge o

f pat

ient

s


0

10

20

30

40

50

60

100



Figure 11.4: Cumulative Propofol dosage over time until absence of winking reflex [mean ± SD; mg]

0

20

40

60

80

100

120

Minutes since induction of anesthesia

Prop

ofol

dos

age

[m

g]


0 1 2 3 4 5 6



Figure 11.5: Cumulative Propofol dosage over time until absence of winking reflex [mean ± SD; mg/kg]

0

1

2

3

4

5

6


Prop

ofol

dos

age

[m

g/kg

]


0 1 2 3 4 5 6



Figure 11.6: Cumulative Propofol dosage over time until absence of winking reflex [mean ± SD; %]

0

20

40

60

80

100


Prop

ofol

dos

age

[%

of d

ose

until

T2]


0 1 2 3 4 5 6



Figure 11.7: Boxplots of Propofol required until absence of winking reflex [mg]

0

25

50

75

100

125

150Pr

opof

ol re

quire

d [

mg]

N= 30 30




Figure 11.8: Distribution of Propofol required until absence of winking reflex [mg/kg]

0

10

20

30

40

50

60

70

80

90

100

Propofol0.5%

Propofol1.0%

Patie

nts

[%

]

>4 4 <4

N= 30 30



Figure 11.9: Cumulative Propofol dosage over time [mean ± SD; mg]

0

20

40

60

80

100

120


Prop

ofol

dos

age

[m

g]


0 1 2 3 4 5 6



Figure 11.10: Cumulative Propofol dosage over time [mean ± SD; mg/kg]

0

1

2

3

4

5

6


Prop

ofol

dos

age

[m

g/kg

]


0 1 2 3 4 5 6



Figure 11.11: Cumulative Propofol dosage over time [mean ± SD; %]

0

20

40

60

80

100


Prop

ofol

dos

age

[%

of t

otal

dos

e]


0 1 2 3 4 5 6



Figure 11.12: Boxplots of Propofol required [mg]

0

25

50

75

100

125

150Pr

opof

ol re

quire

d [

mg]

N= 30 30


.



Figure 11.13: Distribution of Propofol required [mg/kg]

0

10

20

30

40

50

60

70

80

90

100

Propofol0.5%

Propofol1.0%

Patie

nts

[%

]

>4 4 <4

N= 30 30

.



11.4.1.3 Further surgery-induced medication

Further surgery-induced medication is represented in Table 14.10. On the whole, Dormicum, Remifentanyl, Paracetamol, and Sevofluran were administered as planned in the protocol. Further medication was administered in • Propofol 0.5% : 30/30 (100.0%) • Propofol 1.0% : 29/30 ( 96.7%) patients (χ2 test: p=0.3132). Before induction of anesthesia, the following preparations were used:

Table 11.3: Further surgery-induced medication before induction of anesthesia

Parameter Propofol 0.5% Propofol 1.0%

Number of patients 30 30

Number of patients with medication before induction of anesthesia 29 (96.7%) 24 (80.0%)

Total number of ATC codes 41 35

A03 Antispasmodics and anticholinergic agents and propulsives 14 (46.7%) 16 (53.3%) A03BA Belladonna alkaloids, tertiary amines 14 16

J01 Antibacterials for systemic use 1 ( 3.3%) – J01CR Comb of penicillins, incl. beta-lactamase inhib. 1

N01 Anesthetics 26 (86.7%) 19 (63.3%) N01BB Amides 26 19 .



Drugs administered between induction of anesthesia and extubation, and after extubation are shown in Tables 11.4 and 11.5, respectively.

Table 11.4: Further surgery-induced medication between induction of anesthesia and extubation



Number of patients with medication between induction of anesthesia and extubation

26 (86.7%) 26 (86.7%)


A03 Antispasmodics and anticholinergic agents and propulsives 10 (33.3%) 3 (10.0%) A03BA Belladonna alkaloids, tertiary amines 10 3

C01 Cardiac therapy 1 ( 3.3%) – C01CA Adrenergic and dopaminergic agents 1

H02 Corticosteroids for systemic use 1 ( 3.3%) – H02AB Glucocorticoids 1

M03 Muscle relaxants – 3 (10.0%) M03AC Other quaternary ammonium compounds 3

N01 Anesthetics 24 (80.0%) 24 (80.0%) N01AH Opioid anesthetics 2 4 N01AX Other general anesthetics 1 1 N01BB Amides 22 20

N02 Analgesics 3 (10.0%) 2 ( 6.7%) N02AC Diphenylpropylamine derivatives 3 1 N02AF Morphinan derivatives – 1

Table 11.5: Further surgery-induced medication after extubation



Number of patients with medication after extubation 8 (26.7%) 7 (23.3%)


N02 Analgesics 8 (26.7%) 7 (23.3%) N02AB Phenylpiperidine derivatives 1 – N02AC Diphenylpropylamine derivatives 2 3 N02AF Morphinan derivatives 4 2 N02BB Pyrazolones – 1 N02BE Anilides 2 2

R06 Antihistamines for systemic use – 2 ( 6.7%) R06AA Aminoalkyl ethers 2 .



11.4.2 Statistical / analytical issues

11.4.2.1 Adjustments for covariates

Not used in Chapter 11.4.1. In Table 12.5 the course of triglycerides after administration of Propofol was analyzed by means of ANCOVA with baseline values as covariates.

11.4.2.2 Handling of dropouts or missing data

There were no dropouts in this study. Missing data were not replaced.

11.4.2.3 Interim analysis and data monitoring

This was the first analysis of the Propofol study BBMDE-0312.

A data monitoring including the carrying out of all planned data checks was performed. Subsequently a Data Review was carried out prior to the data base lock after the data base was considered as clean. All data checks and all decisions on patient's enrollment into her / his analysis set were summarized in the Data Review Report (DRR) attached in Chapter 16.1.9.

All data management procedures were carried out with unblinded data on the basis of prospectively defined criteria, but no patient who received trial medication was excluded from the analysis, and no data were imputed for any reason. Therefore, no bias resulted from the unblinded data monitoring.

11.4.2.4 Multicenter studies

This was a monocenter study.

11.4.2.5 Multiple comparison / multiplicity

On the one hand only one primary endpoint was considered in this study. On the other hand safety issues were determining factors for the trial which should be compared between the trial groups without adaption of the error rate.

11.4.2.6 Use of an 'efficacy subset' of patients

No efficacy subset was used.



11.4.2.7 Active-control studies intended to show equivalence

Not applicable.

11.4.2.8 Examination of subgroups

Subgroup analyses were not performed.

11.4.3 Tabulation of individual response data

Individual 'injection pain data' are listed in Appendix 16.2.6.

11.4.4 Drug dose, drug concentration, and relationships to response

This was a dose-response study analyzing safety data in young children.

11.4.5 Drug-drug and drug-disease interaction

Drug-drug and drug-disease interactions were neither reported nor detected.

11.4.6 By-patient displays

Individual patient data representations other than tabular listings were not used.



11.4.7 Efficacy conclusions

The study population in our clinical trial is identical in the 'intention-to-treat set' and in the 'per protocol set'. Both the therapy groups can be regarded as homogeneous concerning possible influence factors as is demonstrated by the homogeneity check. Therefore, randomization resulted in comparable treatment groups. Also, when analyzing the course of the operative procedure in the two treatment groups there was no statistically or clinically relevant difference detectable.

Concerning the need of Propofol, results in both groups are similar. No significant or clinically relevant differences in the various efficacy parameters could be seen. As to time until absence of winking reflex, similar Propofol dosages were required. A comparable number of additional boli of Propofol in order to achieve anesthesia was needed, and dosage per bolus was also comparable in both treatment groups.

Further surgery-induced medication before induction of anesthesia (apart from Propofol) was administered as planned in the protocol. The analysis of this medication in the two groups reveals no medically relevant differences. Also, all other medication before or after extubation was comparable, indicating that the two different concentrations of Propofol do not result in different comedication schemes during or after anesthesia.



12. SAFETY EVALUATION

12.1 EXTENT OF EXPOSURE

12.1.1 Trial medication

The trial medication was administered on a 'mg/kg basis', i.e. patients of the 'Propofol 0.5%' trial group received the double the amount of injection emulsion that patients of the 'Propofol 1.0%' trial group got. The total Propofol dosages are shown in Table 12.1 (cf. Table 14.9).

Table 12.1: Total Propofol dosage required for induction of anesthesia


Number of patients 30 30 Test: p-value

Amount of emulsion injection [mL] minimum 7.8 3.6 maximum 30.0 12.0 median 16.5 7.6 mean 17.13 8.01 standard dev. 5.38 1.84

Amount of Propofol injection [mg] minimum 39 36 maximum 150 120 median 82.5 76.0 U test: p=0.6412 mean 85.6 80.1 standard dev. 26.9 18.4 .

12.1.2 Changes in concomitant medication

Changes in concomitant medication occurred in 2 patients who received antihistaminics for systemic use due to nausea / vomiting (diphenhydramine; Table 14.11).



12.2 ADVERSE EVENTS

12.2.1 Brief summary of adverse events

The adverse events were classified as • injection pain during Propofol administration • (other) events during anesthesia until end of observation, injection site reactions and

further adverse events during the study.

Injection pain was described by incidences of spontaneous expressions of injection pain and by the pain profile, while the second group of events was documented by means of usual AE items. Injection pain was differently distributed in both trial groups with clear advantages for Propofol 0.5%.

Table 12.2: Patterns of injection pain

Parameter Propofol 0.5% Propofol 1.0% Test: p-value

Spontaneous expression of injection pain

• incidence 1/30 ( 3.3%) 6/30 (20.0%) Fisher: p=0.1028

• intensity no pain 29 (96.7%) 24 (80.0%) grimacing 1 ( 3.3%) 2 ( 6.7%) crying – 4 (13.3%) U test: p=0.0424

screaming – – Drawing back of the arm 7/30 (23.3%) 21/30 (70.0%) Fisher: p=0.0006

Need to hold the arm tightly 6/30 (20.0%) 18/30 (60.0%) Fisher: p=0.0033

Anesthesist's VAS of injection pain [mm] 2.6 ± 5.2 18.6 ± 18.6 U test: p<0.0001 .

Other adverse events were reported in • Propofol 0.5% : N=5 (16.7%) • Propofol 1.0% : N=6 (20.0%) patients (χ2 test: p=0.7386). A relationship to study drug was ruled out except for the cases of 2 patients who experienced erythemas after administration of Propofol 1.0%. In these patients the relationship was classified as 'unknown'.

A serious adverse event was reported in one patient treated with Propofol 1.0%. The child (male, 5 years) developed a moderate recurrent vomiting and was hospitalized as a precaution.



12.2.2 Display of adverse events

The rates of spontaneous expressions of injection pain were • Propofol 0.5% : 1/30 ( 3.3%) • Propofol 1.0% : 6/30 (20.0%) (Fisher's exact test: p=0.1028). The difference was not significant even if a one-sided test was used at the α=0.05 level (Fisher's exact test: p=0.0514).

In total 32 patients showed at least one pain reaction in the form of spontaneous expressions of injection pain, drawing back of the arm, need to hold the arm of the child tightly, or positive ratings of anesthesist's VAS: • Propofol 0.5% : 8/30 (26.7%) • Propofol 1.0% : 24/30 (80.0%) (Fisher's exact test: p<0.0001).

Details on injection pain are given in Chapters 12.2.3.1 and 12.2.3.2. Further adverse events besides injection pain were reported in 11 patients:

Table 12.3: MedDRA SOCs of further adverse events (besides injection pain; multiple entries)

MedDRA SOCs Propofol 0.5% Propofol 1.0% χ2 test

Patients with at least one entry 5 (16.7%) 6 (20.0%) p=0.7386

Gastr Gastrointestinal disorders – 2 ( 6.7%) p=0.1503 Resp Respiratory, thoracic and mediastinal disorders 5 (16.7%) 4 (13.3%) p=0.7177

Skin Skin and subcutaneous tissue disorders – 2 ( 6.7%) p=0.1503 .

The further adverse events are specified in Chapters 12.2.3.3, 12.2.3.4, and 12.2.3.5.



12.2.3 Analysis of adverse events

12.2.3.1 Injection pain: Incidence of spontaneous reactions

Spontaneous reactions to injection pain were reported in • Propofol 0.5% : 1/30 ( 3.3%) • Propofol 1.0% : 6/30 (20.0%) patients. The treatment difference was not statistically significant (Fisher's exact test: p=0.1028; Table 14.12; Figure 12.1). The verbal comments yielded no additional information (List 16.4.9).

Figure 12.1: Incidence of spontaneous reactions to injection pain

0

10

20

30

40

50

60

70

80

90

100

Propofol0.5%

Propofol1.0%

Perc

enta

ge o

f pat

ient

s

no spontaneous reaction spontaneous reaction

N= 30 30

.



12.2.3.2 Injection pain: Profile of pain

The intensity of the spontaneously expressed pain revealed significant differences between both treatment groups with stronger pain reactions following Propofol 1.0% (Table 14.12; Figure 12.2).

Figure 12.2: Intensity of spontaneous expressions of injection pain

0

10

20

30

40

50

60

70

80

90

100

Propofol0.5%

Propofol1.0%

Perc

enta

ge o

f pat

ient

s

screamingcryinggrimacingno spontaneous reaction

N= 30 30

.



Seven patients (23.3%) treated with Propofol 0.5% and 21 patients (70.0%) treated with Propofol 1.0% tried to draw back the arm (Fisher's exact test: p=0.0006). The treatment difference in favor of Propofol 0.5% was even more pronounced when the intensity of the attempt was considered (U test: p=0.0002; Table 14.12; Figure 12.3).

Figure 12.3: Attempt to draw back the arm

0

10

20

30

40

50

60

70

80

90

100

Propofol0.5%

Propofol1.0%

Perc

enta

ge o

f pat

ient

s

strong attemptmoderate attemptgentle attemptno attempt

N= 30 30

.



In 6 0.5%-treated and 18 1.0%-treated patients the hand / arm needed to be held fast (Fisher's exact test: p=0.0033). Predominantly only the hand was needed to be kept in place. The arm was fixed in 1 (Propofol 0.5%) and 4 (Propofol 1.0%) patients, respectively (U test: p=0.0019; Table 14.12; Figure 12.4).

Figure 12.4: Need to hold the hand / arm tightly

0

10

20

30

40

50

60

70

80

90

100

Propofol0.5%

Propofol1.0%

Perc

enta

ge o

f pat

ient

s

arm needs to be held fast

hand needs to be held fast

not necessary

N= 30 30

.



Significant differences in the judgment of injection pain intensity by the anesthesist (p<0.0001) were received. The mean (± SD) VAS values were • Propofol 0.5% : 2.6 ± 5.2 mm • Propofol 1.0% : 18.6 ± 18.6 mm.

The distribution of the VAS is represented in Table 14.12, Figure 12.5, and Figure 12.6.

Figure 12.5: Boxplots of anesthesist's VAS of the injection pain

0102030405060708090

100

VAS

of in

ject

ion

pain

[m

m]

N= 30 30




Figure 12.6: By-patient display of anesthesist's VAS of the injection pain

0

10

20

30

40

50

60

70

80

90

100

VAS

of in

ject

ion

pain

[m

m]


Median

N= 30 30

.



High VAS values were especially seen upon Propofol 1.0% in children weighing less than 15 kg (Figure 12.7):

Figure 12.7: Scattergram of body weight and anesthesist's VAS of injection pain stratified by Propofol concentration

0

10

20

30

40

50

60

70

80

90

100

10 15 20 25 30

body weight [kg]

VAS

of in

ject

ion

pain

[m

m]


.



The rate of patients who drew the arm back was slightly increased in the lower body weight classes. However, the superiority of Propofol 0.5% did not depend on body weight (Figure 12.8):

Figure 12.8: Rate of children who drew the arm back within 5 body weight classes

0

10

20

30

40

50

60

70

80

90

100

≤13 >13-16 >16-19 >19-22 >22

body weight [kg]

Dra

win

g ba

ck o

f the

arm

[%

]


.



12.2.3.3 Events during anesthesia until end of observation

No statistically significant differences between both trial groups were determined with regard to events during anesthesia until end of observation, but • erythema / exanthema : N=2 (6.7%) • nausea / vomiting : N=2 (6.7%) were reported upon Propofol 1.0% only (Table 14.13).

12.2.3.4 Injection site reactions

No redness, whealing, or other skin reactions were seen at the postoperative examination of the venous punction site (Table 14.14).

12.2.3.5 Summary of further adverse events

A summary of adverse events (except for injection pain) is given in Table 14.15. No other events than those reported in Tables 14.13 and 14.14 occurred during the study.

Details on the course of further adverse events are represented in Table 14.16: • onset • duration • severity of event • frequency • action taken • relationship to study drug • SAE • outcome.

Except for 2 cases, a causal relationship to study drug was ruled out (Table 14.17). Both children were treated with Propofol 1.0%.

Table 12.4: MedDRA SOCs of further adverse events (besides injection pain) with unknown causal relationship to study drug

MedDRA SOCs Propofol 0.5% Propofol 1.0% χ2 test

Patients with at least one symptom possibly related to study drug besides injection pain – 2 (6.7%) p=0.1503

Skin Skin and subcutaneous tissue disorders – 2 (6.7%) p=0.1503 .



12.2.4 Listing of adverse events by patient

For a listing of adverse events by patient see List 14.3.1 (short form) and Chapter 16.2.7 (complete presentation). List 14.3.1 is represented in 2 parts: • List 14.3.1/A : Adverse events (except for injection pain) • List 14.3.1/B : Adverse events with unknown relationship to study medication.

12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS

12.3.1 Listing of deaths, other serious adverse events and other significant adverse events

12.3.1.1 Deaths

No patient died during the study period.

12.3.1.2 Other serious adverse events

Other serious adverse events occurred in 1 patient (cf. List 14.3.2): • Pat. no. 25 : Propofol 1.0%: precautionary hospitalization because of recurrent

vomoting.

A serious adverse event was reported in one patient treated with Propofol 1.0%. The child (male, 5 years) developed pain after routine course of his anesthesia; the patient therefore received 2 mg of Nubain® i.v. (nalbuphin) at about one hour after anesthesia. Thereafter, the patient developed vomiting which was judged as moderate by the physician. The patient received an antiemetic drug (dimenhydrinat) and was hospitalized as a precautionary measure. The patient recovered without any remaining symptoms.

As to the causality assessment, the physician judged that the event was most likely not caused by Propofol, but rather by Nubain® i.v. (nalbuphin).

12.3.1.3 Other significant adverse events

Adverse events requiring therapy were classified as other significant adverse events. Besides Pat. no. 25 only Pat. no. 44 (Propofol 1.0%) was treated due to AE (nausea treated with Vomex® A).



12.3.2 Narratives of deaths, other serious adverse events and certain other significant adverse events


12.3.3 Analysis and discussion of deaths, other serious adverse events and other significant adverse events


12.4 CLINICAL LABORATORY EVALUATION

12.4.1 Listing of individual laboratory measurements by patient (16.2.8) and each abnormal laboratory value

Normal ranges of the only laboratory parameter used in this study, the triglyceride concentration, amounted to 10 – 200 mg/dL. A listing of all individual triglyceride measurements is represented in Appendix 16.2.8.

12.4.2 Evaluation of each laboratory parameter

12.4.2.1 Baseline characteristics of 21 patients selected for triglyceride determination

The triglyceride concentration was measured in 21 patients. The demographics of this sub-population are shown in Table 14.18.

12.4.2.2 Triglyceride values over time

The distribution of the triglycerides at • A0 : before anesthesia induction • A1 : end of anesthesia induction + 3 min • A2 : end of anesthesia induction + 20 min is shown in Table 14.19 and Figure 12.9.



Figure 12.9: Means (± SD) of the triglyceride levels before and after anesthesia induction with Propofol

0

50

100

150

200

250

300

350

Trig

lyce

rides

[m

g/dL

]


before +3min +20minPropofol

.

Three minutes after anesthesia induction the triglyceride levels were markedly increased especially in the Propofol 0.5% trial group. Twenty minutes after Propofol treatment a clear decreasing tendency was observed, but the levels were still increased as compared to the baseline values.



12.4.2.3 Individual patient changes of triglycerides

Statistically significant differences were detected between both trial groups in respect of the triglyceride increase after Propofol administration (Table 14.19):

at A1 (p=0.0070) • Propofol 0.5% : 182.1 ± 59.4 mg/dL • Propofol 1.0% : 101.3 ± 62.7 mg/dL

at A2 (p=0.0397) • Propofol 0.5% : 65.9 ± 32.0 mg/dL • Propofol 1.0% : 27.9 ± 45.0 mg/dL.

Only slight differences between both groups were seen before start of Propofol injection. Therefore, the different changes from baseline resulted in significantly different triglyceride levels at A1 and A2. Using ANCOVA for repeated measurements, the following baseline-adjusted courses of triglycerides were determined:

Table 12.5: ANCOVA for repeated measures of the triglyceride levels after Propofol administration

Propofol 0.5% [N=30]

Propofol 1.0% [N=30] Time of measurement

mean SD mean SD

A0 = Before anesthesia induction 69.6 46.6 47.5 12.2 A1 = End of anesthesia induction + 3 min 251.7 49.4 148.8 70.6

A2 = End of anesthesia induction + 20 min 135.5 64.5 75.5 52.8 ANCOVA • baseline : p=0.0105 • treatment (0.5% vs. 1.0%) : p=0.0126 • time (3 vs. 20) : p<0.0001 • interaction : p=0.0422 • Adjusted means ± SEM


Timeadj. mean SEM adj. mean SEM

t-test

A0 58.0 58.0

A1 240.9 17.0 158.6 16.2 p=0.0021 A2 124.7 17.0 85.3 16.2 p=0.1139

.

A significantly higher increase of the triglycerides was recorded at A1 resulting in an overall higher level in the Propofol 0.5% trial group. At A2, the differences between both groups were no longer significant.



A graphical representation of the adjusted triglyceride levels is given in Figure 12.10.

Figure 12.10: Adjusted means (± SEM) of the triglyceride level after anesthesia induction with Propofol

0

50

100

150

200

250

300Tr

igly

cerid

es

[mg/

dL]


before +3min +20minPropofol

.

12.4.2.4 Individual clinically significant abnormalities of the triglycerides

Not applicable.



12.5 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY

12.5.1 Blood pressure and pulse

12.5.1.1 Blood pressure and pulse rate in the all-patients-group

Blood pressure and pulse rate are shown in Table 14.20 • during Propofol administration (especially: baseline and level at absence of winking reflex) • during the complete course of anesthetics administration (baseline, minimum and

maximum during anesthesia, last value).

The SBP showed a significantly stronger mean decrease at absence of the winking reflex in the Propofol 0.5% group (p=0.0188): • Propofol 0.5% : –13.9 ± 14.0 mmHg • Propofol 1.0% : –6.1 ± 10.8 mmHg.

No statistically significant differences were seen in the individually lowest and highest SBP level, and at the end of anesthetics administration. Very similar trends were observed for the diastolic blood pressure. At absence of the winking reflex, DBP changed from baseline by • Propofol 0.5% : –11.5 ± 13.6 mmHg • Propofol 1.0% : –4.0 ± 13.0 mmHg (p=0.0331). For MAP, the changes from baseline at absence of the winking reflex amounted to • Propofol 0.5% : –12.3 ± 13.1 mmHg • Propofol 1.0% : –4.7 ± 11.6 mmHg (p=0.0206).

With regard to heart rate, a stronger decrease at absence of winking reflex was observed in the Propofol 0.5% group, too. But the treatment differences were not significant (p=0.1008): • Propofol 0.5% : –11.2 ± 19.4 bpm • Propofol 1.0% : –2.3 ± 21.7 bpm.

In case of heart rate, a markedly lower minimum level was detected in the Propofol 0.5% group (p=0.0474): • Propofol 0.5% : 77.5 ± 13.9 bpm • Propofol 1.0% : 85.8 ± 15.0 bpm.

The course of vital signs is visualized in four figures: • Figure 12.11 : Systolic blood pressure (means ± SD) • Figure 12.12 : Diastolic blood pressure (means ± SD) • Figure 12.13 : Mean arterial pressure (means ± SD) • Figure 12.14 : Heart rate (means ± SD).



Figure 12.11: Systolic blood pressure up to absence of winking reflex: means ± SD

70

80

90

100

110

120

130

140[m

mH

g]


T0 T1 T2

T0 : baseline T1 : immediately following inital bolus T2 : absence of winking reflex



Figure 12.12: Diastolic blood pressure up to absence of winking reflex: means ± SD

30

40

50

60

70

80

90[m

mH

g]


T0 T1 T2



Figure 12.13: Mean arterial pressure up to absence of winking reflex: means ± SD

50

60

70

80

90

100

110[m

mH

g]


T0 T1 T2



Figure 12.14: Heart rate up to absence of winking reflex: means ± SD

60

70

80

90

100

110

120

130

140[b

pm]


T0 T1 T2

.



Individual courses of vital signs are shown in Figure 12.15 to Figure 12.18: • Figure 12.15 : Systolic blood pressure (by patient) • Figure 12.16 : Diastolic blood pressure (by patient) • Figure 12.17 : Mean arterial pressure (by patient) • Figure 12.18 : Heart rate (by patient).

Figure 12.15: Systolic blood pressure up to absence of winking reflex: by-patient display

70

80

90

100

110

120

130

140

150

[mm

Hg]

T0 T1 T2 T0 T1 T2




Figure 12.16: Diastolic blood pressure up to absence of winking reflex: by-patient display

30

40

50

60

70

80

90

100

[mm

Hg]

T0 T1 T2 T0 T1 T2




Figure 12.17: Mean arterial pressure up to absence of winking reflex: by-patient display

50

60

70

80

90

100

110

[mm

Hg]

T0 T1 T2 T0 T1 T2




Figure 12.18: Heart rate up to absence of winking reflex: by-patient display

60708090

100110120130140150160170180190

[bpm

]

T0 T1 T2 T0 T1 T2


.



12.5.1.2 Blood pressure and pulse rate related to injection pain

In Tables 14.21 (patients without injection pain) and 14.22 (patients with injection pain) blood pressure and pulse rate were represented in two subgroups to examine whether the higher decrease of blood pressure during the induction of anesthesia with Propofol 0.5% corresponded to the absence of injection pain in this group.

In patients without injection pain, the SBP showed a marked decrease in the Propofol 0.5% group, but no relevant changes in the Propofol 1.0% group:

immediately following initial bolus (p=0.0027) • Propofol 0.5% : –11.6 ± 11.1 mmHg • Propofol 1.0% : 4.8 ± 9.6 mmHg

at absence of winking reflex (p=0.0480) • Propofol 0.5% : –14.5 ± 14.1 mmHg • Propofol 1.0% : –1.0 ± 14.5 mmHg.

No statistically significant differences were seen at the individually lowest and highest SBP level, and at the end of anesthetics administration. Very similar trends were observed for the diastolic blood pressure:

immediately following initial bolus (p=0.0188) • Propofol 0.5% : –9.3 ± 13.0 mmHg • Propofol 1.0% : 6.0 ± 15.0 mmHg

at absence of winking reflex (p=0.0263) • Propofol 0.5% : –12.3 ± 15.0 mmHg • Propofol 1.0% : 5.0 ± 20.0 mmHg.

The changes from baseline in MAP showed the following means ± SDs: immediately following initial bolus (p=0.0093) • Propofol 0.5% : –10.0 ± 12.0 mmHg • Propofol 1.0% : 5.6 ± 12.9 mmHg

at absence of winking reflex (p=0.0268) • Propofol 0.5% : –13.0 ± 14.2 mmHg • Propofol 1.0% : 3.0 ± 17.9 mmHg.



With regard to heart rate, a mean decrease was observed in the Propofol 0.5 % group, but an increase in the Propofol 1.0 % group. Immediately following initial bolus the changes from baseline amounted to • Propofol 0.5% : –6.5 ± 21.2 bpm • Propofol 1.0% : 17.3 ± 26.4 bpm (p=0.0275). The levels of heart rate resulted in • Propofol 0.5% : 100.7 ± 19.5 bpm • Propofol 1.0% : 129.5 ± 29.5 bpm (p=0.0074). The mean maximum levels of the pulse rate differed significantly, too: • Propofol 0.5% : 108.5 ± 18.4 bpm • Propofol 1.0% : 131.5 ± 27.3 bpm (p=0.0310).

In patients with injection pain no statistically significant differences were seen between both trial groups with respect to blood pressure. In case of heart rate, a lower minimum level and a lower level at end of anesthetics administration were seen in the Propofol 0.5% group:

minimum heart rate after T0 (p=0.0042) • Propofol 0.5% : 67.0 ± 7.2 bpm • Propofol 1.0% : 85.3 ± 15.6 bpm

heart rate at end of anesthetics administration (p=0.0009) • Propofol 0.5% : 68.7 ± 9.8 bpm • Propofol 1.0% : 92.7 ± 16.2 bpm.

Analyses of blood pressure with regard to both factors 'treatment' and 'injection pain' are summarized in Table 12.6.

Table 12.6: ANOVA of changes in blood pressure [mmHg]

ANOVA (p-values) Subgroup Parameter InjP Trmt Interaction No 0.5% No 1.0% Yes 0.5% Yes 1.0%

SBP, T1 – T0 0.4215 0.0046 0.0422 –11.6 4.8 –7.4 –4.6 SBP, T2 – T0 0.6399 0.0264 0.2613 –14.5 –1.0 –11.9 –7.3

SBP, T8 – T0 0.3430 0.1252 0.9662 –16.8 –8.3 –22.4 –13.5

DBP, T1 – T0 0.3325 0.0469 0.0150 –9.3 6.0 –4.1 –5.8 DBP, T2 – T0 0.3467 0.0187 0.0793 –12.3 5.0 –8.9 –6.3

DBP, T8 – T0 0.2215 0.0982 0.4729 –14.5 –1.3 –17.3 –12.0

MAP, T1 – T0 0.3290 0.0160 0.0142 –10.0 5.6 –5.2 –5.4 MAP, T2 – T0 0.4063 0.0151 0.1016 –13.0 3.0 –9.8 –6.6

MAP, T8 – T0 0.2355 0.0899 0.6254 –15.3 –3.6 –19.0 –12.5

[InjP = injection pain; Trmt = treatment; yes, no = with or without injection pain].



The blood pressure decreased at T8 as compared to T0 in all four subgroups. At T1 and T2 this was the predominant tendency, too, but not in the trial group 'Propofol 1.0%, no injection pain'. The individual representation of the course of BP and HR in Figures 12.19 to 12.22 shows similar changes over time in patients with (red curves) and without pain (black curves), too.

Figure 12.19: Systolic blood pressure up to absence of winking reflex: by-patient display [red: patients with injection pain; black: patients without injection pain]

70

80

90

100

110

120

130

140

150

[mm

Hg]

T0 T1 T2 T0 T1 T2




Figure 12.20: Diastolic blood pressure up to absence of winking reflex: by-patient display [red: patients with injection pain; black: patients without injection pain]

30

40

50

60

70

80

90

100

[mm

Hg]

T0 T1 T2 T0 T1 T2




Figure 12.21: Mean arterial pressure up to absence of winking reflex: by-patient display [red: patients with injection pain; black: patients without injection pain]

50

60

70

80

90

100

110

[mm

Hg]

T0 T1 T2 T0 T1 T2




Figure 12.22: Heart rate up to absence of winking reflex: by-patient display [red: patients with injection pain; black: patients without injection pain]

60708090

100110120130140150160170180190

[bpm

]

T0 T1 T2 T0 T1 T2


.



12.5.2 Oxygen saturation

In Table 14.20 the oxygen saturation is represented in correspondence to the vital signs shown in Table 14.19. No statistically significant differences between the trial groups were detected.

12.6 SAFETY CONCLUSION

The primary endpoint of this study was the incidence of spontaneous expressions of pain during injection. Secondary endpoints were parameters for further specification of injection pain such as intensity of reaction, intensity of the attempt to draw back the arm, need to keep the hand or arm in position during injection, and anesthesist's VAS for assessment of injection pain.

Other adverse events during anesthesia until the end of observation, injection site reactions, and further adverse events during the study were to be recorded.

Concerning the primary endpoint, injection pain was differently distributed in the two trial groups with clear advantages for Propofol 0.5%. The rate of spontaneous expression of injection pain was much lower in the Propofol 0.5% group (1 out of 30 patients) compared to the Propofol 1.0% group (6 out of 30 patients), the difference being statistically not significant, yet medically relevant. In contrast, the intensity of the spontaneously expressed pain revealed statistically significant and medically relevant differences between both treatment groups with stronger pain reactions following Propofol 1.0%. Seven patients (23.3%) treated with Propofol 0.5% and 21 patients (70.0%) treated with Propofol 1.0% tried to draw back the arm (Fisher's exact test: p=0.0006).

The treatment difference in favour of Propofol 0.5% was even more pronounced when the intensity of the attempt was considered (U test: p=0.0002). Significant differences in the judgment of injection pain intensity by the anesthesist (p<0.0001) were also recorded. The rate of patients who drew the arm back was slightly increased in patients with lower body weight. However, the superiority of Propofol 0.5% did not depend on body weight.

No statistically significant differences between both trial groups were determined with regard to adverse events during anesthesia until end of observation. Erythema / exanthema and nausea / vomiting were reported in the Propofol 1.0% group only (6.7% of patients each). A relationship to study drug was ruled out by the respective investigators except for the 2 patients who experienced erythemas after administration of Propofol 1.0%. In these patients the relationship was classified as 'unknown'.

No redness, wealing, or other skin reactions were seen at the postoperative examination of the venous punction site.

A serious adverse event was reported in one patient treated with Propofol 1.0%. The child (male, 5 years) developed a moderate recurrent vomiting after having received Nubain® i.v. (nalbuphin) against his post-operative pain. He was hospitalized as a measure of precaution. The event was judged by the physician most likely not to be caused by Propofol, but rather by Nubain®. No death occurred throughout the entire study.



Due to the fact that the administered Propofol was diluted in a lipid emulsion in this study, the triglyceride levels were markedly increased especially in the Propofol 0.5% trial group three minutes after anesthesia induction. Twenty minutes after Propofol treatment, however, a clear decreasing tendency was observed, but the levels were still somewhat higher than baseline values. Thus, the increase in triglycerides seems to be only temporary. The serum triglyceride values were always limited to a medically acceptable range, even the highest value of 348 mg/dL need not cause concern, because 227 mg/dL were determined only 20 minutes later. In any case, the administered quantities are not extraordinarily high. In clinical routine, higher amounts than 4-5 mg/kg propofol for induction of anesthesia might be necessary, which might result in higher triglyceride levels, too.

The SBP showed a significantly stronger mean decrease at absence of the winking reflex in the Propofol 0.5% group (p=0.0188).

Regarding heart rate, a markedly lower minimum level was detected in the Propofol 0.5% group.

In summary it is demonstrated in this study that injection pain is lower under Propofol 0.5% administration compared to Propofol 1.0% in children aged 2 – 6 years. Particularly the intensity of pain, the drawing back of the respective arm and the anesthesist's VAS judgment demonstrate better tolerability of Propofol 0.5% compared to Propofol 1.0%. The number and severity of adverse events also is somewhat lower under Propofol 0.5%.



13. DISCUSSION AND OVERALL CONCLUSIONS

This clinical trial BBMDE-0312 was planned and conducted as a prospective, monocenter, parallel group, controlled, randomized, single-blind and, regarding the primary endpoint, double-blind ('observer blind') clinical study.

To each treatment group, 32 patients were to be recruited. The objective of this clinical trial was to compare anesthesia induction by means of Propofol 0.5% and Propofol 1.0% with regard to venous tolerability and injection pain in children. The study was carried out to show superior tolerability of diluted Propofol over standard Propofol.

Patients undergoing elective surgery under general anesthesia were eligible. After parents gave their informed consent, the patients were randomly assigned to one of the two therapy groups. A total of N=64 patients were randomized out of which N=60 were included in the intention-to-treat set, which was identical with the per protocol set (30 patients to each group).

The primary endpoint of the study was the incidence of spontaneous expressions of pain during injection. Secondary endpoints were parameters for further specification of injection pain (intensity of reaction; intensity of the attempt to draw back the arm; need to keep the hand or arm in position during injection; and anesthesist's VAS for assessment of injection pain); Propofol dosage and Propofol requirement; concomitant medication before, during, and after surgery; hemodynamic parameters, triglycerides in a subpopulation; further adverse events; and time course of the operative procedure.

Both therapy groups can be regarded as homogeneous concerning possible influence factors, as demonstrated by the homogeneity check. Therefore, randomization resulted in comparable treatment groups. When analyzing the course of the operative procedure in the two treatment groups, there was no statistically or clinically relevant difference detectable either.

Concerning the need of Propofol, results in both groups are similar. No significant or clinically relevant differences could be seen in the various efficacy parameters. As to time until absence of winking reflex, similar Propofol dosages were required. A comparable number of additional boli of Propofol in order to achieve anesthesia was needed and dosage per bolus was also comparable in both treatment groups. Thus, with regard to efficacy of Propofol 0.5% we did not find any difference in dosage compared to Propofol 1.0%.

Further surgery-induced medication before induction of anesthesia apart from Propofol was administered as planned in the protocol. The analysis of this medication reveals no medically relevant differences. Other medication before or after extubation is also comparable, indicating that the two different concentrations of Propofol do not result in different comedication schemes during or after anesthesia.

The primary endpoint of this study was the incidence of spontaneous expressions of pain during injection. Secondary endpoints were parameters for further specification of injection pain such as intensity of reaction, intensity of the attempt to draw back the arm, need to keep the hand or arm in position during injection, and anesthesist's VAS for assessment of injection pain.



Other events during anesthesia until the end of observation, injection site reactions and further adverse events during the study were to be recorded.

Concerning the primary endpoint, injection pain was differently distributed in the two trial groups with clear advantages for Propofol 0.5%. The rate of spontaneous expression of injection pain was much lower in the Propofol 0.5% group (1 out of 30 patients) compared to the Propofol 1.0% group (6 out of 30 patients), the difference not being statistically significant, yet medically relevant. The intensity of the spontaneously expressed pain, however, revealed statistically significant and medically relevant differences between both treatment groups with stronger pain reactions following Propofol 1.0%. Seven patients (23.3%) treated with Propofol 0.5% and 21 patients (70.0%) treated with Propofol 1.0% tried to draw back the arm (Fisher's exact test: p=0.0006).

The treatment difference in favour of Propofol 0.5% was even more pronounced when the intensity of the attempt was considered (U test: p=0.0002). Significant differences in the judgment of injection pain intensity by the anesthesist (p<0.0001) were also recorded. The rate of patients who drew the arm back was slightly increased in patients with lower body weight. The superiority of Propofol 0.5%, however, did not depend on body weight.

Taking into account the difficulty of pain-assessment in children, particularly in an operating theatre, is seems impossible to compare results of different studies. Given that the incidence of injection pain under Propofol in children is reportedly up to 85% (10), the frequency of injection pain in our present study is very low, particularly after Propofol 0.5%. The reason for Propofol-evoked pain is still to be clarified, and our study was not intended to investigate this aspect of Propofol.

No statistically significant differences between both trial groups were determined with regard to adverse events during anesthesia until end of observation. Erythema / exanthema and nausea / vomiting were reported in the Propofol 1.0% group only (6.7% patients each). A relationship to study drug was ruled out except for the 2 patients who experienced erythemas after administration of Propofol 1.0%. In these patients the relationship was classified as 'unknown'.

A serious adverse event was reported in one patient treated with Propofol 1.0%. The child (male, 5 years) developed a moderate recurrent vomiting after having received Nubain® i.v. (nalbuphin) against his post-operative pain. He was hospitalized as a measure of precaution. The event was judged by the physician most likely not to be caused by Propofol, but rather by Nubain®. No death occurred throughout the entire study.

The triglyceride levels were markedly increased especially in the Propofol 0.5% trial group three minutes after anesthesia induction. Twenty minutes after Propofol treatment a clear decreasing tendency was observed, but the levels were still increased as compared to the baseline values.

The systolic blood pressure showed a significantly stronger mean decrease at absence of the winking reflex in the Propofol 0.5% group (p=0.0188). Regarding heart rate, a markedly lower minimum level was detected in the Propofol 0.5% group. Whether this decrease is caused by lower sympathetic tone due to an attenuated pain stimulus in the Propofol 0.5% group can not be answered by our data.



In summary it is demonstrated in this study that injection pain is lower under Propofol 0.5% administration compared to Propofol 1.0% in children aged 2 – 6 years. Particularly the intensity of pain, the drawing back of the respective arm, and the anesthesist's VAS judgment demonstrate better tolerability of Propofol 0.5% compared to Propofol 1.0%. The number and severity of adverse events are also somewhat lower under Propofol 0.5%.

Based upon these results Propofol 0.5% is a valuable alternative to Propofol 1.0% to be used in children aged 2 – 6 years for induction of anesthesia. Pain under Propofol 0.5% is less frequent and particularly intensity of pain is lower. What is more, during the study less adverse events were reported under Propofol 0.5%.


B. Braun Melsungen AG BBMDE-0312

14. TABLES REFERRED TO BUT NOT INCLUDED IN THE TEXT

14.1 DEMOGRAPHIC DATA

Table 14.1 : Inclusion criteria Table 14.2 : Exclusion criteria Table 14.3 : Demographic data Table 14.4 : Specific history (indication for surgery) Table 14.5 : General history (concomitant diseases and medication) Table 14.6 : Baseline characteristics Table 14.7 : Homogeneity of treatment groups

14.2 EFFICACY DATA

Table 14.8 : Course of operative procedure Table 14.9 : Propofol required Table 14.10 : Further surgery-induced medication

14.3 SAFETY DATA

Table 14.11 : Changes in concomitant diseases medication Table 14.12 : Injection pain Table 14.13 : Events during anesthesia until end of observation Table 14.14 : Injection site reactions Table 14.15 : Summary of adverse events (except for injection pain) Table 14.16 : Onset, duration, intensity, frequency of adverse events, actions taken,

relationship to study drug, SAEs and outcome Table 14.17 : Adverse events with unknown causal relationship to study drug List 14.3.1A : Adverse events (except for injection pain) List 14.3.1B : Adverse events with unknown relationship to study medication List 14.3.2 : Serious adverse events (SAE) Table 14.18 : Demographic data in patients analyzed for triglyceride concentration Table 14.19 : Triglycerides [mg/dL] before and after anesthesia induction Table 14.20 : Blood pressure and pulse during anesthesia Table 14.21 : Blood pressure and pulse during anesthesia in patients without injection

pain Table 14.22 : Blood pressure and pulse during anesthesia in patients with injection pain Table 14.23 : Oxygen saturation [%] during anesthesia



BBMDE-0312 INCLUSION CRITERIA

Table 14.1 / 1-1

P a r a m e t e r Propofol 0.5% Propofol 1.0% Study population


Age between 2 and 6 years. no 4 ( 13.3%) 2 ( 6.7%) 6 ( 10.0%)

Check: Table 14.3 yes 26 ( 86.7%) 28 ( 93.3%) 54 ( 90.0%)

The parents (at least one parent) have been instructed by the investigator of the nature, significance and extent of the clinical study previous to enrollment of their (his / her) child, and have given their (his / her) written informed consent.

no – – – No check yes 30 (100.0%) 30 (100.0%) 60 (100.0%)

Anesthetic risk classified as ASA I – III. no – – – Check: Table 14.4 yes 30 (100.0%) 30 (100.0%) 60 (100.0%)

Patient undergoing elective surgery under general anesthesia.

no – – – No check yes 30 (100.0%) 30 (100.0%) 60 (100.0%)

Venous access for induction of anesthesia situated on the dorsum of the hand.

no – – – Check: Table 14.8 yes 30 (100.0%) 30 (100.0%) 60 (100.0%)

Hospital care for at least 3 hrs after end of anesthesia guaranteed.

no – – – No check yes 30 (100.0%) 30 (100.0%) 60 (100.0%)


BBMDE-0312 EXCLUSION CRITERIA

Table 14.2 / 1-2



Simultaneous participation in another trial or participation during the month preceding the study on hand.

no 30 (100.0%) 30 (100.0%) 60 (100.0%) No check yes – – –

Known hypersensibility to Propofol, other ingredients of the emulsion, or to any other necessary co-medication.

no 30 (100.0%) 30 (100.0%) 60 (100.0%) Check: Table 14.5 yes – – –

Patient who receives psychopharmacologic agents, tranquillizers, or centrally active analgesics as concomitant medication.

no 27 ( 90.0%) 27 ( 90.0%) 54 ( 90.0%) Check: Table 14.5, Text Tables 11.3, 11.4, 11.5 yes 3 ( 10.0%) 3 ( 10.0%) 6 ( 10.0%)

Patient is expected to require concomitant medication not allowed in this study.

no 28 ( 93.3%) 26 ( 86.7%) 54 ( 90.0%) Check: Table 14.5, Text Tables 11.3, 11.4, 11.5 yes 2 ( 6.7%) 4 ( 13.3%) 6 ( 10.0%)

History of decompensated renal failure. no 30 (100.0%) 30 (100.0%) 60 (100.0%) Check: Table 14.5 yes – – –

History of severe hepatic dysfunction, hepatic cirrhosis.


Angiographically confirmed CHD (coronary heart disease) or cerebral ischemia.


History of convulsive disorders. no 30 (100.0%) 30 (100.0%) 60 (100.0%)

Check: Table 14.5 yes – – –


BBMDE-0312 EXCLUSION CRITERIA

Table 14.2 / 2-2


Decompensated cardiac insufficiency. no 30 (100.0%) 30 (100.0%) 60 (100.0%) Check: Table 14.5 yes – – –

Hypovolemia. no 30 (100.0%) 30 (100.0%) 60 (100.0%)


Increased intracranial pressure. no 30 (100.0%) 30 (100.0%) 60 (100.0%)


Lack of parents' informed consent. no 30 (100.0%) 30 (100.0%) 60 (100.0%)

No check yes – – –

Patient who receives parenteral fat emulsion, e.g. intralipid.

no 30 (100.0%) 30 (100.0%) 60 (100.0%) No check yes – – –


BBMDE-0312 DEMOGRAPHIC DATA

Table 14.3 / 1-2



Age [years] minimum 2.2 2.1 2.1 maximum 6.6 6.3 6.6

median 4.8 4.4 4.5

mean 4.6 4.2 4.4 standard dev. 1.3 1.4 1.3

2 – < 3 5 ( 16.7%) 8 (26.7%) 13 (21.7%) 3 – < 4 5 ( 16.7%) 6 (20.0%) 11 (18.3%) 4 – < 5 6 ( 20.0%) 6 (20.0%) 12 (20.0%) 5 – < 6 10 ( 33.3%) 8 (26.7%) 18 (30.0%) ≥ 6 4 ( 13.3%) 2 ( 6.7%) 6 (10.0%)

Sex male 30 (100.0%) 28 (93.3%) 58 (96.7%) female – 2 ( 6.7%) 2 ( 3.3%)

Body weight [kg] male minimum 11.0 12.0 11.0 maximum 30.0 30.0 30.0

median 18.0 18.0 18.0


female minimum – 13.0 13.0 maximum – 19.0 19.0

median – 16.0 16.0

mean – 16.0 16.0 standard dev. – 4.2 4.2

total minimum 11.0 12.0 11.0 maximum 30.0 30.0 30.0

median 18.0 18.0 18.0



BBMDE-0312 DEMOGRAPHIC DATA

Table 14.3 / 2-2


Body height [cm] male minimum 90 90 90 maximum 120 122 122

median 107 103 105

mean 107 105 106 standard dev. 9 10 9

female minimum – 95 95 maximum – 110 110

median – 103 103

mean – 103 103 standard dev. – 11 11

total minimum 90 90 90 maximum 120 122 122

median 107 103 105



BBMDE-0312 SPECIFIC HISTORY (INDICATION FOR SURGERY)

Table 14.4 / 1-1



ASA classification ASA I 30 (100.0%) 29 (96.7%) 59 (98.3%) ASA II – 1 ( 3.3%) 1 ( 1.7%) ASA III – – –

Individual number of main indications for surgery (MedDRA LLTs)

1 26 ( 86.7%) 25 (83.8%) 51 (85.0%) 2 4 ( 13.3%) 5 (16.7%) 9 (15.0%)

Individual number of main indications for surgery (MedDRA PTs)

1 26 ( 86.7%) 25 (83.8%) 51 (85.0%) 2 4 ( 13.3%) 5 (16.7%) 9 (15.0%)

Total number of preferred terms 34 35 69

SOC / MedDRA Preferred Terms

Cong Congenital, familial and genetic disorders 2 ( 6.7%) 1 ( 3.3%) 3 ( 5.0%) Cryptorchism 1 1 2 Hypospadias 1 – 1

Gastr Gastrointestinal disorders – 4 (13.3%) 4 ( 6.7%) Inguinal hernia 4 4

Infec Infections and infestations – 1 ( 3.3%) 1 ( 1.7%) Urinary tract infection 1 1

Renal Renal and urinary disorders 2 ( 6.7%) – 2 ( 3.3%) Obstructive uropathy 1 1 Vesicoureteric reflux 1 1

Repro Reproductive system and breast disorders 26 ( 86.7%) 25 (83.3%) 51 (85.0%) Hydrocele – 1 1 Penile adhesion 1 – 1 Phimosis 24 24 48 Testicular retraction 4 3 7

Surg Surgical and medical procedures 1 ( 3.3%) 1 ( 3.3%) 2 ( 3.3%) Penile operation – 1 1 Pyeloplasty 1 – 1


BBMDE-0312 GENERAL HISTORY (CONCOMITANT DISEASES AND MEDICATION) Table 14.5 / 1-1



Diabetes no 30 (100.0%) 30 (100.0%) 60 (100.0%) yes – – –

History of anesthetic nausea no 30 (100.0%) 30 (100.0%) 60 (100.0%) yes – – –

Allergies no 27 ( 90.0%) 29 ( 96.7%) 56 ( 93.3%) yes 3 ( 10.0%) 1 ( 3.3%) 4 ( 6.7%)

IF YES:

• antibiotics 1 – 1 • food – 1 1 • plaster, food ingredients 1 – 1 • plaster 1 – 1

Other risk factors no 28 ( 93.3%) 30 (100.0%) 58 ( 96.7%)

cf. List 16.4.4 yes 2 ( 6.7%) – 2 ( 3.3%)

Concomitant medication no 29 ( 96.7%) 30 (100.0%) 59 ( 98.3%) yes 1 ( 3.3%) – 1 ( 1.7%)

IF YES:

• fluoride tablets 1 – 1


BBMDE-0312 BASELINE CHARACTERISTICS

Table 14.6 / 1-1



Systolic blood pressure [mmHg] minimum 80 89 80 maximum 150 150 150

median 114.5 110.0 110.5


Diastolic blood pressure [mmHg] minimum 44 42 42 maximum 99 85 99

median 67.5 64.0 65.0


MAP [mmHg] minimum 56.3 60.0 56.3 maximum 110.0 102.7 110.0

median 82.2 79.7 81.5


Heart rate [bpm] minimum 69 70 69 maximum 163 174 174

median 99.0 97.5 98.0


Oxygen saturation [%] minimum 95 93 93 maximum 100 100 100

median 99.0 99.0 99.0


Triglycerides before anesthesia induction [mg/dL]

minimum 36 31 31 maximum 171 66 171

median 48.0 48.0 48.0


not done 20 19 39


BBMDE-0312 HOMOGENEITY OF TREATMENT GROUPS

Table 14.7 / 1-1

P a r a m e t e r Test DF Test statistics p-value

Deviations from inclusion criteria χ2 test 1 0.74 0.3894 Deviations from exclusion criteria χ2 test 1 1.00 0.3169 Deviations from criteria related to the study conduct χ2 test 1 2.44 0.1180

Violations of the protocol (total) χ2 test 1 1.09 0.2974

Age t-test 58 0.97 0.3338 Gender χ2 test 1 2.07 0.1503

Body weight (total) t-test 58 0.66 0.5098 Body height (total) t-test 58 0.87 0.3889

ASA classification χ2 test 1 1.02 0.3132

Main indication for surgery • inguinal hernia χ2 test 1 4.29 0.0384 • phimosis χ2 test 1 0.00 1.0000 • testicular retraction χ2 test 1 0.16 0.6876

Allergies χ2 test 1 1.07 0.3006 Other risk factors χ2 test 1 2.07 0.1503

Systolic blood pressure t-test 58 0.74 0.4596 Diastolic blood pressure t-test 58 0.86 0.3939 Mean arterial pressure t-test 58 0.87 0.3899 Heart rate t-test 58 0.18 0.8570 Oxygen saturation t-test 58 0.09 0.9308 Triglycerides t-test 10.1 1.45* 0.1768

[*: unequal variances, therefore method according to Satterthwaite]


BBMDE-0312 COURSE OF OPERATIVE PROCEDURE

Table 14.8 / 1-3

P a r a m e t e r Propofol 0.5% Propofol 1.0%


Venous access dorsum of the hand 30 (100.0%) 30 (100.0%) other access – –

blue cannula 28 ( 93.3%) 28 ( 93.3%) yellow cannula 2 ( 6.7%) 2 ( 6.7%) χ2 test: p=1.000

Clock time Propofol injection started minimum 8:25 8:24 median 9:08 8:58 maximum 12:01 12:20

Duration of time periods from start of anesthesia to …

• absence of winking reflex [min]

minimum 0 0 maximum 5 4

median 1.00 1.50 U test: p=0.3050

mean 1.47 1.67 standard dev. 0.94 0.88

0 2 ( 6.7%) 1 ( 3.3%) 1 16 ( 53.3%) 14 ( 46.7%) 2 10 ( 33.3%) 10 ( 33.3%) 3 1 ( 3.3%) 4 ( 13.3%) ≥ 4 1 ( 3.3%) 1 ( 3.3%)

• intubation [min] minimum 0 1 maximum 5 5

median 3.00 3.00 U test: p=0.5535


0 1 ( 3.3%) – 1 2 ( 6.7%) 2 ( 6.7%) 2 11 ( 36.7%) 11 ( 36.7%) 3 12 ( 40.0%) 10 ( 33.3%) 4 2 ( 6.7%) 6 ( 20.0%) 5 2 ( 6.7%) 1 ( 3.3%)



Table 14.8 / 2-3

P a r a m e t e r Propofol 0.5% Propofol 1.0% Test: p-value

Duration of time periods from start of anesthesia to … [cont.]

• skin incision [min] minimum 1 7 maximum 27 31

median 15.00 16.00 U test: p=0.9645


≤ 10 5 (16.7%) 6 (20.0%) 11 – 15 12 (40.0%) 7 (23.3%) 16 – 20 9 (30.0%) 13 (43.3%) > 20 4 (13.3%) 4 (13.3%)

• skin suture [min] minimum 10 18 maximum 150 129

median 30.00 34.00 U test: p=0.4115


≤ 20 2 ( 6.7%) 2 ( 6.7%) 21 – 30 14 (46.7%) 10 (33.3%) 31 – 40 7 (23.3%) 10 (33.3%) 41 – 50 2 ( 6.7%) – 51 – 60 – 2 ( 6.7%) > 60 5 (16.7%) 6 (20.0%)

• end of anesthetics administration [min]


median 29.00 30.50 U test: p=0.5390


≤ 20 3 (10.0%) 3 (10.0%) 21 – 30 17 (56.7%) 12 (40.0%) 31 – 40 3 (10.0%) 6 (20.0%) 41 – 60 3 (10.0%) 3 (10.0%) > 60 4 (13.3%) 6 (20.0%)



Table 14.8 / 3-3


Duration of time periods from start of anesthesia to … [cont.]

• extubation [min] minimum 22 27 maximum 165 143

median 42.00 42.00 U test: p=0.7224


≤ 30 2 ( 6.7%) 2 ( 6.7%) 31 – 40 12 (40.0%) 11 (36.7%) 41 – 50 10 (33.3%) 7 (23.3%) 51 – 60 1 ( 3.3%) 4 (13.3%) > 60 5 (16.7%) 6 (20.0%)

Duration of anesthetics administration minimum 10 16 maximum 147 126

median 26.00 27.00 U test: p=0.6148


≤ 15 2 ( 6.7%) – 16 – 30 19 (63.3%) 16 (53.3%) 31 – 45 4 (13.3%) 5 (16.7%) 46 – 60 2 ( 6.7%) 3 (10.0%) > 60 3 (10.0%) 6 (20.0%)


BBMDE-0312 PROPOFOL REQUIRED

Table 14.9 / 1-4



Number of boli until T2* 1 3 (10.0%) 5 (16.7%) 2 17 (56.7%) 14 (46.7%) 3 7 (23.3%) 9 (30.0%) 4 2 ( 6.7%) 2 ( 6.7%) U test: p=0.8277

5 – –

6 1 ( 3.3%) –

Number of boli after T2 0 23 (76.7%) 23 (76.7%) 1 5 (16.7%) 5 (16.7%) U test: p=1.0000

2 2 ( 6.7%) 2 ( 6.7%)

Total number of boli minimum 1 1 median 2.5 2.5 U test: p=0.9311 maximum 6 4

Time between 1st and 2nd bolus [min] [N=27] [N=28]

minimum 1.0 1.0 median 1.0 1.0

maximum 1.0 2.0

Time between 2nd and 3rd bolus [min] [N=15] [N=15]


maximum 1.0 1.0

Time between 3rd and 4th bolus [min] [N=5] [N=4]


maximum 1.0 2.0

Time between 4th and last bolus [min] [N=3] [N=–]

minimum 1.0 median 1.0

maximum 2.0

Time between 1st and last bolus [min] [N=27] [N=28]


maximum 5.0 4.0

[*: T2 = absence of winking reflex]



Table 14.9 / 2-4


Total duration of Propofol administration [min]

minimum 0.5 0.5 maximum 5.5 4.5 median 1.92 1.75 U test: p=0.9566

mean 2.16 2.08

duration of a single bolus = 0.5 min

standard dev. 1.15 0.92

Individual minimum Propofol dosage per bolus

• weight [mg] minimum 11.0 12.5 maximum 63.0 60.0

median 18.0 18.0 U test: p=0.4063


• weight / body weight [mg/kg]

minimum 0.97 1.00 maximum 3.00 3.00

median 1.00 1.00 U test: p=0.9887


Individual mean Propofol dosage per bolus


median 33.7 33.7 U test: p=0.7170




median 1.82 1.84 U test: p=0.6615




Table 14.9 / 3-4


Individual maximum Propofol dosage per bolus


median 54.0 54.0 U test: p=0.6834


• weight / body weight [mg/kg] minimum 2.97 3.00 maximum 3.13 3.71

median 3.00 3.00 U test: p=0.3131


Propofol required until T2


median 73.5 75.5 U test: p=0.6463


• weight / body weight [mg/kg] minimum 3.00 3.00 maximum 8.00 6.00

median 4.00 4.00 U test: p=0.9621




Table 14.9 / 4-4


Propofol required after T2 no 23 (76.7%) 23 (76.7%)

yes 7 (23.3%) 7 (23.3%) χ2 test: p=1.0000

IF YES, dosage [mg] minimum 14.5 14.0 maximum 38.6 44.0 median 20.0 16.0


IF YES, dosage [mg/kg] minimum 1.00 1.00 maximum 2.00 2.00 median 1.00 1.00


Total Propofol required


median 82.5 76.0 U test: p=0.6412




median 4.50 4.86 U test: p=0.9379



BBMDE-0312 FURTHER SURGERY-INDUCED MEDICATION

Table 14.10 / 1-3



Administration of 0.5 mg/kg Dormicum before start of anesthesia

no – –

yes 30 (100.0%) 30 (100.0%) not applicable

IF YES: time of administration before start of anesthesia [min]

minimum 23 16 maximum 136 98 median 46.0 42.0 U test: p=0.3669

mean 55.5 47.1 standard dev. 29.8 15.5 ≤ 30 5 ( 16.7%) 2 ( 6.7%) 31 – 40 5 ( 16.7%) 8 ( 26.7%) 41 – 50 6 ( 20.0%) 9 ( 30.0%) 51 – 60 3 ( 10.0%) 8 ( 26.7%) > 60 11 ( 36.7%) 3 ( 10.0%)

Administration of Remifentanyl 0.25 µg/kg/min for 1 min before start of anesthesia

no – –

yes 30 (100.0%) 30 (100.0%) not applicable



Table 14.10 / 2-3


Administration of Paracetamol after intubation

no 5 (16.7%) 7 ( 23.3%)

yes 25 (83.3%) 23 ( 76.7%) χ2 test: p=0.5186

IF YES:

• dose [mg] 250 8 12 500 16 8 750 – 2 U test: p=0.3752

1000 1 1

• time after intubation [min] minimum 1 1 maximum 8 12 median 3.00 4.00 U test: p=0.2424

mean 3.76 4.78 standard dev. 1.92 2.78 1 – 2 7 4 3 – 4 9 8 5 – 6 7 6 7 – 8 2 3 > 8 – 2

Administration of Sevofluran 1/3 MAC inhalational

*: Pat. no. 35 no 1* ( 3.3%) –

yes 29 (96.7%) 30 (100.0%) χ2 test: p=0.3132

Administration of other preparations before induction of anesthesia

no 1 ( 3.3%) 6 ( 20.0%)

yes 29 (96.7%) 24 ( 80.0%) χ2 test: p=0.0444

IF YES:

• individual number of drugs 1 17 13 2 12 11

• total number of drugs 41 35

cf. Chapter 11.4.1.3 / Table 11.3

• ATC classification



Table 14.10 / 3-3


Administration of other preparations between induction of anesthesia and extubation

no 4 (13.3%) 4 (13.3%)

yes 26 (86.7%) 26 (86.7%) χ2 test: p=1.0000

IF YES:

• individual number of drugs 1 15 19 2 9 7 3 1 – 4 1 –




Administration of other preparations after extubation

no 22 (73.3%) 23 (76.7%)

yes 8 (26.7%) 7 (23.3%) χ2 test: p=0.7656

IF YES:

• individual number of drugs 1 7 5 2 1 1 3 – 1





BBMDE-0312 CHANGES IN CONCOMITANT MEDICATION

Table 14.11 / 1-1

Propofol 0.5% Propofol 1.0% A T C c o d e

A + – E A + – E

Number of patients with concomitant medication 1 – – 1 – 2 – 2

A01 Stomatological preparation 1 – – 1 – – – – R06 Antihistaminics – – – – – 2* – 2

A = at admission + = started during study (not related to surgery) – = stopped during study (not related to surgery) E = at end of study

[*: cf. Table 11.5]


BBMDE-0312 INJECTION PAIN

Table 14.12 / 1-1



Spontaneous expression of injection pain no 29 (96.7%) 24 (80.0%) yes 1 ( 3.3%) 6 (20.0%) Fisher: p=0.1028

Intensity of injection pain no pain 29 (96.7%) 24 (80.0%) grimacing 1 ( 3.3%) 2 ( 6.7%) crying – 4 (13.3%) U test: p=0.0424

screaming – –

Drawing back of the arm? no 23 (76.7%) 9 (30.0%) yes 7 (23.3%) 21 (70.0%)

Fisher: p=0.0006

Intensity of the attempt to draw back the arm

no attempt 23 (76.7%) 9 (30.0%) gentle 4 (13.3%) 5 (16.7%) moderate 2 ( 6.7%) 13 (43.3%) U test: p=0.0002

strong 1 ( 3.3%) 3 (10.0%)

Assessment by the anesthesist: Arm needs to be fixed?

no 24 (80.0%) 12 (40.0%) yes 6 (20.0%) 18 (60.0%) Fisher: p=0.0033

Assessment by the anesthesist: Graduation of the intervention

no intervention 24 (80.0%) 12 (40.0%) hand was fixed 5 (16.7%) 14 (46.7%) U test: p=0.0019 arm was fixed 1 ( 3.3%) 4 (13.3%)

Assessment by the anesthesist: VAS of the injection pain [mm]


median 0.0 14.0 U test: p<0.0001


0 23 (76.7%) 6 (20.0%) > 0 7 (23.3%) 24 (80.0%) Fisher: p<0.0001


BBMDE-0312 EVENTS DURING ANESTHESIA UNTIL END OF OBSERVATION Table 14.13 / 1-1



Myoclonia upon anesthesia induction no 30 (100.0%) 30 (100.0%) yes – – not applicable

Coughing no 30 (100.0%) 30 (100.0%) yes – – not applicable

Singultus no 27 ( 90.0%) 26 ( 86.7%) yes 3 ( 10.0%) 4 ( 13.3%) χ2 test: p=0.6876

Erythema, exanthema no 30 (100.0%) 28 ( 93.3%) yes – 2 ( 6.7%) χ2 test: p=0.1503

IF YES:

• facial erythema 1 • left lower arm 1

Nausea, vomiting no 30 (100.0%) 28 ( 93.3%)

yes – 2 ( 6.7%) χ2 test: p=0.1503

Headache no 30 (100.0%) 30 (100.0%) yes – – not applicable

Spontaneous movements during operative procedure

no 30 (100.0%) 30 (100.0%)

yes – – not applicable

Others no 28 ( 93.3%) 30 (100.0%) yes 2 ( 6.7%) – χ2 test: p=0.1503

IF YES:

• mild laryngospasm 1 • inspiratory stridor after extubation 1


BBMDE-0312 INJECTION SITE REACTIONS

Table 14.14 / 1-1



Injection site reactions no 30 (100.0%) 30 (100.0%) yes – –

not applicable


BBMDE-0312 SUMMARY OF ADVERSE EVENTS (EXCEPT FOR INJECTION PAIN) Table 14.15 / 1-1



Further adverse events (besides injection pain) no 25 (83.3%) 24 (80.0%) yes 5 (16.7%) 6 (20.0%)

IF YES:

• Individual number of symptoms (LLTs) 1 5 4 2 – 2

• Total number of symptoms (LLTs) 5 8

• Individual number of High Level Terms 1 5 4 2 – 2

• Total number of High Level Terms 5 8

M e d D R A S O C / H L T

Gastr Gastrointestinal disorders – 2 ( 6.7%) Nausea and vomiting symptoms 2

Resp Respiratory, thoracic and mediastinal disorders 5 (16.7%) 4 (13.3%) Laryngeal spasm, oedema and obstruction 2 – Lower respiratory tract signs and symptoms 3 4

Skin Skin and subcutaneous tissue disorders – 2 ( 6.7%) Erythemas 2


BBMDE-0312 ONSET, DURATION, INTENSITY, FREQUENCY OF ADVERSE EVENTS, ACTIONS TAKEN, RELATIONSHIP TO STUDY DRUG, SAEs AND OUTCOME Table 14.16 / 1-1

„ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒ† ‚ ‚ ‚ ‚ Onset [min] ‚ Duration [min] ‚Inten- ‚ Fre- ‚ Action taken ‚ Relation-‚ SAE ‚ Outcome ‚ ‚ ‚ ‚ ‚ ‚ ‚ sity ‚quency ‚ ‚ ship ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ Treatment ‚ SOC System organ class/High level term ‚ N ‚ min median max mv ‚ min median max mv ‚ 0 1 2 ‚ 1 2 ‚ 0 1 2 3 4 5 6 ‚ 0 1 2 ‚ 0 1 ‚ 1 2 3 4 5 ‚ ‡ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒ‰ ‚ Propofol 0.5% ‚ Resp Respiratory, thoracic and mediastinal disorder ‚ 5 ‚ 0 3.0 42 0 ‚ 2 7 8 0 ‚ 3 2 - ‚ 5 - ‚ 5 - - - - - - ‚ 5 - - ‚ 5 - ‚ 5 - - - - ‚ ‚ Propofol 0.5% ‚ Laryngeal spasm, oedema and obstruction ‚ 2 ‚ 39 40.5 42 0 ‚ 7 8 8 0 ‚ 1 1 - ‚ 2 - ‚ 2 - - - - - - ‚ 2 - - ‚ 2 - ‚ 2 - - - - ‚ ‚ Propofol 0.5% ‚ Lower respiratory tract signs and symptoms ‚ 3 ‚ 0 1.0 3 0 ‚ 2 3 8 0 ‚ 2 1 - ‚ 3 - ‚ 3 - - - - - - ‚ 3 - - ‚ 3 - ‚ 3 - - - - ‚ ‡ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒ‰ ‚ Propofol 1.0% ‚ Gastr Gastrointestinal disorders ‚ 2 ‚ 121 121.0 121 1 ‚ 190 190 190 1 ‚ 1 1 - ‚ 1 1 ‚ - - - 1 1 - - ‚ 2 - - ‚ 1 1 ‚ 2 - - - - ‚ ‚ Propofol 1.0% ‚ Nausea and vomiting symptoms ‚ 2 ‚ 121 121.0 121 1 ‚ 190 190 190 1 ‚ 1 1 - ‚ 1 1 ‚ - - - 1 1 - - ‚ 2 - - ‚ 1 1 ‚ 2 - - - - ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 1.0% ‚ Resp Respiratory, thoracic and mediastinal disorder ‚ 4 ‚ -1 1.0 3 0 ‚ 2 6 20 0 ‚ 4 - - ‚ 4 - ‚ 4 - - - - - - ‚ 4 - - ‚ 4 - ‚ 4 - - - - ‚ ‚ Propofol 1.0% ‚ Lower respiratory tract signs and symptoms ‚ 4 ‚ -1 1.0 3 0 ‚ 2 6 20 0 ‚ 4 - - ‚ 4 - ‚ 4 - - - - - - ‚ 4 - - ‚ 4 - ‚ 4 - - - - ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 1.0% ‚ Skin Skin and subcutaneous tissue disorders ‚ 2 ‚ 2 2.0 2 1 ‚ 15 15 15 1 ‚ 2 - - ‚ 2 - ‚ 2 - - - - - - ‚ - - 2 ‚ 2 - ‚ 2 - - - - ‚ ‚ Propofol 1.0% ‚ Erythemas ‚ 2 ‚ 2 2.0 2 1 ‚ 15 15 15 1 ‚ 2 - - ‚ 2 - ‚ 2 - - - - - - ‚ - - 2 ‚ 2 - ‚ 2 - - - - ‚ Šƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒŒ

Onset (Time after induction of anesthesia): mv = missing value Duration: mv = missing value Intensity: 0 = mild, 1 = moderate, 2 = severe Frequency: 1 = single episode, 2 = intermittent Action taken: 0 = none, 1 = study drug dose interrupted, 2 = study drug discontinued, 3 = other therapy administered, 4 = hospitalization, 5 = study drug reduced, 6 = study drug increased Relationship (Relationship to study drug): 0 = no, 1 = yes, 2 = unknown SAE (Seriousness): 0 = no, 1 = yes Outcome: 1 = resolved, 2 = ongoing, 3 = sequela, 4 = unknown, 5 = death


BBMDE-0312 ADVERSE EVENTS WITH UNKNOWN CAUSAL RELATIONSHIP TO STUDY DRUG Table 14.17 / 1-1



Adverse events (besides injection pain) with unknown* relationship to study drug

no 30 (100.0%) 28 (93.3%) yes – 2 ( 6.7%)

IF YES:

• Individual number of symptoms (LLTs) 1 2 > 1 –

• Total number of symptoms (LLTs) – 2

• Individual number of High Level Terms 1 2 > 1 –

• Total number of High Level Terms – 2

M e d D R A S O C / H L T

Skin Skin and subcutaneous tissue disorders – 2 ( 6.7%) Erythemas 2

[*: In all other patients the causality was explicitly excluded.]


BBMDE-0312 ADVERSE EVENTS (EXCEPT FOR INJECTION PAIN)

List 14.3.1A / 1-1

„ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ† ‚ ‚ ‚ Onset of event ‚ Surgery ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ Start of Time of ‚ ‚ Treatment Pat.no. ‚ Event/symptom (as documented) ‚ Date Time ‚ Date anesthesia extubation ‚ ‡ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‰ ‚ Propofol 0.5% 1 ‚ Singultus ‚ 15/08/03 9:02 ‚ 15/08/03 9:01 9:36 ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 0.5% 34 ‚ Singultus ‚ 31/03/04 8:35 ‚ 31/03/04 8:32 9:10 ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 0.5% 40 ‚ Singultus ‚ 07/05/04 9:45 ‚ 07/05/04 9:45 10:20 ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 0.5% 55 ‚ Leichter Laryngospasmus ‚ 08/10/04 9:12 ‚ 08/10/04 8:30 9:12 ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 0.5% 64 ‚ Inspiratorischer Stridor ‚ 09/02/05 12:15 ‚ 09/02/05 11:36 12:11 ‚ ‡ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‰ ‚ Propofol 1.0% 4 ‚ Singultus ‚ 13/10/03 8:45 ‚ 13/10/03 8:46 9:25 ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 1.0% 5 ‚ Singultus ‚ 13/10/03 9:49 ‚ 13/10/03 9:48 10:32 ‚ ‚ Propofol 1.0% 5 ‚ Gesichtserythem ‚ 13/10/03 9:50 ‚ 13/10/03 9:48 10:32 ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 1.0% 10 ‚ Singultus ‚ 10/11/03 8:45 ‚ 10/11/03 8:44 9:22 ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 1.0% 25 ‚ Rezidivierendes Erbrechen ‚ 04/02/04 11:50 ‚ 04/02/04 9:49 11:29 ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 1.0% 44 ‚ Erythem Unterarm ‚ 19/05/04 ‚ 19/05/04 8:24 9:07 ‚ ‚ Propofol 1.0% 44 ‚ Übelkeit ‚ 19/05/04 ‚ 19/05/04 8:24 9:07 ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 1.0% 56 ‚ Singultus ‚ 25/10/04 8:36 ‚ 25/10/04 8:33 9:30 ‚ Šƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒŒ


BBMDE-0312 ADVERSE EVENTS WITH UNKNOWN RELATIONSHIP TO STUDY MEDICATION List 14.3.1B / 1-1

„ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ† ‚ ‚ ‚ Onset of event ‚ Surgery ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ Start of Time of ‚ Relationship ‚ ‚ Treatment Pat.no. ‚ Event/symptom (as documented) ‚ Date Time ‚ Date anesthesia extubation ‚ to study drug ‚ ‡ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‰ ‚ Propofol 1.0% 5 ‚ Gesichtserythem ‚ 13/10/03 9:50 ‚ 13/10/03 9:48 10:32 ‚ unknown ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ Propofol 1.0% 44 ‚ Erythem Unterarm ‚ 19/05/04 ‚ 19/05/04 8:24 9:07 ‚ unknown ‚ Šƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒŒ


BBMDE-0312 SERIOUS ADVERSE EVENTS (SAE)

List 14.3.2 / 1-1

„ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ…ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ† ‚ ‚ SAE ‚ Surgery ‚ ‚ ‚ ‚ ‚ ‚ ‚ Event/symptom ‚ Start of Time of ‚ ‚ Treatment Pat.no. ‚ (as documented) Reason Date Time ‚ Date anesthesia extubation ‚ ‡ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒˆƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‰ ‚ Propofol 1.0% 25 ‚ Rezidivierendes Erbrechen Hospitalisation 04/02/04 11:50 ‚ 04/02/04 9:49 11:29 ‚ Šƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ‹ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒŒ


BBMDE-0312 DEMOGRAPHIC DATA IN PATIENTS ANALYZED FOR TRIGLYCERIDE CONCENTRATION Table 14.18 / 1-1

P a r a m e t e r Propofol 0.5% Propofol 1.0% All patients treated


Age [years] minimum 2.3 2.3 2.3 maximum 6.2 6.2 6.2

median 3.5 3.5 3.5


2 – < 3 4 ( 40.0%) 4 ( 36.4%) 8 ( 38.1%) 3 – < 4 2 ( 20.0%) 3 ( 27.3%) 5 ( 23.8%) 4 – < 5 – 3 ( 27.3%) 3 ( 14.3%) 5 – < 6 3 ( 30.0%) – 3 ( 14.3%) ≥ 6 1 ( 10.0%) 1 ( 9.1%) 2 ( 9.5%)

Sex male 10 (100.0%) 11 (100.0%) 21 (100.0%) female – – –

Body weight [kg] minimum 13.0 12.0 12.0 maximum 24.0 22.0 24.0

median 16.5 17.0 17.0


Body height [cm] minimum 90 90 90 maximum 120 120 120

median 103 100 100



BBMDE-0312 TRIGLYCERIDES [mg/dL] BEFORE AND AFTER ANESTHESIA INDUCTION Table 14.19 / 1-1



A0: before anesthesia induction minimum 36 31

maximum 171 66

median 48.0 48.0 mean 69.6 47.5 t-test: p=0.1457


A1: end of anesthesia induction + 3 min minimum 155 96

maximum 323 348



Difference A1 – A0 minimum 99 59

maximum 270 282



A2: end of anesthesia induction + 20 min minimum 63 41

maximum 250 227



Difference A2 – A0 minimum 20 6

maximum 137 161




BBMDE-0312 BLOOD PRESSURE AND PULSE DURING ANESTHESIA

Table 14.20 / 1-8

Systolic blood pressure [mmHg]



T0: baseline minimum 80 89

maximum 150 150



T1: immediately following initial bolus minimum 72 82

maximum 143 143



T2: absence of winking reflex minimum 70 73

maximum 135 136



Difference T1 – T0 minimum –40 –24

maximum 14 23

median –7.5 –3.0 mean –10.6 –2.7 t-test: p=0.0056



maximum 7 21





Table 14.20 / 2-8

Systolic blood pressure [mmHg] [continued]


Minimum after T0 minimum 70 71

maximum 107 121

median 88.5 88.5 U test: p=0.5688

mean 87.5 90.1


Maximum after T0 minimum 80 88

maximum 143 152

median 108.5 111.0 U test: p=0.4201

mean 108.3 112.3


T8: end of anesthetics administration minimum 74 77

maximum 128 130




maximum 17 16





Table 14.20 / 3-8

Diastolic blood pressure [mmHg]



maximum 99 85




maximum 91 92




maximum 81 97




maximum 20 33




maximum 16 38





Table 14.20 / 4-8

Diastolic blood pressure [mmHg] [continued]



maximum 70 71

median 45.0 44.5 U test: p=0.7166

mean 46.1 45.6



maximum 93 97

median 67.0 69.0 U test: p=0.6411

mean 68.3 69.8



maximum 84 83




maximum 20 25





Table 14.20 / 5-8

MAP [mmHg]


T0: baseline minimum 56.3 60.0

maximum 110.0 102.7



T1: immediately following initial bolus minimum 51.3 51.3

maximum 102.3 104.7



T2: absence of winking reflex minimum 50.0 51.0

maximum 95.7 107.3



Difference T1 – T0 minimum –30.7 –23.3

maximum 18.0 29.7




maximum 13.0 32.3





Table 14.20 / 6-8

MAP [mmHg] [continued]


Minimum after T0 minimum 44.7 45.3

maximum 80.0 89.0

median 59.5 60.3 U test: p=0.9293

mean 60.5 61.1


Maximum after T0 minimum 54.0 57.3

maximum 104.7 107.3

median 80.7 83.4 U test: p=0.6048

mean 81.3 83.1


T8: end of anesthetics administration minimum 50.3 49.3

maximum 89.7 98.7




maximum 19.0 20.4





Table 14.20 / 7-8

Pulse [bpm]



maximum 163 174




maximum 140 183




maximum 138 168




maximum 32 40

median –2.5 –1.5 mean –4.7 0.1 t-test: p=0.3851



maximum 28 47





Table 14.20 / 8-8

Pulse [bpm] [continued]



maximum 102 120

median 76.0 83.0 U test: p=0.0474

mean 77.5 85.8



maximum 145 183

median 105.5 110.0 U test: p=0.2485

mean 107.1 115.8



maximum 130 122




maximum 53 28




BBMDE-0312 BLOOD PRESSURE AND PULSE DURING ANESTHESIA IN PATIENTS WITHOUT INJECTION PAIN Table 14.21 / 1-8





maximum 150 120




maximum 143 130




maximum 135 128




maximum 14 23

median –8.0 3.0 mean –11.6 4.8 t-test: p=0.0027



maximum 7 21

median –12.0 2.0 mean –14.5 –1.0 t-test: p=0.0480







maximum 107 105

median 90.0 92.0 U test: p=0.5532

mean 89.1 92.0



maximum 143 130

median 110.0 121.0 U test: p=0.1383

mean 109.8 117.7



maximum 128 130




maximum 17 16








maximum 99 80




maximum 91 92




maximum 81 97




maximum 20 33




maximum 16 38








maximum 70 60

median 46.0 45.0 U test: p=1.0000

mean 47.3 47.2



maximum 93 97

median 68.0 71.0 U test: p=0.5002

mean 70.4 74.7



maximum 84 82




maximum 20 19

median –18.0 3.5 mean –14.5 –1.3 t-test: p=0.1316




MAP [mmHg]



maximum 107.0 93.3




maximum 102.3 104.7




maximum 95.7 107.3




maximum 18.0 29.7




maximum 13.0 32.3








maximum 80.0 76.7

median 61.0 63.2 U test: p=0.5716

mean 61.7 63.1



maximum 104.7 107.3

median 82.7 86.4 U test: p=0.3890

mean 83.1 88.8



maximum 89.7 98.0




maximum 19.0 16.7





Pulse [bpm]



maximum 163 174




maximum 140 183




maximum 138 168




maximum 31 40




maximum 28 32








maximum 102 104

median 82.0 86.0 U test: p=0.3319

mean 80.7 87.5



maximum 145 183

median 104.0 123.5 U test: p=0.0310

mean 108.5 131.5



maximum 130 111




maximum 53 15




BBMDE-0312 BLOOD PRESSURE AND PULSE DURING ANESTHESIA IN PATIENTS WITH INJECTION PAIN Table 14.22 / 1-8





maximum 150 150




maximum 132 143




maximum 130 136




maximum 6 14




maximum 2 20








maximum 90 121

median 84.0 88.5 U test: p=0.2101

mean 82.3 89.6



maximum 132 152

median 102.0 109.5 U test: p=0.3206

mean 103.3 111.0



maximum 92 130




maximum 2 11








maximum 90 85




maximum 70 80




maximum 71 84




maximum 5 4




maximum 1 29








maximum 49 71

median 43.0 44.0 U test: p=0.4921

mean 42.3 45.2



maximum 72 90

median 64.0 67.5 U test: p=0.1630

mean 61.4 68.6



maximum 55 83




maximum –4 25





MAP [mmHg]



maximum 110.0 102.7




maximum 90.7 99.0




maximum 86.7 95.0




maximum 3.4 7.4




maximum –2.0 26.0








maximum 62.7 89.0

median 58.0 59.5 U test: p=0.3206

mean 56.4 60.6



maximum 90.7 105.3

median 76.7 80.4 U test: p=0.2568

mean 75.3 81.7



maximum 65.7 98.7




maximum –2.0 20.4





Pulse [bpm]



maximum 134 173




maximum 122 175




maximum 100 165




maximum 32 24

median –5.0 –3.0 mean 1.3 –4.2 t-test: p=0.4930



maximum 0 47








maximum 75 120

median 65.0 83.0 U test: p=0.0042

mean 67.0 85.3



maximum 122 175

median 109.0 107.0 U test: p=0.5866

mean 102.4 111.9



maximum 85 122




maximum –11 28




BBMDE-0312 OXYGEN SATURATION [%] DURING ANESTHESIA

Table 14.23 / 1-2




maximum 100 100




maximum 100 100




maximum 100 100



Difference T1 – T0 minimum –2 0

maximum 4 6



Difference T2 – T0 minimum 0 0

maximum 4 7




BBMDE-0312 OXYGEN SATURATION [%] DURING ANESTHESIA

Table 14.23 / 2-2



maximum 100 100

median 100.0 99.5 U test: p=0.4320

mean 99.2 99.2



maximum 100 100

median 100.0 100.0 U test: p=1.0000

mean 99.9 99.9



maximum 100 100




maximum 4 5



B. Braun Melsungen AG BBMDE-0312

15. REFERENCE LIST

1. Bryson HM, Fulton BR, Faulds D: Propofol – An update of its use in anaesthesia and conscious sedation. Drugs 50 (3) 513-559, 1995.

2. McCollum JSC, Dundee JW: Comparison of induction characteristics of four intravenous anaesthetic agents. Anaesthesia 41: 995-1000, 1986.

3. Sebel PS, Lowdon JD: Propofol: A new intravenous anesthetic. Anesthesiology 71 (2): 260-277, 1989.

4. Stark RD, Binks SM, Dutka VN, O'Connor KM, Arnstein MJA, Glen JB: A review of the safety and tolerance of propofol. Postgrad Med J 61 (Suppl 3): 152-156, 1985.

5. Alyafi WA, Rangasami J: Reduction of propofol pain – fentanyl vs lidocaine. MEJ Anesthesiol 13 (6): 613-619, 1996.

6. Pang WW, Mok MS, Huang S, Hwang MH: The analgesic effect of fentanyl, morphine, meperidine, and lidocaine in the peripheral veins: A comparative study. Anesth Analg 86: 382-386, 1998.

7. Yokota S, Komatsu T, Komura Y, Nishiwaki K, Kimura T, Hosoda R, Shimada Y: Pretreatment with topical 60% lidocaine tape reduces pain on injection of propofol. Anesth Analg 85: 672-674, 1997

8. Parmar AK, Koay CK: Pain on injection of propofol – A comparison of cold propofol with propofol premixed with lignocaine. Anaesthesia 53: 79-88, 1998.

9. Tan CH, Onsiong MK: Pain on injection of propofol. Anaesthesia 53: 468-476, 1998.

10. Beh T et al: In children, nitrous oxide decreases pain on injection of propofol mixed with lidocaine. Obstetrical and Pediatric Anesthesia, Can J Anesth 49 (10): 1061-1063, 2002.


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