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EMA Pediatric Web SynopsisProtocol A1501050 29 November 2011 Final

PFIZER INC.

These results are supplied for informational purposes only.Prescribing decisions should be made based on the approved package insert.

For publications based on this study, see associated bibliography.

PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Vfend®/Voriconazole

PROTOCOL NO.: A1501050

PROTOCOL TITLE: An Open Label, Non-Comparative Protocol for the Emergency Use of Voriconazole in Patients with Life-threatening, Invasive Mycoses who are failing on Currently Available Antifungal Agents

Study Centres: Information not available

Study Initiation Date and Primary Completion or Completion Dates: 30 January 2003 to 15 February 2006

Phase of Development: Information not available

Study Objective: To provide emergency use of voriconazole to patients with life-threatening, invasive fungal infections who were failing to respond to or who were intolerant of currently available antifungal agents.

METHODS

Study Design: This study was an open label, non-comparative protocol for the emergency use of voriconazole in subjects with life-threatening, invasive fungal infections, who were failing to respond to or who were intolerant of currently available antifungal agents. The maximum total duration of voriconazole therapy was dependent on the efficacy and tolerability the subject to treatment with voriconazole.

Number of Subjects (Planned and Analyzed): Given the nature of this study, the anticipated number of emergency subjects was not defined. A total of 89 subjects were enrolled for treatment with voriconazole. Of the 89 subjects enrolled, 76 subjects were treated and analysed for safety.

Diagnosis and Main Criteria for Inclusion: Subjects who demonstrated definitive invasive fungal infection and received at least 7 days of pertinent antifungal therapy at appropriate dose levels for their current episode of infection within 4 weeks prior to study entry were considered for this study.

Subjects had to demonstrate signs and/or symptoms of failure or intolerance to the currently available and marketed anti-fungal agents. Failure was defined as evidence of deterioration in clinical status or the development of new or worsening diagnostic imagining, serological 09

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and/or mycological findings. Intolerance was defined as one or more of the following symptoms: fever >40°C (grade III), severe or life-threatening symptoms (grade III-IV), intractable nausea/vomiting (grade IV) or deterioration in renal function (increase in serum creatinine ≥2.5 mg/dL). In addition, these subjects did not have access to or had not met the criteria for any trials that were currently ongoing for voriconazole.

Study Treatment: Voriconazole was initially administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by 4 mg/kg every 12 hours. Oral voriconazole was given at a dose of 200 mg every 12 hours. Determination of dosage route (intravenous or oral) was based on the Investigator’s assessment. Dose regimes for both intravenous and oral administration could be adjusted according to various body weights and tolerance. Total duration of treatment was determined by the Investigator and the clinical monitor after assessing the subject’s response to treatment.

Voriconazole for oral use: 50mg tablets; Voriconazole for Intravenous administration: lyophile in vials containing 200mg of voriconazole.

Efficacy Evaluations: Final end of study status and global response at the end of the treatment were measured.

Safety Evaluations: Adverse events (AEs) were reported and safety laboratory tests (total bilirubin, aspartate aminotranferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], and creatinine) were measured.

Statistical Methods: All subjects enrolled in the study were included in the subject data listings. Continuous data were summarised using descriptive statistics (n, mean, standard deviation, median, minimum, and maximum). Categorical variables were summarised by counts and percent. Core safety data were summarised using the standard format for safety data reporting. No statistical testing was performed in this study.

The statistical information presented in this report is based on information gathered from study subjects for the duration of their treatment with compassionate supply of voriconazole. Due to the nature of the study, many data points could not be retrieved from Investigators in spite of a rigorous effort for data collection and were unavailable at database lock.

RESULTS

Subject Disposition and Demography: A total of 89 subjects (54 male, 33 female, and 2 of unknown gender) with ages ranging from 1 year to 87 years were enrolled for treatment with voriconazole in this study. Enrolment into this emergency use protocol was to be permitted for patients having completed a previous clinical trial with the drug. However, most subjects enrolled (50 confirmed) had not participated in a previous clinical trial with voriconazole.

A total of 76 subjects were treated with voriconazole for a median (range) duration of 84.0 (4-1145) Days. Due to the nature of the study, data collection was largely dependent on the Investigators’ responsiveness to data requests, and for some of these subjects, this was incomplete.09

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A summary of the final subject status is presented in Table 1. Of the 76 subjects who were treated, 34 (44.4%) subjects completed the study. Ten (13.2%) subjects discontinued due to insufficient clinical response, and 6 (7.9%) subjects discontinued due to various AEs. Six (7.9%) subjects died while being treated. Twenty subjects (26.3%) discontinued for various reasons such as “other reasons” (7 subjects), termination by Sponsor (6 subjects), the subject’s own decision (4 subjects). Two other subjects were lost to follow-up and 1 subject was discontinued due to laboratory abnormalities. For the remaining 13 subjects, the final status in the study was not known.

Table 1. Summary of Final Subject Status

Final Status Number (%) of SubjectsStudy completed 34 (44.7)Study not completed

Insufficient clinical response 10 (13.2)Adverse event 6 (7.9)Laboratory abnormalities 1 (1.3)Subject died 6 (7.9)Lost to follow-up 2 (2.6)Other 7 (9.2)Subject decision 4 (5.3)Subject terminated by Sponsor 6 (7.9)Unknown 13

Unknown final status was not included in percentages.

Reasons for treatment discontinuation are presented in Table 2.

Table 2. Reasons for Treatment Discontinuation

Reason for Discontinuation Number (%) of SubjectsSubjects discontinued 42 (55.3)Subject died 6 (7.9)Related to study drug 22 (28.9)

Adverse event 5 (6.6)Laboratory abnormalities 1 (1.3)Lack of efficacy 10 (13.2)Other 6 (7.9)

Not related to study drug 14 (18.4)Adverse event 1 (1.3)Other 7 (9.2)Subject defaulted 6 (7.9)

The primary site of infection for the majority of subjects (38) was pulmonary. The other primary sites of infection are detailed in Table 3.

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Table 3. Primary Infection Site

Infection Site Number (%) of SubjectsPulmonary 38 (43.7)Cerebral 6 (6.9)Hepatic/hepatosplenic 2 (2.3)Bone 3 (3.5)Skin 2 (2.3)Sinus 4 (4.6)Other 32 (36.8)Unknown 2

Unknown infection site at baseline was not included in percentages.

The summary of underlying diseases is presented in Table 4. For 27 subjects, the treated infection was associated with an unspecified underlying hematological condition. Twelve (12) subjects had infections associated with organ transplant (10 subjects) and bone marrow or stem cell transplants (1 subject each) and 8 subjects had infections associated with HIV/AIDS. A further 8 subjects had infections associated with high dose corticosteroid treatment or immunosuppressive therapy and 31 subjects had infections associated with other diseases or conditions than those described above.

Table 4. Summary of Underlying Diseases

Disease/ Condition Number (%) of SubjectsAllogeneic bone marrow transplant 1 (1.2)Allogeneic peripheral stem cell transplant 1 (1.2)Other hematological condition 27 (31.4)Advanced HIV infection/ AIDs 8 (9.3)Solid organ transplant 10 (11.6)High dose corticosteroid/immunosuppressive therapy 8 (9.3)Other 31 (36.1)Unknown 1

Unknown underlying disease or condition at baseline was not included in percentages.HIV=human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome.

Safety Results: A summary of all causality treatment-emergent AEs by body system is presented in Table 5. Forty-five (45) subjects experienced at least one treatment-emergent AE. There were 199 treatment-emergent AEs reported in total.

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Table 5. Treatment‑Emergent Adverse Events by Body System (All Causalities)

Number of Subjects: Number(%) of SubjectsEvaluable for adverse events 76With adverse events 45 (59.2)Discontinued due to adverse events 12 (15.8)

Number of Subjects with Adverse Events by Body System

Body as a whole 21 (27.6)Cardiovascular 8 (10.5)Digestive 15 (19.7)Hemic and lymphatic 6 (7.9)Metabolic and nutritional 18 (23.7)Musculoskeletal 4 (5.3)Nervous 11 (14.5)Respiratory 16 (21.1)Skin and appendages 8 (10.5)Special senses 10 (13.2)Urogenital 1 (1.3)

Of the 76 subjects evaluable for AEs, 28 subjects reported a total of 75 treatment-related AEs(for a total of 53 distinct terms). Nine AEs were severe. Seven (7) subjects discontinued due to treatment-related AEs. This information included data up to 7 days after the last dose of the study drug.

A total of 28 subjects (36.8%) who received voriconazole experienced treatment-emergent, treatment-related AEs. Of these subjects, 2(2.6%) experienced SAEs and 7 (9.2%) experienced severe AEs. Seven (9.2%) subjects discontinued the study due to treatment-related AEs and 6 (7.9%) had their dose reduced or were temporarily discontinued due to treatment-related AEs.

One subject experienced a worsening skin rash that was serious and was considered to be caused by the study drug resulting in a temporary interruption of treatment. Another subject had a serious increase in liver enzymes that was deemed caused by the study drug resulting in permanent discontinuation of the voriconazole.

Six (6) subjects died prior to completion of treatment. The following diseases were reported for 1 subject each and were associated with the subject’s death: Progressive pulmonary blastomycosis; overwhelming sepsis; septic shock; brain death secondary to histoplasma meningitis; blood aspiration secondary to bilateral ethmoidectomy; refractory acute myeloid leukemia.

A total of 44 serious AE (SAE) case reports were filed. Some of these reports consisted ofmultiple events. A listing of the SAEs reported is presented in Table 6.

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Table 6. Listing of Serious Adverse Events

Item Serious Adverse Event

1 Hemoptysis/hemoptysis/haemoptysis Pseudomonas lung infection (lung infection pseudomonal / lung infection

pseudomonal/lung infection pseudomonal2 Right lower lobe pneumonia (lobar pneumonia/lobar pneumonia/lobar pneumonia)

3 Worsening cryptosporidiosis (cryptosporidiosis/cryptosporidiosis / gastroenteritis cryptosporidial)

4 Worsening maculopapular rash(maculopapular rash/maculopapular rash/rash maculo-papular)

5 Sepsis (sepsis/sepsis/sepsis)

6 Heart failure (heart failure/heart failure/cardiac failure)

7 Rhinal mucormycosis (mucormycosis / mucormycosis / murcomycosis) Septum perforation (nasal septum perforation / nasal septum perforation / nasal septum

perforation) Nasal cavity mass (mass/mass/mass)

8 Sepsis (sepsis/sepsis/sepsis) General edema (edema/edema/edema) Respiratory failure (respiratory failure / respiratory failure / respiratory failure)

9 Worsening hemoptysis (hemoptysis / hemoptysis / haemoptysis)

10 Blood aspiration (aspiration tracheal abnormal/aspiration tracheal abnormal/aspiration

tracheal abnormal) Subject presently unconscious (loss of consciousness / loss of consciousness / loss of

consciousness)

11 Klebsiella pneumonia (klebsiella pneumonia/klebsiella pneumonia/pneumonia klebsiella) Cytomegelous virus (cytomegalovirus infection/ cytomegalovirus

infection/cytomegalovirus infection)

12

Septic shock (septic shock/septic shock/septic shock) Multi organ failure (multiorgan failure/multiorgan failure/multi-organ failure Hypovolemic shock (hypovolemic shock / hypovolemic shock / hypovolaemic shock) Upper digestive hemorrhage (upper gastrointestinal hemorrhage/upper gastrointestinal

hemorrhage / upper gastrointestinal haemorrhage13 Persistent sepsis (sepsis/sepsis/sepsis)

14 Worsening pulmonary aspergillosis (pulmonary aspergillosis/pulmonary aspergillosis / bronchopulmonary aspergillosis)

15 Overwhelming septic shock (septic shock/septic shock/septic shock) Multi-organ failure (multi-organ failure / multi-organ failure / multi-organ failure)

16 Anaphylactic reaction (anaphylactic reaction / anaphylactic reaction/anaphylactic reaction)

17 Progression of disseminated histoplasmosis / meningitis (disseminated histoplasmossis /

disseminated histoplasmossis/histoplasmosis disseminated)

18 Allergic reaction to contrast dye/optiray 320 (allergic reaction / allergic reaction / hypersensitivity)

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Item Serious Adverse Event

Table 6. Listing of Serious Adverse Events (continued)

Item Serious Adverse Event19 Acute myeloid leukemia relapse (acute myeloid leukemia aggravated/acute myeloid

leukemia aggravated/accute myeloid leukaemia)20 Progressive fungal pneumonia (pneumonia fungal/pneumonia fungal/pneumonia fungal)

21

Hyperkalemia/hyperkalemia/hyperkalaemia Congestive heart failure/congestive heart failure/cardiac failure congestive Renal failure/renal failure/renal failure Elevated liver enzymes (elevated liver enzymes/elevated liver enzymes/hepatic enzyme

increased)22 Pneumonia (pneumonia/pneumonia/pneumonia)

23 Gastric perforation (gastric perforation / gastric perforation/gastric perforation) Septic shock (septic shock/septic shock/septic shock)

24 Hemoptysis (hemoptysis/hemoptysis/haemoptysis)

25a

26 Pulmonary deterioration (pulmonary disorder/pulmonary disorder/lung disorder)

27 Relapse of acute myeloid leukemia (acute myeloid leukemia recurrent/acute myeloid leukemia recurrent/acute myeloid leukaemia)

28 Progression of Ewing`s sarcoma (Ewing`s sarcoma/Ewing`s sarcoma/Ewing`s sarcoma)

29 Post menopausal bleeding (postmenopausal bleeding/postmenopausal bleeding/ postmenopausal haemorrhage)

30

Progression of Hodgkin`s disease (Hodgkin`s disease/Hodgkin`s disease/Hodgkin`s disease)

Elevated alkaline phosphatase (alkaline phosphatase increased/alkaline phosphatase increased/blood alkaline phosphatase increased)

Central nervous system thrombosis (thrombosis/thrombosis/thrombosis) Paralysis (paralysis/paralysis/paralysis) Aphasia (aphasia/aphasia/aphasia) Decreased level of consciousness (depressed level of consciousness/depressed level of

consciousness/depressed level of consciousness) Possible retinal detachment (retinal detachment/retinal detachment/retinal detachment) Possible vitreous hemorrhage (vitreous hemorrhage/vitreous hemorrhage/vitreous

haemorrhage)31 Acute pseudomembraneous colitis (pseudomembranous colitis/pseudomembranous colitis/

colitis pseudomembranous)32 Post menopausal bleeding (postmenopausal bleeding/postmenopausal bleeding/

postmenopausal haemorrhage)33 Progressive AML (acute myeloid leukemia/acute myeloid leukemia/acute myeloid

leukaemia)34 Relapse rsv (respiratory syncytial virus infection/respiratory syncytial virus infection/

respiratory syncytial virus infection)35 Progression of aspergillosis (progression of aspergillosis/aspergillosis/aspergillosis)0901

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Item Serious Adverse EventPage 2 of 3a

In the original clinical study report, no entry was made to Case Number 25.

Table 6. Listing of Serious Adverse Events (continued)

Item Serious Adverse Event36 Recurrent postmenopausal bleeding (postmenopausal bleeding/postmenopausal

bleeding/postmenopausal haemorrhage)37 Progressive AML(acute myeloid leukaemia aggravated/acute myeloid leukaemia

aggravated / acute myeloid leukaemia)38 Pneumonia (pneumonia/pneumonia/pneumonia)

39 Hemoptysis/hemoptysis/hemoptysis/haemoptysis Left sided cva (cva/cva/cerebrovascular accident) Septic/cardiogenic shock (septic shock/septic shock/septic shock)

40 Clostridium difficile (Clostridium difficile infection / Clostridium difficile infection / clostridial infection

41 Fever (fever/fever/pyrexia)

42 Urosepsis (urosepsis/urosepsis/urosepsis)

43 Megalovirus retinitis (cytomegalovirus retinitis / cytomegalovirus retinitis / cytomegalovirus chorioretinitis

44 Liver abscess (bartonella infection/liver abscess / liver abscess / liver abscess)

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Monitoring of liver function was conducted for safety evaluation. Overall, no clinically significant changes were noted in total bilirubin, alanine aminotransferase, asparatate aminotransferase, alkaline phosphatease, or creatinine values on Day 10 of treatmentcompared with baseline.

Efficacy Results: Voriconazole was administered in this study to treat a variety of infections involving a large number of different infection sites. The most common primary infection sites reported that were also solitary infection sites were: pulmonary (38 subjects), cerebral (6 subjects), and sinus (4 subjects) (refer to Table 3). However, if more than one infection site was reported, distinction of the primary infection site was not possible. All non-singular infection sites were recorded as “Other” infection sites and these also included pulmonary, sinus, or cerebral infections. Overall, the most frequently identified infection sites were: pulmonary (47), sinus (11) cerebral (9), and skin (4).

At Day 10 of treatment, most subjects were deemed to have stabilised (61%). A considerable number were deemed to have responded either partially (28.6%) or completely (5.2%).

At the final clinical assessment visit, partial responders increased to 43% and complete responders amounted to 19.8%.

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Global response complete response rates were highest for subjects with underlying hematological conditions (40%) and advanced HIV/AIDS related infections (25%). However, only one subject with a solid organ transplant (11%) had a complete global response

A summary of the global response at the end of the treatment is presented in Table 7. Overall, the global response for the entire study showed that 26.7% of treated subjects had a complete response, 36.0% of subjects responded partially, 18.7% of subjects had stable infections while 18.7% had a failed treatment outcome.

Table 7. Summary of Global Response at the End of Treatment

Global Response Number (%) of SubjectsComplete Response 20 (26.7)Partial Response 27 (36.0)Stable 14 (18.7)Failure 14 (18.7)Unknown 1

CONCLUSIONS: Protocol A1501050 was implemented to provide access to treatment for subjects with life-threatening, invasive fungal infections who were failing to respond to or intolerant of currently available antifungal agents. The statistical information presented in this report is based on information gathered from these subjects for the duration of their treatment with compassionate supply of voriconazole. Due to the nature of the study, many data points could not be retrieved from Investigators in spite of a rigorous effort for data collection and were unavailable at database lock.

Of the 89 subjects who participated in the study, 34 (44.4%) subjects completed the study. Ten (13.2%) discontinued due to insufficient clinical response and 6 (7.9%) due to various AEs. Six (7.9%) subjects died while being treated. Twenty subjects (26.4%) discontinued for various reasons such as “other reasons” (7 subjects), termination by Sponsor (6 subjects), the subject’s own decision (4 subjects). Two other subjects were lost to follow-up and 1 subject was discontinued due to laboratory abnormalities. For the remaining 13 subjects, the final status in the study was not known.

A majority of the cases involved a pulmonary infection (47 subjects). Less frequent but relatively common infections included sinus, cerebral, and skin infections.

Overall, 26.7% of subjects had a complete response and 36.0% of subjects responded partially. Subjects who were considered to have a failed global response amounted to 18.7% and global response for another 18.7% of the subjects was not reported.

Voriconazole was safely used in this study. However, 1 subject experienced a worsening skin rash that was serious and was considered to be caused by the study drug resulting in a temporary interruption of treatment. Another subject had a serious increase in liver enzymes that was deemed caused by the study drug resulting in permanent discontinuation of the voriconazole.

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Of the 76 subjects evaluable for AEs, 28 subjects reported a total of 75 treatment-related AEs (for a total of 53 distinct terms). Nine AEs were severe and 7 subjects discontinued due to treatment-related AEs.

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