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abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis ‐ which is part of the clinical study report ‐ had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non‐approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim.

Boehringer Ingelheim BI Trial No.: 1160.102 Post Marketing Surveillance Study Report Page 6

Name of company/Marketing Authorisation Holder: Boehringer Ingelheim

Tabulated PMS Study Report

Synopsis No.:

Name of finished product: Pradaxa®

Name of active ingredient: Dabigatran etexilate mesilate BIBR 1048 MS

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Report date: 15 MAY 2013

Trial No. / U No.: 1160.102 / c05079154-04

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Date of trial: 20 SEP 2010 – 26 JUL 2012

Date of revision (if applicable):

Proprietary confidential information 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.

This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

Title of study: Cohort study in prevention of venous thromboembolic events after orthopaedic surgery in patients treated with Pradaxa®

Principal/Coordinating Investigator:

There was no coordinating or principal investigator.

Study sites: 45 public and private centres in France

Publication (reference): Not yet published

Clinical phase: IV

Objectives: The primary objective of this study was to evaluate the incidence of clinical venous thromboembolic (VTE) events in patients treated with Pradaxa® (dabigatran etexilate) after orthopaedic surgery (THR or TKR) in real-life conditions of use; the incidence of major bleeding events (MBE) was considered as the primary co-variable. The secondary objectives were: • to describe the demographic, medical and surgical characteristics of

patients included in this study, • to evaluate the actual conditions of use of Pradaxa® (dabigatran etexilate)

in real-life practice (respect of the indication, posology, treatment duration according to the SPC)

• to determine the impact on the organisation of care for thromboprophylaxis with an oral anticoagulant such as Pradaxa® during the hospital stay and, subsequently, in community care.




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Methodology: Observational, non-comparative, prospective, multicentre, national study

No. of patients:

planned: 1600

actual: Treatment: [Pradaxa®] entered: 1676; treated: 1675; analysed: 1675

Diagnosis and main criteria for inclusion:

All consecutive patients undergoing surgery for total hip replacement or total knee replacement in one of the participating centers who gave informed consent and who did not present contraindications to treatment with Pradaxa®

Test product(s): Pradaxa® (dabigatran etexilate)

dose: In this study the administered treatment was based on usual practice in a real-life setting, with no randomized assignment

mode of admin.: Oral

Comparator product(s): N.A.

dose:

mode of admin.:

Duration of treatment: As recommended in the SmPC: Elective total knee replacement: 10 days; Elective total hip replacement: 28-35 days. The individual treatment duration was decided by the investigator

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Criteria for evaluation:

Efficacy The primary endpoint was the occurrence of symptomatic clinical venous thromboembolic events (primary variable) and major bleeding events (MBEs) (primary covariate). Symptomatic VTE events were defined as:

• Symptomatic, proximal or distal deep vein thrombosis (DVT). Complementary examinations were performed to confirm the diagnosis (venous compression ultrasonography or venography).

• Symptomatic pulmonary embolism (PE). Complementary tests were performed to confirm the diagnosis (pulmonary ventilation-perfusion scan and chest X-ray or pulmonary angiography or spiral CT).

Major bleeding events were defined as: • Any fatal hemorrhage; • Any overt bleeding greater than could be expected, combined with a loss

of hemoglobin ≥ 2 g/dL or requiring transfusion ≥ 2 packed red blood

cells (PRBC); • Any symptomatic retroperitoneal, intracranial, intraocular or intraspinal

haemorrhage; • Any bleeding requiring treatment cessation or reoperation.

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Efficacy (continued):

The definition for MBEs was in accordance with the ISTH recommendations (International Society on Thrombosis and Haemostasis)The incidence of symptomatic VTE and MBEs were also evaluated in sub-groups defined by type of orthopedic surgery (THR or TKR), type of anesthesia (general or not) and age (< 75 years or ≥ 75 years). The secondary endpoints were the following:

• Patient characteristics, grouped into demographic, medical and surgical characteristics:

• The actual conditions of use of Pradaxa® in real-life practice were evaluated using the following criteria:

• The impact of Pradaxa® on the organization of care was based on the following criteria evaluated

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Safety: The analyzes of related adverse events used the treatment-emergent concept, which meant that all events occurring during the treatment period (from 1st dose to 72 hours after the last dose) or any event that began before the first dose but worsened during the treatment period were considered as occurring during treatment. Events occurring 72 hours after the last dose were considered as occurring in the post-treatment period. These events were analyzed descriptively by type of surgery and by subgroup defined by type of anesthesia and age.

Statistical methods: The analyses in this observational study were all descriptive and presented with confidence intervals and p values according to the statistical methods used. The confidence interval was based on the Clopper-Pearson exact method. It was intended to include and follow-up for three months a maximum of 1600 patients treated with 220 mg or 150 mg of Pradaxa® in this observational study. It was planned to stop the recruitment when the 1600 patients had been recruited, provided that a minimum number of 160 patients were recruited in the defined sub-groups. The two main sub-groups were defined by the type of surgery: TKR or THR. These sub-groups were further divided into sub-groups defined by:

• the type of anesthesia: general or not; • the age of the patient: < 75 years or ≥ 75 years.

In addition, analyses were performed for the following sub-groups: • sex: male or female; • annual number of procedures in the study center: > 500; 300-500; <300.

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SUMMARY – CONCLUSIONS: Efficacy results:

Demographic and baseline characteristics

A total of 1676 consecutive patients undergoing either total hip replacement (THR; N=929) or total knee replacement (TKR; N=747) were recruited to this observational, non-comparative, prospective cohort study in France.

The study centers were randomly selected to obtain a representative sample of centres performing THR and TKR surgery in France. There were three groups of centers, defined by their activity (annual number of THR and TKR procedures >500, 300-500, <300) with a pre-defined number of centers in each group in order to obtain a representative sample of French healthcare facilities. All the active centers recruited more patients than planned with an overall 105% of the target number of patients being recruited (1676 vs. 1600). Only 38 patients were recorded in the register for eligible non-enrolled patients; they were similar to those included except they tended to be older (74.6 (±9.0) vs. 68.7 (±10.9)). The main reasons for non-enrolment were an underlying medical condition or treatment (N=39; 47.6%) and patient refusal (N=17; 20.7%).

The percentage of patients who had THR surgery was lower than estimated using the data from the PMSI 2006 database: 56% vs. 66% and the percentage of patients who had TKR surgery was higher than estimated: 44% vs. 33%. In addition, the percentage of patients aged ≥75 years was lower than estimated:

31% vs. 40%.

The differences seen between the study population and the expected population, based on the PMSI data should be interpreted cautiously since the data in the PMSI does not correspond to a population of patients treated with Pradaxa® and accepting to participate in an observational study.

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Efficacy results (continued):

Efficacy In a real-life setting in the PETRA study, the patients who underwent TKR had a higher incidence of symptomatic DVT than the patients in the 1160.85 study (2.0% vs. 1.5%). The rates of proximal DVT were similar (0.3% vs. 0.2%) but the rate of distal DVT was higher in PETRA than in 1160.85 (1.6% vs. 1.2%). The rate of symptomatic non-fatal PE was on a low level but slightly higher in PETRA than in 1160.85 (0.5% vs. 0.1%).The observed incidence of PE (0.5%) was equal to the estimated upper limit of the 95% CI in the RE-MODEL study (no PEs occurred in RE-MODEL 220 mg / day arm). However the observed incidence of DVT in patients who underwent TKR in the PETRA study (2.0%) was higher than the estimated upper limit of the 95% CI in the RE-MODEL study (0.8%). The subgroup analyses did not show any differences in the observed incidences. The patients included in PETRA were older than in the other trials. They were also generally sicker with a higher incidence of comorbidities and a higher percentage of patients had had a previous VTE compared with those in the other trials and history of VTE is a known risk factor for recurrent VTE [R09-2237]. In PETRA 25 % of the patients with a VTE had a history of VTE. In the general study population only 6.7% of the patients had a history of VTE. The incidences for DVT (all, distal and proximal) were comparable between PETRA and 1160.85 for patients undergoing THR (0.4% versus 0.5% respectively). In the real-life setting in the PETRA study, for the patients who underwent THR, the observed incidences of DVT and PE are compatible with the results from RE-NOVATE I for patients who received 220mg of Pradaxa®. The incidences as well as the estimated upper limits of the 95% CI were lower than or equal to the estimated upper limit of the 95% CI in the RE-NOVATE I study (220 mg / day) (0.4% versus 0.6% respectively). The subgroup analyses did not show any differences in the observed incidences. There seemed to be a higher incidence of symptomatic DVT in the 150mg group of RE-NOVATE I compared with PETRA: 0.4% v. 1.0%.

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Name of active ingredient: Dabigatran etexilate mesilate

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In 2012, the ACCP guidelines for the prevention of VTE in patients undergoing orthopaedic sugery estimated that the cumulative post-surgical rate of non-fatal symptomatic VTE in patients undergoing orthopedic surgery, up to 35 days post-surgery, was 4.3% in the absence of prophylaxis and 1.8% in patients treated with LMWH [R12-2362 ; P12-02756]. This rate in patients treated with LMWH is compatible with the results from PETRA. In the FOTO study, the rate of symptomatic VTEs was reported to be 1.3% and 2.8% in patients undergoing THR and TKR, with an overall rate of 1.8% [R09-2242]. Although this study reported data from 2003, it is considered as a reference for France, and the results from PETRA, also performed in France, are compatible with these results.

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The patients who underwent THR in PETRA had a higher rate of MBEs compared with that in the 1160.85 study (1.7% vs.0.7%), but patients aged >75 years were excluded from the 1160.85 study and in the PETRA study, the observed incidence of MBEs was higher in patients aged ≥ 75 years than

younger (2.9% vs. 1.2%). The observed incidence of MBEs is compatible with the results from RE-NOVATE I for patients who received 220mg of Pradaxa®. The incidences as well as the estimated upper limits of the 95% CI were lower than or equal to the estimated upper limit of the 95% CI in the RE-NOVATE study (220 mg / day). The analyses of the subgroups defined by type of anesthesia, age, sex and center activity did not show any differences in the observed incidences. The rate of MBEs observed in PETRA study was consistent to those observed in other studies (varying from 0.7 in 1160.85 study to 2.0 in RE-NOVATE 220 mg/day. In the PETRA study, the observed incidence of MBEs for patient who underwent TKR, was higher in patients aged ≥ 75 years than younger (1.3% vs

1.0%). There was a slightly higher rate of MBEs in PETRA compared with that in the 1160.85 study (1.1% vs.0.7%), but patients aged >75 years were excluded from the 1160.85 study. The observed incidence of MBEs in patients who underwent TKR in PETRA was consistent with that reported for RE-MODEL taking into consideration the 95% CI, The incidences as well as the estimated upper limits of the 95% CIs were lower than or equal to the estimated upper limit of the 95% CI in the RE-MODEL study.

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Actual Conditions of PRADAXA ® use Although there was over 25% of data missing (mainly due to the lack of ALAT dosage at the pre-surgery stage), a majority of patients undergoing THR (93%) and TKR (94%) were treated in accordance with the SmPC of Pradaxa®. None of the patients in either group were receiving concomitant hydroquinidine, fewer than 1% had severe renal failure (<30 ml/min) and fewer than 9% had a creatinine clearance between 30 and 50 ml/min. In addition, fewer than 6% of the patients had an elevated ALAT level (THR: 4.5% between 2 and 3 times the normal upper limit and 1.3% between 3 and 5 times; TKR: 3.8% between 2 and 3 times the normal upper limit; 1.3% between 3 and 5 times and a patient had a ALT level close to 10 times the normal upper limit). For over 95% of the patients the delay between the end of surgery and initiation of Pradaxa® treatment was between 1h to 24h. The mean time between end of surgery and Pradaxa® initiation was 7 hours in both type of surgeries. More than 70% of patients in THR group and 60 % in TKR one have started Pradaxa® after 4hours. In many patients an initial treatment with an injectable anticoagulant (LMWH) was followed by Pradaxa® the day after surgery reflecting adherence to usual practice and local protocols: 88% (TKR) and 87% (THR) of the patients who started Pradaxa® at least one day after the surgery took LMWH before initiation of Pradaxa®. The daily dose of Pradaxa® prescribed was also generally in accordance with the recommendations (THR: 83.1%; TKR: 81.3%).

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The most frequent unrespects were: to take the 220 mg dosage instead of 150 mg recommended (5.0% of the patients undergoing THR and 7.2% of the patients undergoing TKR); to take the 150 mg dosage instead of 220 mg recommended (3.3% of the patients undergoing THR and 2.7% of the patients undergoing TKR); to start Pradaxa® at the second day after the surgery (2.5% of the patients undergoing THR and 3.3% of the patients undergoing TKR) and to start with the higher dose the day of the surgery (1.6% of the patients undergoing THR and only one patient undergoing TKR). For the patients who underwent TKR, the duration of treatment was longer than recommended in the SmPC. Fewer than 2% of the patients undergoing TKR were prescribed Pradaxa® for 10 days, which is the recommended duration. The bimodal distribution showed that 12% of patients received treatment for between 11 and 15 days and 56% of the patients received treatment for between 26 and 40 days.

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In 2003 and considered as a reference for France, another observational, prospective, cohort study in France in consecutive patients undergoing either THR or TKR reported that the mean duration of anticoagulant treatment was 35.6 days for patients undergoing TKR [R09-2242]. In a randomized, non-inferiority trial in France 857 patients were randomized to short (7±2 days) or long (35±5 days) anticoagulant treatment [R13-2477]. The results suggest that VTE risk can persist beyond 7 days, particularly in patients with asymptomatic distal DVT. Thus, in the updated SFAR guidelines, published in 2011, the recommended treatment duration for both TKR is 35 days [P12-00236]. In PETRA, coherent with these guidelines, over 60% of the patients were treated for between 11 and 35 days. For the patients who underwent THR, the distribution of the duration of treatment was not bimodal. A total of 43.3% of the patients received treatment for between 28 and 35 days in accordance with the recommendations in the SmPC. In addition, 32.8% of the patients received treatment for between 36 and 42 days in accordance with the 2005 guidelines from the SFAR. The mean duration of treatment (33.3 ± 10.4 days) is in accordance with the SmPC and coherent with the 2011 SFAR guidelines. In PETRA the median compliance with Pradaxa® prescription was 100% for patients undergoing both type of surgery. A recent study in France assessed the adherence to Pradaxa® after hospital discharge in a prospective cohort study using an electronic pill counter [P12-04533]. The overall adherence in the 56 patients was found to be 98.1% (3 188/3 246 capsules taken correctly); the adherence declined over time, but never went below 97.1%. These results are compatible with the results from PETRA.

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Impact on healthcare organization at hospital and in community care The median duration of the patients’ hospital stay in the study was shorter than

that estimated from the PMSI 2011: 8.1 days vs. 10 days for THR and 8.3 days vs. 9 days for TKR. At discharge from the surgery ward, less than 10% of the patients were transferred to another ward in the same hospital. Only a few patients were prescribed platelet count blood tests at discharge. During the study follow-up, very few patients were re-hospitalized or had consultations in addition to the usual follow-up consultations.

Safety results: During the study the incidence rates of MBEs were consistent with those reported in RCTs. There were no major concerns in terms of incidence of treatment-emergent SAEs. Overall, 6 (0.6%) and 17 (2.3%) of the patients in the THR and TKR groups, respectively, had at least one treatment-emergent serious adverse events related to treatment. The most frequent type of events was vascular disorders, that affected 4 (0.4%) and 15 (2.0%) patients in the THR and TKR groups, respectively. Overall seven patients, five from the THR group and two from the TKR group, died. Six of them were over 75 years old and three of them had history of cancer. For four of the seven fatal cases, death is near the end of treatment (next day) and 3 patients died well after discontinuation of treatment. The deaths of six patients were judged to be unrelated to treatment with Pradaxa® and one was judged as being possibly related.

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