Clinical Study Report Synopsis

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1 Clinical Study Report Synopsis Efficacy and Safety of Long-Term (6 Months) Innohep Treatment Versus Anticoagulation with a Vitamin K Antagonist (Warfarin) for the Treatment of Acute Venous Thromboembolism in Cancer Patients / IN 0901 INT A Phase 3 Study of Subcutaneous Innohep 20,000 anti-xa IU/mL for the Treatment of Venous Thromboembolism (VTE) in Cancer Patients Multi-National, Multi-Centre, 6-Month, Randomised, Active Controlled, Open-Label Study with Blinded Adjudication LEO Pharma A/S Trial ID: IN 0901 INT 23-Apr

2 Trial ID: IN 0901 INT 23-Apr-2015 Page 2 of 8 Clinical Study Report Synopsis Statement Approval Statement, LEO Pharma A/S The following persons have approved this Clinical Study Report on behalf of LEO Pharma A/S using electronic signatures: Biostatistics Medical Department Approval Statement, International Coordinating Investigator The international co-ordinating investigator approves the Clinical Study Report Synopsis by manually signing the International Coordinating Investigator Clinical Study Report Approval Form, which is a separate document adjoined to the Clinical Study Report. The following person has approved this Clinical Study Report Synopsis:, MD, MSc, FRCPC International co-ordinating investigator

3 Trial ID: IN 0901 INT 23-Apr-2015 Page 3 of 8 Trial Registration Number NCT EudraCT Number Title of Trial Efficacy and safety of long-term (6 months) innohep treatment versus anticoagulation with a vitamin K antagonist (warfarin) for the treatment of acute venous thromboembolism in cancer patients / IN 0901 INT. Investigators, MD, MSc, FRCPC,, University of British Columbia, Diamond Health Care Centre, Vancouver, Canada was signatory investigator. Trial Centres This trial was conducted at 164 centres in 32 countries: Argentina (3), Austria (1), Brazil (14), Bulgaria (4), Canada (2), Chile (1), Czech republic (4), Egypt (6), Germany (7), Greece (4), Guatemala (1), India (21), Israel (4), Italy (3), Jordan (1), Republic of Korea (14), Latvia (2), Lebanon (4), Mexico (4), Peru (4), Poland (2), Portugal (2), Romania (6), Russian federation (4), Saudi Arabia (4), Serbia (5), Slovakia (6), South Africa (6), Spain (5), Taiwan, Province of China (5), Thailand (10), and Ukraine (5). Publications Lee AY, Bauersachs R, Janas MS, Jarner MF, Kamphuisen PW, Meyer G, et al. CATCH: a randomised clinical trial comparing long-term tinzaparin versus warfarin for treatment of acute venous thromboembolism in cancer patients. BMC Cancer Jun 13;13(1):284. Bauersachs R on behalf of the CATCH investigators. CATCH a randomised clinical trial comparing long-term tinzaparin versus warfarin for treatment of acute venous thromboembolism in cancer patients. Hematology Reports. 2011;3(s1):13. Lee AY, Bauersachs R, Janas MS, Jarner MF, Kamphuisen PW, Meyer G, Paz-Ares L, Khorana AA, on behalf of the CATCH Investigators. CATCH: A randomized trial comparing tinzaparin versus warfarin for treatment of acute venous thromboembolism (VTE) in cancer patients. J Clin Oncol. 2012;30 suppl: abstr # TPS9149. Araújo A. Cancer and deep venous thrombosis: the purpose of the CATCH clinical trial. Acta Med Port Mar- Apr;26(2):83 [Article available in Portuguese, abstract available in English]. Lee AYY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA, on behalf of the CATCH Investigators. A randomized trial of long-term Tinzaparin, a low molecular weight heparin (LMWH), versus warfarin for treatment of acute venous thromboembolism (VTE) in cancer patients the CATCH study. Blood Dec 5; 124(21): Abstract LBA-2. Khorana AA, Bauersachs R, Kamphuisen PW, Meyer G, Janas MS, Jarner M, et al. on behalf of the CATCH investigators. Clinical predictors of recurrent venous thromboembolism (VTE) in cancer patients from a randomized trial of long-term tinzaparin versus warfarin for treatment: the CATCH study. Abstract accepted for the 2015 ASCO annual meeting. Trial Period date of first enrolment (informed consent signed and CRF started): 30-Aug-2010 date of last completed: 31-May-2014 Development Phase Phase 3 Objectives The primary objective was to assess the efficacy of innohep in preventing the recurrence of venous thromboembolism (VTE) in patients with active cancer who had had an acute VTE episode. Secondary objectives were to: assess the safety of long-term innohep identify clinical risk factors for recurrent VTE and major bleeding assess overall mortality at 6 months identify the possible role of coagulation parameters to predict recurrent VTE or prognosis assess incidence and severity of post-thrombotic syndrome (PTS) assess health-related quality of life (QoL) assess healthcare resource utilisation (analyses of health care resource utilisation not included in the clinical study report will be reported separately)

4 Trial ID: IN 0901 INT 23-Apr-2015 Page 4 of 8 Methodology CATCH was a randomised, active-controlled, multi-national, open-label 6-month clinical trial with blinded adjudication of all efficacy endpoints (i.e. lower limb deep vein thromboses [DVTs] and pulmonary embolism [PE]) and major safety endpoints (i.e. bleeding events, heparin-induced thrombocytopenia [HIT] events, and deaths). CATCH compared the efficacy and safety of extended (6 months) subcutaneous (s.c.) innohep treatment with oral warfarin (with concomitant 5 to 10 days initial treatment with s.c. innohep ) in cancer-associated VTE. The subjects attended the trial centre for up to 11 scheduled visits: the Screening Visit (within 72 hours prior to randomisation), the Randomisation Visit (Visit 1, Day 1), Visit 2 (Day 7), Visit 3 (Day 14), Visits 4 to 8 (Day 30 to Day 150), Visit 9 (Day 180/ End of Treatment) and Visit 10 (30-day post-treatment follow-up). In addition, subjects could be asked to return to the clinic between scheduled visits for urgent assessment of recurrent VTE, bleeding events or adverse events (AEs) (unscheduled visit). All subjects were contacted by the trial site staff by telephone 14 days after each monthly visit (Visits 4-8). The subjects were interviewed using a standardised questionnaire during these telephone contacts in order to assess treatment compliance, concomitant medication(s), recurrent VTE, bleeding events, AEs, and serious adverse events (SAEs). All subjects were followed up for 1 month (30 days) after termination of investigational medicinal product (IMP) for safety, healthcare resource utilisation, QoL, and PTS. Subjects who discontinued IMP, for any reason other than death prior to Day 180 were asked to stay in the trial to be followed up by telephone at the time of the remaining regular scheduled trial visits for assessment of recurrent VTE, survival, QoL up to Day 180, and SAEs (up to 1 month after the last dose of IMP). A stratified randomisation scheme was used that accounted for the following factors: tumour stratum ( Known distant metastasis / No distant metastasis / Haematological malignancy ), geographical region (Western Europe/Eastern Europe/Americas/Asia), and history of VTE (yes/no). Number of Subjects Planned and Analysed In accordance with the first protocol amendment, it was planned to randomise 900 subjects (1000 subjects according to the original clinical study protocol), 450 (500 subjects according to the original clinical study protocol) in each treatment group. All 900 randomised subjects were included in the full analysis set and analysed for efficacy (innohep : 449; warfarin: 451). All 900 randomised subjects were dispensed IMP and were included in the safety analysis set and analysed for safety (innohep : 449; warfarin: 451). 658 subjects were included in the per protocol (PP) analysis set, 351 in the innohep group and 307 in the warfarin group. Diagnosis and Main Criteria for Inclusion This trial enrolled adult subjects ( 18 years or above the legal age of consent) with a diagnosis of active cancer with a histologically or cytologically diagnosed solid tumour or haematological malignancy (evidence of early stage, regional, or metastatic disease). Active cancer was defined as: diagnosed within the past 6 months, recurrent/advanced/metastatic disease, any treatment for cancer during the previous 6 months, or not in complete remission of a chronic haematological malignancy. The subjects had to have symptomatic and objectively confirmed acute proximal lower-limb DVT (anatomically including popliteal, femoral [superficial and common] and iliac [external and common]) and/or PE (located in segmental or larger pulmonary arteries) diagnosed within 72 hours prior to randomisation. Diagnosis of DVT/PE (at randomisation and at recurrence) had to be made by appropriate objective imaging. Other inclusion criteria were: an Eastern Co-operative Oncology Group (ECOG) performance status of 0, 1, or 2 prior to the VTE episode and signed informed consent. Investigational Product, Dose and Mode of Administration, Batch Number Innohep (tinzaparin sodium) 20,000 anti-xa IU/mL was dispensed in syringes of 0.5 ml, 0.7 ml, and 0.9 ml. Dosing: 175 anti-xa IU/kg body weight once daily by s.c. injection. Batch numbers: Complete records have been retained of each batch of each treatment used by each subject but are not presented here in the interest of brevity. Duration of Treatment 6 months (180 calendar days). Post-treatment follow-up period: 1 month.

5 Trial ID: IN 0901 INT 23-Apr-2015 Page 5 of 8 Reference Therapy, Dose and Mode of Administration, Batch Number Warfarin was dispensed as oral tablets of 1 mg, 3 mg, and 5 mg in combination with initial (5-10 days) overlapping s.c. treatment with innohep. Dosing: the dose was adjusted to maintain international normalised ratio (INR) target levels of 2-3. Batch numbers: Complete records have been retained of each batch of each treatment used by each subject but are not presented here in the interest of brevity. Criteria for Evaluation The primary efficacy endpoint was a composite endpoint represented by the time in days from randomisation to the first occurrence of any of the following 5 objectively documented components: symptomatic non-fatal DVTs symptomatic non-fatal PEs fatal PEs incidental proximal DVTs (popliteal vein or higher) incidental proximal PEs (segmental arteries or larger). Secondary efficacy endpoints were the time in days from randomisation to the first occurrence of: the 5 individual components of the composite primary efficacy endpoint a composite endpoint of symptomatic DVT and/or PE, including fatal PE. Results from the central adjudication of events were used for the analyses. Safety endpoints consisted of major and clinically relevant non-major bleeding events, overall mortality, HIT events, other thromboses, clinically significant laboratory data, clinically significant vital signs, and all other AEs/SAEs. Other endpoints were coagulation biomarkers (D-dimer, tissue factor, factor VIII, CRP, and soluble P-selectin), PTS, healthrelated QoL, and healthcare resource utilisation (analyses of health care resource utilisation not included in the clinical study report will be reported separately). Statistical Methods Analysis of the Primary Endpoint All recurrent VTE outcomes confirmed by central adjudication occurring from the time of randomisation to the end of the scheduled 6-month treatment period (including 24 hours after the last dose of IMP) were eligible for the primary efficacy analysis. In the event that the diagnoses made by the local investigator and central adjudication results were discrepant, the central adjudication results were used in the analysis. The primary efficacy endpoint was a composite endpoint represented by the time in days from randomisation to the first occurrence of any of the 5 objectively documented components described above. The statistical comparison was based on the time to the first recurrent VTE event per subject. To correct for competing risks, a cumulative incidence approach was used including the stratification variables as main effects. The competing risks considered in the primary analysis were deaths other than fatal PE. A regression model described by Fine and Gray was used to model the cumulative incidence functions (CIFs) for the two treatment groups (assuming proportionality) in the presence of competing risks and adjusted for the stratification factors. The strata, region, tumour stratum, and history of VTE, were included in the model as main effects, as was the treatment allocation. The estimated subdistribution hazard ratio (SHR) is presented as a measure of relative risk between the two treatment groups (innohep versus warfarin) together with the 95% confidence interval (CI). The test for no treatment effect was conducted as a Wald s test within this model. Analysis of Secondary Efficacy Endpoints The 6 secondary efficacy endpoints were the time in days from randomisation to the first occurrence of the 5 individual components of the composite primary efficacy endpoint and any symptomatic DVT and/or PE, including fatal PE. To examine the consistency of the results between the different components of the primary endpoint, the time to the first occurrence of each of the primary endpoint components or the end of the trial period, whichever occurred first, was analysed separately. In addition, the composite endpoint of the 3 symptomatic components of the primary endpoint comprised a composite secondary endpoint. All secondary endpoints with more than 5 confirmed events were analysed and presented as described for the primary efficacy endpoint. For each time-to-event analysis, the components not defined as the event of interest were considered a competing risk. In case of a statistically significant primary analysis, the p-values for the secondary endpoints were corrected for multiplicity using the Hoechberg method. Analysis of Safety Endpoints The time to death (overall mortality) up to and including Day 180 was assessed in a proportional hazards model including treatment group and the 3 stratification factors as main effects. The hazard ratio (HR) and associated 95% CI is presented. The test for no treatment effect was conducted as a Wald s test within this model. The overall mortality status on Day 180 is summarised by treatment group. The adjudicated primary causes of death are

6 Trial ID: IN 0901 INT 23-Apr-2015 Page 6 of 8 summarised separately by treatment group. Major bleeding was the primary safety outcome. The proportion of subjects with a major bleeding event was compared between the treatment groups using a Chi-square test. Similarly, the proportions of subjects with a clinically relevant nonmajor bleeding event, or trivial bleeding event were compared between the treatment groups using Chi-square tests. The combination of major bleeding events and clinically relevant non-major bleeding events, were also analysed. As for the primary efficacy endpoint, a cumulative incidence approach correcting for competing risks was used to analyse the time to the first major bleeding event. Competing risks were deaths from all causes other than fatal bleeding. Exploratory analyses As an initial screening for risk factors having a potential impact on VTE recurrence or the occurrence of a major or clinically relevant non-major (non-trivial) bleeding event, Fisher s exact test was carried out for each risk factor separately testing the null-hypothesis of no dependence between having a specified risk factor and getting an event. Risk factors resulting in a p- value <0.05 were investigated in the competing risk regression. Fine and Gray s modelling methods were used to estimate the SHR and corresponding 95% CI for selected risk factors to assess their effect on the recurrence of VTE and non-trivial bleeding events when taking account of competing risks. Summary Trial Population 900 subjects were treated (innohep : 449; warfarin: 451) with at least one dose of IMP. Based on the date of End of Trial, the vast majority of the subjects completed the trial on or off treatment: in the innohep group, 57.5% completed at least 173 days in the trial and 35.2% met a primary endpoint or died, and in the warfarin group, 55.9% completed at least 173 days in the trial and 33.0% met a primary endpoint or died. The mean treatment duration was longer in the innohep group (123.6 days; range: days) than in the warfarin group (112.7 days; range: days), i.e. the difference in treatment duration was approximately 10%. The mean age was similar between the innohep group (59.7 years; range: years) and the warfarin group (58.8 years; range: years). More than half the subjects were women (innohep : 58.4%; warfarin: 60.5%). 340 subjects (37.8%) were from Europe (divided into 2 regions: Western Europe n=150; Eastern Europe: n=190), 169 (18.8%) from Americas, and 391 (43.4%) from Asia. A majority of the subjects were Caucasian (50.4%) or Asian (33.8%). The mean body mass index was almost identical in the innohep group (25.3 kg/m 2 ; range: kg/m 2 ) and the warfarin group (25.3 kg/m 2 ; range: kg/m 2 ). The distribution of subjects was similar between the treatment groups within each tumour stratum (54.7% of the subjects had metastatic disease, 34.9% had non-metastatic disease, and 10.4% had haematological disease). The 3 most common types of cancers (the primary site of cancer) were gynaecological (overall 22.6%), lower gastrointestinal (colorectal; overall 13.2%), and lung cancers (overall 11.6%). A majority of the subjects (93.7%) had no history of VTE. A total of 86% of the subjects in the innohep group had a treatment compliance of at least 75% as assessed by the number of dosing days (injection taken according to the subject diary) relative to the number of days on treatment. Compliance in the warfarin group was assessed as the percentage of time that the INR was within the target range (TTR). The overall trial TTR was 47.0%. Efficacy Results All results in this section are based on the full analysis set unless otherwise stated. The 6-month incidence of recurrent VTE was 6.9% in the innohep group versus 10.0% in the warfarin group, similar to the 6-month cumulative incidence of 7.2% in the innohep group versus 10.5% in the warfarin group. The competing risk regression analysis of time to the first event adjusting for region, tumour stratum, and history of VTE resulted in a subdistribution hazard ratio (SHR) for innohep : warfarin of 0.65 (95% CI: ) in favour of innohep, i.e. subjects in the innohep group were 35% less likely relative to subjects in the warfarin group to experience VTE within the first 6 months. Although the primary endpoint did not meet the 5% significance level (p=0.068), the size of this difference is clinically relevant as described in clinical recommendations. The 6-month incidence of recurrent VTE in the PP analysis set was 8.3% in the innohep group versus 12.7% in the warfarin group. The competing risk regression analysis based on the PP analysis set and adjusting for region, tumour stratum, and history of VTE resulted in an SHR of 0.62 (95% CI: ) in favour of innohep (p=0.048), i.e. very similar to that of the primary analysis based on the full analysis set. The 6-month incidence of recurrent non-fatal symptomatic DVT was statistically significantly lower in the innohep group (2.7%) than in the warfarin group (5.3%) with an SHR of 0.48 (95% CI: ; p=0.038). The 6-month incidence of fatal PE (whereof none of those counted in the efficacy analyses was objectively confirmed) was identical in the two treatment groups (3.8% in each group; SHR: 0.96; 95% CI: ; p=0.90).

7 Trial ID: IN 0901 INT 23-Apr-2015 Page 7 of 8 The 6-month incidences of recurrent symptomatic non-fatal PE, recurrent incidental DVT, and recurrent incidental non-fatal PE were all low, not allowing for separate statistical analyses. The pre-planned secondary efficacy analysis of symptomatic VTEs (i.e. symptomatic DVTs, symptomatic non-fatal PEs, and fatal PEs) was in favour of innohep with a 6-month incidence of 6.9% in the innohep group versus 9.5% in the warfarin group (SHR: 0.69; 95% CI: ; p=0.109). Overall, Asia had the highest 6-month incidence of recurrent VTE (10.0%) followed by Americas (9.5%), Eastern Europe (6.3%), and Western Europe (6.0%). The 6-month incidence of recurrent VTE was 4.3% in subjects with haematological disease, 7.0% in those with nonmetastatic malignancy, and highest, 10.2%, in subjects with metastatic malignancy. The 6-month incidence of recurrent VTE by tumour type ranged from 0% in subjects with brain (0 of 13) or breast tumours (0 of 84) to 24.0% (6 of 25) in subjects with hepatobiliary tumours. The 6-month incidence of recurrent VTE was 13.3% (27 of 203) in subjects with gynaecological tumours, which was the most common tumour type in this trial. The competing risk regression of recurrent VTE and risk factors showed that 2 risk factors were associated with an increased risk of VTE: venous compression from mass or adenopathy present at Baseline (SHR: 2.96; 95% CI: ; p<0.001) and hepatobiliary cancer (SHR: 2.91; 95% CI: ; p=0.018). There was a trend of the 6-month incidence of recurrent VTE being higher in the highest Baseline quartile than in the lower quartiles of D-dimer, tissue factor, factor VIII, and CRP (while no specific trend was observed with regard to recurrence of VTE and soluble P-selectin quartile at Baseline). When looking at values available from End of Treatment, there was a trend of the 6-month incidence of recurrent VTE being higher in the highest quartile than in the lower quartiles of D-dimer, tissue factor, CRP, and soluble P-selectin (while this trend was not observed for factor VIII). Safety Results Overall, the safety pattern for innohep in this trial with extended anticoagulation treatment in subjects with cancerassociated thrombosis was as expected and the extended treatment period did not reveal new safety concerns. Bleeding Events were sent to the central adjudication committee for blinded adjudication. The overall incidence of bleeding events (innohep : 25.4%; warfarin: 24.4%), as well as the major bleeding events (innohep : 2.7%; warfarin: 2.4%) were similar between the innohep group and the warfarin group. None of the differences were statistically significant at a 5% significance level. Deaths: In total, 306 subjects died in the 217-day reporting period (trial period [180 days] + the follow-up period [30 days] + the visit window [7 days]); 159 subjects (35.4%) in the innohep group and 147 subjects (32.6%) in the warfarin group. The overall mortality status on Day 180 was 288 deaths in total; 150 subjects (33.4%) in the innohep group and 138 subjects (30.6%) in the warfarin group (one case in the warfarin group was not adjudicated). The deaths occurred evenly distributed throughout the trial and similarly between the treatment groups. The HR of 1.08 indicates that there was no difference in mortality across the 6 months trial period. The causes of death were based on the adjudicated outcome and the distribution was: 36 deaths were related to a VTE (11.3% in the innohep group and 13.9% in the warfarin group), 6 deaths were due to bleeding (2.0% in the innohep group and 2.2% in the warfarin group), 198 deaths were due to progression of cancer (70.0% in the innohep group and 67.9% in the warfarin group), and 47 cases were due to other known cause (16.7% in the innohep group and 16.1% in the warfarin group). The deaths due to other known cause were primarily due to infections (pneumonia and/or sepsis; 38 subjects), while 5 subjects died from nervous system disorders, 3 subjects died of cardiac disorders, and 1 subject died from an anaphylactic shock (after intravenous chemotherapy). HIT: None of the reported suspected cases were confirmed by the adjudication committee to be HIT events. Other SAEs: Overall, the incidence of treatment-emergent SAEs was higher in the innohep group (49.2%) than in the warfarin group (43.2%); whereas the incidence of post-treatment SAEs was lower in the innohep group (13.1%) than in the warfarin group (19.3%). The most common SAE was malignant neoplasm progression (approximately 22% in the innohep group and 18% in the warfarin group including both treatment-emergent and post-treatment SAEs). Fewer subjects in the innohep group than in the warfarin group had an SAE assessed as related to treatment; 1.6% in the innohep group versus 6.2% in the warfarin group. This difference was mainly driven by the higher incidences in the warfarin group of SAEs associated with an abnormal INR value or prolonged prothrombin time. Adverse Events: The majority of subjects had at least one AE during the trial; 87.5% in the innohep group versus 85.4% in the warfarin group. The incidence of the individual AEs varied between the two groups; overall more subjects in the innohep group (19.6%) than in the warfarin group (10.6%) had treatment-emergent malignant neoplasm progression, whereas more subjects in the warfarin group had AEs associated with increased INR (0% in the innohep group versus 33.9% in the warfarin group). The overall intensity of the AEs was similar in the 2 treatment groups and the vast majority of AEs were mild or moderate (approximately 86%). The severe AEs (approximately 14%) were more prominent in the Blood and lymphatic system disorders SOC, the Infections and infestations SOC, the Neoplasms benign, malignant and unspecified SOC, as well as the MedDRA (Medical Dictionary for Regulatory Activities) preferred term deep vein thrombosis. In the innohep group, fewer subjects had AEs related to treatment and fewer of the AEs were related to treatment compared

8 Trial ID: IN 0901 INT 23-Apr-2015 Page 8 of 8 to the warfarin group; 24.7% of the subjects had at least one AE related to treatment and 7.8% of the AEs were related to treatment in the innohep group versus 50.6% of the subjects and 25.4% of the AEs in the warfarin group. This difference is mainly driven by the higher incidences of AEs in the warfarin group related to an abnormal INR value or changes in prothrombin time and AEs related to bleeding. The incidence of subjects who had one or more AEs that led to discontinuation of treatment was similar between the groups (34.5% in the innohep group and 32.2% in the warfarin group). Progression of the cancer disease was the most common AE leading to discontinuation of treatment. Safety by Region: The overall incidence pattern of safety events was similar across the regions, although variations exist. Overall, the incidence of all reported AEs was lower in the Eastern Europe region than in the rest of the regions. Safety by Duration of Exposure: The mean treatment duration and total exposure of IMP was approximately 10% higher in the innohep group than in the warfarin group. Analysing AEs in relation to exposure of IMP, there are fewer AEs per 100 subject-treatment years in the innohep group than in the warfarin group; 1544 versus 1740 per 100 subject-treatment years. The difference is more pronounced for the AEs related to treatment for which the number of AEs per 100 subjecttreatment years was less than one-third in the innohep group (120) compared to the warfarin group (442). For SAEs, the number per 100 subject-treatment years was higher in the innohep group (278) than in the warfarin group (234). Adverse Events of Special Interest in this Patient Population: The incidence of thrombotic events (arterial and/or venous), other than those sent for blinded adjudication, was very low in both groups; 1.6% in the innohep group and 1.8% in the warfarin group. Adverse events related to thrombocytopenia, osteoporosis, serious allergic reactions, hyperkalaemia, overdose, or liver enzymes were analysed separately; overall the incidences were low and there were no clinically relevant differences between the groups. Other Safety Assessments: The development and severity of post-thrombotic syndrome (PTS) were analysed using the Villalta scale. The total mean Villalta scores declined over time with no difference between the two treatment groups. Safety Associated with Investigations: Clinical safety laboratory values, vital signs, or BMI did not give rise to any safety concerns. Quality of Life Results Subjects who stayed on treatment for the full treatment period had a small improvement in EQ-5D and EQ visual analogue scale (VAS) scores, while the opposite was observed for subjects who discontinued the treatment. Among subjects with both Baseline and End of Treatment assessments, the increase in mean EQ VAS score was slightly larger in the innohep group than in the warfarin group, but the difference was small compared to the standard deviations. Conclusions The efficacy data were consistent and robust. The 6-month incidence of recurrent VTE was 6.9% in the innohep group versus 10.0% in the warfarin group, similar to the 6-month cumulative incidence of 7.2% in the innohep group versus 10.5% in the warfarin group. The competing risk regression analysis resulted in a subdistribution hazard ratio (SHR) of 0.65 (95% CI: ) in favour of innohep. Although the primary endpoint did not meet the 5% significance level (p=0.068), the size of this difference is clinically relevant as described in clinical recommendations. Approximately half the cases adjudicated as recurrent VTE were recurrent symptomatic DVTs and the other half were cases of fatal PE (whereof none was objectively confirmed). The incidence of recurrent symptomatic DVT was statistically significantly lower in the innohep group than in the warfarin group with an SHR of 0.48 (95% CI: ; p=0.038), while the incidence of fatal PE was identical in the treatment groups (3.8% in each group; SHR: 0.96; 95% CI: ; p=0.90). Overall, the safety pattern for innohep in this trial with extended anticoagulation treatment in subjects with cancerassociated thrombosis was as expected and the extended treatment period did not reveal new safety concerns. The clinical trial was conducted in compliance with the consolidated clinical study protocol, ICH Good Clinical Practice, the applicable regulatory requirements, and the Declaration of Helsinki as adopted by the 18 th World Medical Association General Assembly, 1964, and subsequent amendments.

9 IN 0901 INT Clinical Study Report Synopsis EudraCT no Apr English ELECTRONIC SIGNATURES Electronic signature made within edoc LEO by LEO Pharma A/S employees or employees of any LEO Pharma A/S affiliate located anywhere in the world, are to be considered to be legally binding equivalent of traditional handwritten signatures. Signed by Meaning of Signature Server Date (dd-mmm-yyyy HH:mm GMT Z), Clinical 28-Apr :53 GMT+02 Development and Safety Approval Biostatistics Approval 29-Apr :04 GMT+02