IN0901INT

LEO Pharma A/S

Industriparken 55, Ballerup, Denmark,

Clinical Trial Disclosure Manager, LEO Pharma A/S, +45 44945888, ctr.disclosure@leo-pharma.com

Clinical Trial Disclosure Manager, LEO Pharma A/S, +45 44945888, ctr.disclosure@leo-pharma.com

No

No

No

Final

31 May 2014

Yes

31 May 2014

Yes

31 May 2014

No

The primary objective of the study is to assess the efficacy of Innohep® in preventing the recurrence of Venous Thromboembolism (VTE) in patients with active cancer who have had an acute Venous Thromboembolism (VTE) episode.

Frequent visits and telephone contacts.

30 Aug 2010

No

Yes

Portugal: 7

Romania: 28

Slovakia: 31

Spain: 34

Austria: 10

Bulgaria: 20

Czech Republic: 16

Russian Federation: 32

Poland: 5

Serbia: 20

Germany: 20

Greece: 12

Ukraine: 24

Italy: 13

Latvia: 14

Argentina: 12

South Africa: 30

Brazil: 75

Chile: 5

Guatemala: 7

Mexico: 24

Peru: 46

Egypt: 43

India: 148

Jordan: 2

Korea, Republic of: 73

Lebanon: 29

Saudi Arabia: 12

Canada: 6

Israel: 18

Taiwan: 16

Thailand: 68

900

210

0

0

0

0

0

0

579

312

9

6-month treatment period (overall period)

Randomised - controlled

This was an open-label trial. All efficacy endpoints (lower limb DVTs and PEs) and major safety endpoints (bleeding events, HIT events, and causes of death) were adjudicated blindly by the independent adjudication committee (IAC)

Yes

Innohep® (tinzaparin sodium)

Solution for injection in pre-filled syringe

Subcutaneous use

Innohep® (tinzaparin sodium) 20,000 anti-Xa IU/mL was dispensed in syringes of 0.5 mL, 0.7 mL, and 0.9 mL. The dose was 175 anti-Xa IU/kg body weight once daily by s.c. injection. The duration of the treatment was 6 months (180 calendar days).

Warfarin

Tablet

Oral use

Wafarin 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®. The dose was adjusted to maintain international normalised ratio (INR) target level 2-3.

Innohep®

Warfarin

Innohep®

Warfarin

The primary efficacy endpoint is 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 deep vein thrombosis (DVT), symptomatic non-fatal pulmonary embolism (PE), fatal pulmonary embolism (PE), incidental proximal deep vein thrombosis (DVT) (popliteal vein or higher), incidental proximal pulmonary embolism (PE) (segmental arteries or larger). All recurrent VTE outcomes were adjudicated blindly by a independent adjudication committee. 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).

Primary

All recurrent VTE outcomes occurring from the time of randomisation up until day 180 regardless of whether the patient was on or off IMP-treatment (including 24 hours after the last dose of IMP) were eligible for the primary efficacy analysis.

Competing Risk Regression of Recurrent VTE (Full analysis set 900 subjects): The competing risk regression analysis adjusting for region, tumour stratum, and history of VTE

Innohep® v Warfarin

900

Pre-specified

Per protocol analysis set (658 subjects): The competing risk regression analysis adjusting for region, tumour stratum, and history of VTE

Innohep® v Warfarin

900

Pre-specified

0.62

2-sided

Sensitivity analysis: The stratified competing risk analyses of recurrent VTE including a combination of all stratification factors or 1 covariate at a time.

Innohep® v Warfarin

900

Pre-specified

Stratified competing risk analysis: A proportional hazards regression analysis (treating deaths other than fatal PEs as censored) was performed with treatment group, region, tumour stratum, and history of VTE as main effects

Innohep® v Warfarin

900

Pre-specified

0.66

2-sided

6 subjects (innohep®: 3; warfarin: 3) experienced a symptomatic PE whereof 5 were bilateral; 1 of the symptomatic PEs in the warfarin group was not a first event and was thus not counted in the efficacy analyses. 5 subjects with symptomatic PE (innohep®: 3; warfarin: 2) are counted in the efficacy analyses. The 6-month incidence of recurrent symptomatic non-fatal PE was low, not allowing for a meaningful competing risk regression analysis.

Secondary

The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.

Adjudication of cause of death classified a death due to PE as: PE confirmed by autopsy; PE confirmed by objective testing/imaging; sudden and unexplained death, which could not be attributed to a documented cause and for which PE was the most probably cause.

Secondary

The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.

full analysis set

Innohep® v Warfarin

900

Pre-specified

0.96

2-sided

1 subject in the warfarin group experienced an incidental DVT, which is counted in the efficacy analyses. The 6-month incidence or recurrent incidental DVT was low with only 1 case occurring in the warfaring group, not allowing for a meaningful competing risk regression analysis.

Secondary

The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.

2 subjects (innohep®: 1; warfarin: 1) had an incidental proximal PE whereof 1 in the innohep® group was not a first event and thus not counted in the efficacy analyses. 1 incidental non-fatal PEs in the warfarin group is counted in the efficacy analyses. The 6-month incidence of recurrent incidental PE was low with only 1 case occurring in the warfarin group, not allowing for a meaningful competing risk regression analysis.

Secondary

The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.

The composite endpoint of the 3 symptomatic components of the primary endpoint

Secondary

The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.

Competing risk regression analysis of the secondary efficacy analysis of symptomatic events (i.e. symptomatic DVTs plus symptomatic non-fatal PEs plus fatal PEs) adjusting for region, tumour stratum, and history of VTE.

Innohep® v Warfarin

900

Pre-specified

0.69

2-sided

36 subjects (innohep®: 12; warfarin: 24) who experienced 41 symptomatic DVTs are counted in the efficacy analyses. 5 of the confirmed DVTs were bilateral events (innohep®: 2; warfarin: 3) and only count once in the efficacy analyses.

Secondary

The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.

Competing risk regression analysis of symptomatic non-fatal DVT adjusting for region, tumor stratum, and history of VTE

Innohep® v Warfarin

900

Pre-specified

0.48

2-sided

Bleeding events were sent to the central adjudication committee for blinded adjudication. Bleeding was defined in accordance with the International Society of Thrombosis and Haemostasis (ISTH). Major bleeding criteria were defined as any event meeting any one or more of the following: bleeding with a fall in haemoglobin of >2 g/dL; bleeding requiring a transfusion of >2 units of red cells or whole blood; bleeding in a critical location, i.e. intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, or pericardial; bleeding causing death. All non-major bleeding events (i.e. bleeding events that did not meet the criteria for major bleeding above) that required any medical or surgical intervention, including unscheduled contact (visit or telephone call) with a physician, or (temporary) cessation of IMP were classified as "clinically relevant non-major bleeding".

Secondary

From the first dose of IMP and included in the analysis up to 24 hours following the last administration of IMP (i.e. more than 5 x the half-life of innohep®)

Innohep® v Warfarin

900

Pre-specified

Innohep® v Warfarin

900

Pre-specified

Innohep® v Warfarin

900

Post-hoc

Bleeding events were sent to the central adjudication committee for blinded adjudication. Bleeding was defined in accordance with the International Society of Thrombosis and Haemostasis (ISTH). Major bleeding criteria were defined as any event meeting any one or more of the following: bleeding with a fall in haemoglobin of >2 g/dL; bleeding requiring a transfusion of >2 units of red cells or whole blood; bleeding in a critical location, i.e. intracranial, intraspinal, intraocular, retroperitoneal,intraarticular, or pericardial; bleeding causing death.

Secondary

Bleeding events were recorded througout the trial, starting from the first dose of IMP and included in the analysis up to 24 hours (i.e. more thatn 5 x the half-life of innohep®) following the last administration of IMP.

Innohep® v Warfarin

900

Pre-specified

The diagnosis of heparin-induced thrombocytopenia (HIT) reported as AEs required both clinical and laboratory diagnostic confirmation that was consistent with standard practice including the use of the Warkentin 4T score. The IMP treatment was permanently discontinued if HIT was confirmed. Laboratory analyses performed for confirmation of HIT were performed locally and had to be confirmed at the central laboratory. The subject was treated according to the site practice and followed up. All cases of HIT occurring up to 1 month after the last dose of IMP were sent to the blinded independent adjudication committee (IAC) for adjudication. No statistical analyses for this end point (as there were no confirmed events).

Secondary

The period from the first dose of IMP up to 1 month after the last dose of IMP.

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 and associated 95% CI is presented. The test for no treatment effect was conducted as a Wald’s test within this model. All deaths were adjudicated and cause of death was classified in the following way: 1) due to PE, 2) due to cancer progression, 3) due to bleeding or due to 4) other specific cause (as specified by the IAC)

Secondary

The overall mortality status on Day 180

Innohep® v Warfarin

900

Pre-specified

1.08

2-sided

Other objectively confirmed thromboses, i.e. other than objectively confirmed VTE, were collected throughout the trial and included e.g. upper limb DVT, incidental subsegmental PE, portal or renal vein thrombosis, as well as arterial thrombosis, e.g. myocardial infarction (MI), stroke, or systemic embolic events.

Secondary

The period from the first dose of IMP until day 180 regardless of whether the patient was on or off IMP treatment (including 24 hours after the last dose of IMP).

Innohep® v Warfarin

900

Pre-specified

Vital signs include: systolic and diastolic blood pressure and heart rate. If an investigator found a vital sign to be of clinical significance, this was to be reported as an AE. In a population of subjects with cancer, and in addition different cancer diagnoses and stages, the vital signs are likely to fluctuate due to the underlying disease. Hence, analyses were made for change from Baseline to End of Treatment, only. The results from these analyses did not give reason to perform any further analyses. Two AEs associated with vital signs were reported in the innohep® group; blood pressure increased and blood pressure fluctuation – both were mild and not related to treatment.

Secondary

Vital signs were assessed at all visits, except at Visit 3 (Week 2) and Visit 10 (Month 7)

In a population of subjects with cancer, and in addition with different cancer diagnoses and stages, the values of liver enzymes are likely to fluctuate due to the underlying disease and treatment regimens. Hence, analyses were made of change from Baseline to End of Treatment, only. The results from these analyses did not give reason to perform any further analyses. If an investigator found a laboratory result to be of clinical significance, this was to be reported as an AE. No subject discontinued treatment due to liver enzyme elevation.

Secondary

Clinical laboratory safety parameters were assessed every month

The development and severity of post-thrombotic syndrome (PTS) were analysed using the Villalta scale. PTS was assessed after diagnosis of the initial VTE at Baseline; therefore, the Baseline Villalta score reflects signs and symptoms of both the initial VTA as well as any previous VTE(s). Consequently, the Baseline Villalta score does not reflect the presence of absence of PTS. The villalta scores are given for the completers. The total mean Villalta score declined (improved) in both groups during the trial. At End of Treatment, 398 subjects in the innohep® group and 409 in the warfarin group had no or mild PTS, whereas 15 and 18 subjects had moderate PTS, and 17 versus 9 had severe PTS, respectively.

Secondary

From the first dose of IMP until completion of the 30-day follow-up visit for subjects who completed treatment

The EQ-5D is a brief questionnaire designed to measure health status. The 5-item descriptive portion addresses 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with respondents indicating 1 of 3 possible responses for each dimension. The second portion, EQ VAS, is a single item (0 to 100) visual analogue scale (VAS), on which 0 corresponds to ‘the worst health you can imagine’ and 100 corresponds to ‘the best health you can imagine’. The VAS is used to report overall health status and offers a simple method for obtaining a self-rating of current health status. Overall, the health status levels were similar between the treatment groups both at Visit 1 and End of Treatment.

Secondary

The health related QoL was assessed at Baseline, at all monthly visits, at the End of Treatment Visit and at the Post-Treatment Follow-Up Visit.

Percentage of subjects with blood transfusion

Secondary

From the first dose of IMP and up to 30 days following the last administration of IMP

Percentage of subjects with adverse events including serious adverse events

Secondary

The period from the first dose of IMP up to 24 hours after the last dose of IMP. Serious adverse events were collected up to 30 days following the last dose of IMP.

The period from the first dose of IMP up to 24 hours after the last dose of IMP. Serious-adverse events were collected up to 30 days following the last dose of IMP.

16.0

Innohep®

Warfarin