Evaluation of AVE5026 in the Prevention of Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy (SAVE-ONCO)
The primary objective was to compare the efficacy of once daily subcutaneous injections of Semuloparin sodium (AVE5026) with placebo in the prevention of venous thromboembolism [VTE] in cancer patients at high risk for VTE and who were undergoing chemotherapy.
The secondary objectives were to evaluate the safety of Semuloparin sodium (AVE5026), to document Semuloparin sodium (AVE5026) exposures, to try identifying a metagene predictor of VTE and to assess the survival status at one year in this population.
Drug: Semuloparin sodium
Drug: Placebo (for semuloparin)
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|Official Title:||A Multinational, Randomized, Double Blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AVE5026 in the Prevention of Venous Thromboembolism (VTE) in Cancer Patients at High Risk for VTE and Who Are Undergoing Chemotherapy|
- Percentage of Participants Who Experienced Venous Thromboembolism Event [VTE] or VTE-related Death [ Time Frame: From randomization up to 3 days after last study drug injection ] [ Designated as safety issue: No ]
VTE included any symptomatic Deep Vein Thrombosis [DVT] of lower or upper limbs and any non-fatal Pulmonary Embolism [PE] as confirmed by a Central Independent Adjudication Committee [CIAC] after review of compression ultrasound or venography for DVT, ventilation/perfusion lung scan, pulmonary angiogram or spiral computer tomography lung scan for PE.
VTE-related death included fatal PE and unexplained deaths without confirmatory autopsy. Any sudden death could be classified as fatal PE by the CIAC unless diagnostic test results strongly indicated an alternative diagnosis".
- Time-to-first Occurrence of VTE or VTE-related Death (Cumulative Incidence Function) [ Time Frame: From randomization up to 3 days after last study drug injection ] [ Designated as safety issue: No ]Participants alive and not having experienced VTE were right censored at last study drug injection plus 3 days. In order to correct for competing risks (Deaths other than VTE-related death), a model of cause-specific hazards was used to estimate the Cumulative incidence Function with Prentice non-parametric estimator.
- Percentage of Participants who required the initiation of curative anticoagulant or thrombolytic treatment after VTE assessment [ Time Frame: From randomization up to 3 days after last study drug injection ] [ Designated as safety issue: No ]Initiation of curative anticoagulant or thrombolytic treatment after VTE assessment was defined from investigator's answer to the question "was the subject treated for VTE?" asked after diagnostic tests for suspected VTE and after lung imaging test for tumor evaluation.
- Percentage of Participants Who Experienced Clinically Relevant Bleedings [ Time Frame: From first study drug injection up to 3 days after last study drug injection ] [ Designated as safety issue: Yes ]
Clinically Relevant Bleedings included overt bleedings classified by the CIAC as:
- "major" (fatal, in a critical area/organ, causing a drop in hemoglobin ≥2 g/dL or requiring transfusion ≥2 units of blood)
- "clinically relevant non-major" (requiring medical intervention and not meeting criteria for major bleeding).
- Overall survival [OS] [ Time Frame: From randomization up to 1 year after randomization or 7 months following randomization of the last participant, whichever came first ] [ Designated as safety issue: No ]
Survival status was collected for all participants either one year after randomization, or at the study end date, (ie, 7 months following randomization of the last patient), whichever came first.
OS was defined as the time from date of randomization to date of death due to any cause. Participants alive were censored at last date of contact that they were known to be alive.
- Platelets Count: Percentage of Participants With Potentially Clinically Significant Abnormalities [PCSA] [ Time Frame: From first study drug injection up to 3 days after last study drug injection ] [ Designated as safety issue: Yes ]
PCSA are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review.
Thresholds for platelet counts were defined as follows:
- Platelets count <50 Giga/L;
- Platelets count ≥50 and <100 Giga/L;
- Liver Function: Percentage of Participants With Potentially Clinically Significant Abnormalities [PCSA] [ Time Frame: From first study drug injection up to 3 days after last study drug injection ] [ Designated as safety issue: Yes ]
Thresholds were defined as follows:
- Alanine Aminotransferase [ALAT] >3 Upper Normal Limit [ULN];
- Total Bilirubin [TB] >2 ULN;
- ALAT >3 ULN and TB >2 ULN;
Cases with ALAT >3 ULN and TB >2 ULN (not necessarily concomitant) were evaluated by blinded independent adjudicator to determine if they met Hy's law criteria.
|Study Start Date:||June 2008|
|Study Completion Date:||November 2010|
|Primary Completion Date:||November 2010 (Final data collection date for primary outcome measure)|
Semuloparin sodium 20 mg once daily until change in chemotherapy regimen
Drug: Semuloparin sodium
0.4 mL solution in ready-to-use 0.5 ml pre-filled syringe
Other Name: AVE5026
Placebo Comparator: Placebo
Placebo (for semuloparin) once daily until change in chemotherapy regimen
Drug: Placebo (for semuloparin)
0.4 mL solution in ready-to-use 0.5 ml prefilled syringe strictly identical in appearance but without active component
Randomization had to take place just prior to the first study drug injection (randomization ratio 1:1).
The study period per participant was variable depending on the duration of chemotherapy. It included:
- a screening period up to 3 weeks,
- a double-blind treatment period,
- a follow-up period of 1 month.
Study end date was at the latest 7 months following the randomization of the last participant (6 months treatment and 1 month follow-up).
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|Study Chair:||Alexander Turpie, MD||HHS-General Hospital, Hamilton, Canada|
|Principal Investigator:||Giancarlo Agnelli, MD||University of Perugia, Italy|