RIVET - Retrospective Cohort Study on the Risk of Venous Thromboembolism

Study Overview
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Brief Summary
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The risk of venous thromboembolism (VTE) associated with the use of chlormadinone acetate (CMA) compared to the gold-standard progestin levonorgestrel (LNG) as component of combined oral contraceptives (COC) is currently unknown. The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommended a pooled analysis of four prospective cohort studies carried out by the Berlin Center for Epidemiology and Health Research (ZEG Berlin) in order to clarify whether CMA-containing COCs carry a different VTE risk compared to LNG-containing COCs.

Detailed Description
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This study is designed as a retrospective cohort study. ZEG Berlin conducted several large prospective cohort studies on the risk of VTE associated with the use of hormonal contraceptives. Four of these studies included a substantial number of women using CMA/EE or LNG/EE-containing COCs. For this study, the data on CMA/EE and LNG/EE from the following four prospective cohort studies are combined: 1) EURAS-OC/LASS 2) INAS-OC 3) INAS-SCORE and 4) INAS-FOCUS. Participants will be identified retrospectively from a pooled dataset which comprises four large, controlled, prospective, non-interventional active surveillance studies that focused on the risk of VTE associated with the use of combined oral contraceptives. All data were prospectively collected by ZEG Berlin and follow the EURAS/INAS study design. Inclusion and exclusion criteria, the method of patient recruitment and follow-up as well as research methods were similar across studies. The EURAS-OC/LASS study was conducted in Europe only; the other three studies are transatlantic studies that include subjects from both Europe and the United States of America. This analysis is specifically designed to assess the risk of VTE associated with the use of COCs containing CMA/EE compared to LNG/EE.

Official Title
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Retrospective Cohort Study on the RIsk of VEnous Thromboembolism Associated With the Use of Combined Oral Contraceptives Containing Chlormadinone Acetate/Ethinylestradiol and Levonorgestrel/Ethinylestradiol

Conditions
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Venous Thromboembolism

Participation Criteria
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Eligibility Criteria
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Inclusion: female, aged 15 to 49 years, participation in one of the 4 observational studies conducted between 2000 and 2019 (LASS/EURAS-OC, INAS-OC, INAS-SCORE, INAS-FOCUS), COC new user (starters, switchers, and re-starters), applied COCs: CMA/EE or LNG/EE. Exclusion of women with a personal history of VTE.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Users of Chlormadinone Acetate (CMA) combined with Ethinylestradiol (EE)<br>CMA/EE users are defined as aged 15 to 49 years Participation in one of the 4 observational studies conducted between 2000 and 2019 (LASS/EURAS-OC, INAS-OC, INAS-SCORE, INAS-FOCUS) COC new user (starters, switchers, and re-starters) | |
| Users of Levonorgestrel (LNG) combined with Ethinylestradiol (EE)<br>LNG/EE users are defined as aged 15 to 49 years Participation in one of the 4 observational studies conducted between 2000 and 2019 (LASS/EURAS-OC, INAS-OC, INAS-SCORE, INAS-FOCUS) COC new user (starters, switchers, and re-starters) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The risk of venous thromboembolic events (VTE) in the cohort of users of combined oral contraceptives (COCs) containing 2 mg CMA/30 µg EE compared to 0.15 mg LNG/30 µg EE. | VTE risk of users of CMA 2mg / EE 30µg compared to the VTE risk of users of LNG 0.15 mg / EE 30µg. | VTEs will be identified during the follow-up intervals, typically scheduled every 6 - 12 months, with a maximum follow-up of 10 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the risk of venous thromboembolic events stratified by: COC user type, age and BMI |  | During the follow-up intervals, typically scheduled every 6 - 12 months, with a maximum follow-up of 10 years. | 
| To assess the risk of VTE in the sub-cohort of users of COCs containing CMA compared to LNG both combined with ≤30 µg EE. |  | During the follow-up intervals, typically scheduled every 6 - 12 months, with a maximum follow-up of 10 years. | 
| To characterize the baseline risk of users of the two formulations (lifetime history of co-morbidity, prognostic factors for VTE, co-medication, socio-demographic and life¬style data). |  | During the follow-up intervals, typically scheduled every 6 - 12 months, with a maximum follow-up of 10 years. |