Ignite Creation Date:
2024-05-06 @ 7:56 PM
Last Modification Date:
2024-10-26 @ 3:17 PM
Study NCT ID:
NCT06186271
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-01-03
First Post:
2023-12-15
Brief Title:
International Active Surveillance Study Safety of Estrogen Estetrol E4 Contraceptive Study INAS-SEECS
Sponsor:
Center for Epidemiology and Health Research Germany
Organization:
Center for Epidemiology and Health Research Germany
Study Overview
Official Title:
International Active Surveillance Study Safety of Estrogen Estetrol E4 Contraceptive Study INAS-SEECS
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
INAS-SEECS
Brief Summary:
The combined oral contraceptive COC containing estetrol E4 and drospirenone DRSP E4DRSP is a novel oral contraceptive containing a fixed dose of E4 142 mg and DRSP 3 mg The proposed study will address post-market requirements for E4DRSP under section 505o in response to the Food and Drug Administration FDA request
The primary objective of the study is to characterize and compare the risks of E4DRSP with EEDRSP and E4DRSP with a pooled cohort of users of EELNG EENETA and EENGM combinations non-DRSP-containing COCs in a study population of actual users of these preparations under routine clinical practice The main clinical outcome of interest is VTE
The primary objective of the study is to characterize and compare the risks of E4DRSP with EEDRSP and E4DRSP with a pooled cohort of users of EELNG EENETA and EENGM combinations non-DRSP-containing COCs in a study population of actual users of these preparations under routine clinical practice The main clinical outcome of interest is VTE
Detailed Description:
Rationale and background The combined oral contraceptive COC containing estetrol E4 and drospirenone DRSP E4DRSP is a novel oral contraceptive containing a fixed dose of E4 142 mg and DRSP 3 mg E4 is a natural estrogen only produced during pregnancy by the fetal liver When combined with the progestin DRSP ovarian activity is suppressed and there is less impact on hepatic parameters and hemostasis in comparison to combinations of ethinyl estradiol EE and levonorgestrel LNG or EE and DRSP The E4DRSP combination has now received marketing authorization in multiple locations including the United States of America USA The proposed study will address post-market requirements for E4DRSP under section 505o in response to the Food and Drug Administration FDA request
Two co-primary comparisons will be conducted regarding the risk of venous thromboembolism VTE and arterial thromboembolism ATE new users of E4DRSP vs non-DRSP COCs comprising LNG norethisteronenorethindrone acetate NETA and norgestimate NGM in combination with EE and E4DRSP vs other DRSP-containing products EEDRSP among women of reproductive age using COCs primarily for contraceptive reasons An adequate number of obese women in the US population will be included for analysis The study will be adequately powered to rule out a 20-fold increase in the risk of VTE for both the E4DRSP vs non-DRSP COCs and the E4DRSP vs EEDRSP COCs analyses
Research question and objectives The primary objective of the study is to characterize and compare the risks of E4DRSP with EEDRSP and E4DRSP with a pooled cohort of users of EELNG EENETA and EENGM combinations non-DRSP-containing COCs in a study population of actual users of these preparations under routine clinical practice The main clinical outcome of interest is VTE Secondary objectives include measuring the occurrence of unintended pregnancy assessing the risk of ATE deep venous thrombosis DVT of the lower extremities and pulmonary embolism PE describing the drug utilization pattern and describing the baseline risk for VTE and ATE
Study design The INAS-SEECS study is a comparative prospective active surveillance study that follows three cohorts The cohorts consist of new users starters and restarters of hormonal contraceptives and focus on two co-primary comparisons E4DRSP versus EEDRSP and E4DRSP versus non-DRSP COCs The study uses a non-interventional approach to provide comprehensive information on these treatments in a routine clinical practice setting Study participants will be enrolled via an international network of COC-prescribing health care professionals HCPs and followed up for two years All outcomes of interest will be captured by direct contact with the study participants Reported outcomes of interest will be validated via attending physicians andor relevant source documents The classification of outcomes of interest into confirmed and not confirmed will be verified by blinded independent adjudication
Population Approximately 68100 study participants 22700 E4DRSP 22700 EEDRSP and 22700 EELNG EENETA and EENGM users will be recruited via a network of COC-prescribing HCPs in the USA All new users starters and restarters with at least two months break prescribed E4DRSP EEDRSP EELNG EENETA or EENGM who are willing to participate may be eligible for enrollment in the study The distribution of body mass index BMI categories will be monitored during the recruitment period and if necessary a quota will be introduced However women who have given birth six weeks before treatment starts will be excluded from the study Participants with a prior cancer diagnosis less than six months and a prior VTE Medical history of VTE at study entry and those using anticoagulants will be excluded from the primary analysis of VTE However they will be considered in the sensitivity analyses
Variables The variable to determine the primary endpoint is the occurrence of a new VTE during follow-up Two co-primary comparisons will be investigated between E4DRSP versus EEDRSP and between E4DRSP versus non-DRSP COC users Variables to determine the secondary endpoints include the occurrence of ATE DVT of the lower extremities PE and unintended pregnancies Variables to characterize the baseline risk profile of users are baseline population characteristics including BMI and smoking status socio-economic factors concomitant medication and reproductive contraceptive and medical histories
Data sources The INAS-SEECS is a field study that entails exposure to COCs and the occurrence of clinical outcomes of interest by completing questionnaires at baseline study entry and follow-up at 6 12 18 and 24 months post-baseline in addition to potential confounding factors and potential effect modifiers Study participants will be sent a reminder email at three and nine months to enhance the accuracy of self-reported information Medical confirmation of the occurrence of a clinical outcome of interest will be sought from the attending HCP andor study participant eg diagnostic report discharge letter
Study size The sample size calculation is based on an assumed incidence rate of nine VTE per 10000 women-years WY for EEDRSP and nine VTE per 10000 WY for EELNG EENETA and EENGM A total of 68100 women 22700 E4DRSP users 22700 EEDRSP users and 15000 EELNG users plus 7700 EENETA and EENGM users will be recruited within three years and followed up for two years considering treatment adherence treatment stoppingswitching and lost-to-follow-up LTFUdropout at a rate of 20 Sample size calculations show that approximately 109000 WY of observation is statistically sufficient power80 α0025 one-sided allocation rate 11 to exclude a 20-fold VTE risk for E4DRSP users compared to users of EEDRSP and for E4DRSP users compared to users of non-DRSP COCs ie EELNG EENETA and EENGM
Data analysis The final analyses will include both an as-treated AT and an intention-to-treat ITT analysis All eligible women will be assigned to the ITT and AT population at baseline Only women with follow-up information will be considered for longitudinal analysis Women who never started their prescribed baseline medication will be considered in the ITT analysis but excluded from the AT analysis Population characteristics eg socio-economic factors parameters of reproductive contraceptive history and medical history will be summarized descriptively and used to estimate the probability of treatment differences A Marginal Structural Cox Model MSM with Inverse Probability Weighting IPW of treatment and censoring will be applied for the primary analysis Hazard ratios for the VTE risk will be provided with corresponding 95 confidence intervals Non-Inferiority of E4DRSP will be concluded if the upper confidence limit for the point estimate of the adjusted VTE hazard ratio HRVTE is below the predefined non-inferiority limit of HRni2 for both comparisons HR for E4DRSP vs EEDRSP AND E4DRSP vs non-DRSP COCs is less 20 If non-inferiority of E4DRSP could be demonstrated superiority to EEDRSP or non-DRSP COCs will be subsequently evaluated
Milestones The INAS-SEECS study is expected to start in 122023 after the FDA approval of the protocol The final study report will be available in 122029
Two co-primary comparisons will be conducted regarding the risk of venous thromboembolism VTE and arterial thromboembolism ATE new users of E4DRSP vs non-DRSP COCs comprising LNG norethisteronenorethindrone acetate NETA and norgestimate NGM in combination with EE and E4DRSP vs other DRSP-containing products EEDRSP among women of reproductive age using COCs primarily for contraceptive reasons An adequate number of obese women in the US population will be included for analysis The study will be adequately powered to rule out a 20-fold increase in the risk of VTE for both the E4DRSP vs non-DRSP COCs and the E4DRSP vs EEDRSP COCs analyses
Research question and objectives The primary objective of the study is to characterize and compare the risks of E4DRSP with EEDRSP and E4DRSP with a pooled cohort of users of EELNG EENETA and EENGM combinations non-DRSP-containing COCs in a study population of actual users of these preparations under routine clinical practice The main clinical outcome of interest is VTE Secondary objectives include measuring the occurrence of unintended pregnancy assessing the risk of ATE deep venous thrombosis DVT of the lower extremities and pulmonary embolism PE describing the drug utilization pattern and describing the baseline risk for VTE and ATE
Study design The INAS-SEECS study is a comparative prospective active surveillance study that follows three cohorts The cohorts consist of new users starters and restarters of hormonal contraceptives and focus on two co-primary comparisons E4DRSP versus EEDRSP and E4DRSP versus non-DRSP COCs The study uses a non-interventional approach to provide comprehensive information on these treatments in a routine clinical practice setting Study participants will be enrolled via an international network of COC-prescribing health care professionals HCPs and followed up for two years All outcomes of interest will be captured by direct contact with the study participants Reported outcomes of interest will be validated via attending physicians andor relevant source documents The classification of outcomes of interest into confirmed and not confirmed will be verified by blinded independent adjudication
Population Approximately 68100 study participants 22700 E4DRSP 22700 EEDRSP and 22700 EELNG EENETA and EENGM users will be recruited via a network of COC-prescribing HCPs in the USA All new users starters and restarters with at least two months break prescribed E4DRSP EEDRSP EELNG EENETA or EENGM who are willing to participate may be eligible for enrollment in the study The distribution of body mass index BMI categories will be monitored during the recruitment period and if necessary a quota will be introduced However women who have given birth six weeks before treatment starts will be excluded from the study Participants with a prior cancer diagnosis less than six months and a prior VTE Medical history of VTE at study entry and those using anticoagulants will be excluded from the primary analysis of VTE However they will be considered in the sensitivity analyses
Variables The variable to determine the primary endpoint is the occurrence of a new VTE during follow-up Two co-primary comparisons will be investigated between E4DRSP versus EEDRSP and between E4DRSP versus non-DRSP COC users Variables to determine the secondary endpoints include the occurrence of ATE DVT of the lower extremities PE and unintended pregnancies Variables to characterize the baseline risk profile of users are baseline population characteristics including BMI and smoking status socio-economic factors concomitant medication and reproductive contraceptive and medical histories
Data sources The INAS-SEECS is a field study that entails exposure to COCs and the occurrence of clinical outcomes of interest by completing questionnaires at baseline study entry and follow-up at 6 12 18 and 24 months post-baseline in addition to potential confounding factors and potential effect modifiers Study participants will be sent a reminder email at three and nine months to enhance the accuracy of self-reported information Medical confirmation of the occurrence of a clinical outcome of interest will be sought from the attending HCP andor study participant eg diagnostic report discharge letter
Study size The sample size calculation is based on an assumed incidence rate of nine VTE per 10000 women-years WY for EEDRSP and nine VTE per 10000 WY for EELNG EENETA and EENGM A total of 68100 women 22700 E4DRSP users 22700 EEDRSP users and 15000 EELNG users plus 7700 EENETA and EENGM users will be recruited within three years and followed up for two years considering treatment adherence treatment stoppingswitching and lost-to-follow-up LTFUdropout at a rate of 20 Sample size calculations show that approximately 109000 WY of observation is statistically sufficient power80 α0025 one-sided allocation rate 11 to exclude a 20-fold VTE risk for E4DRSP users compared to users of EEDRSP and for E4DRSP users compared to users of non-DRSP COCs ie EELNG EENETA and EENGM
Data analysis The final analyses will include both an as-treated AT and an intention-to-treat ITT analysis All eligible women will be assigned to the ITT and AT population at baseline Only women with follow-up information will be considered for longitudinal analysis Women who never started their prescribed baseline medication will be considered in the ITT analysis but excluded from the AT analysis Population characteristics eg socio-economic factors parameters of reproductive contraceptive history and medical history will be summarized descriptively and used to estimate the probability of treatment differences A Marginal Structural Cox Model MSM with Inverse Probability Weighting IPW of treatment and censoring will be applied for the primary analysis Hazard ratios for the VTE risk will be provided with corresponding 95 confidence intervals Non-Inferiority of E4DRSP will be concluded if the upper confidence limit for the point estimate of the adjusted VTE hazard ratio HRVTE is below the predefined non-inferiority limit of HRni2 for both comparisons HR for E4DRSP vs EEDRSP AND E4DRSP vs non-DRSP COCs is less 20 If non-inferiority of E4DRSP could be demonstrated superiority to EEDRSP or non-DRSP COCs will be subsequently evaluated
Milestones The INAS-SEECS study is expected to start in 122023 after the FDA approval of the protocol The final study report will be available in 122029
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None