Back to resultsA Dose-Finding Study to Evaluate Ovarian Function and Vaginal Bleeding in Next Generation Rings (P06109/MK-8175A/MK-8342B-012)
Primary Purpose
Contraception
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Nomegestrol acetate (NOMAC)
Etonogestrel (ENG)
Ethinyl estradiol (EE)
Estradiol (E2)
Sponsored by
About this trial
This is an interventional treatment trial for Contraception
Eligibility Criteria
Inclusion Criteria:
- Body mass index (BMI) ≥18 and ≤35
- Regular cycles from 24 to 35 days in length, with an intra-individual variation of ±3 days permitted within this range
- Good physical and mental health
Exclusion Criteria:
- Diabetes mellitus with vascular involvement
- Presence of a severe or multiple risk factor(s) for venous or arterial thrombosis
- Severe dyslipoproteinemia
- Severe hypertension
- Presence or history of pancreatitis associated with severe hypertriglyceridaemia
- Presence or history of severe hepatic disease
- Undiagnosed vaginal bleeding
- Known or suspected pregnancy
- Participation in another investigational drug study within 30 days prior to screening visit
- History of malignancy ≤5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer
- Documented abnormal cervical smear result in 6 months prior to screening visit
- Sterilization using a fallopian tube occlusion device (e.g., Essure method)
- Sex hormone therapy within 2 months prior to screening visit for purpose other than contraception, or injectable hormonal contraception within 6 months prior to screening
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Active Comparator
Arm Label
Nomegestrol Acetate-17β-Estradiol (NOMAC-E2) 500/300 μg/day
Nomegestrol Acetate-17β-Estradiol (NOMAC-E2) 700/300 μg/day
Nomegestrol Acetate-17β-Estradiol (NOMAC-E2) 900/300 μg/day
Etonogestrel-17β-Estradiol (ENG-E2) 75/300 μg/day
Etonogestrel-17β-Estradiol (ENG-E2) 100/300 μg/day
Etonogestrel-17β-Estradiol (ENG-E2) 125/300 μg/day
NuvaRing®
Arm Description
Participants will receive nomegestrol acetate 17β-estradiol (NOMAC-E2) 500/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Participants will receive nomegestrol acetate 17β-estradiol (NOMAC-E2) 700/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Participants will receive nomegestrol acetate 17β-estradiol (NOMAC-E2) 900/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Participants will receive etonogestrel 17β-estradiol (ENG-E2) 75/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Participants will receive etonogestrel 17β-estradiol (ENG-E2) 100/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Participants will receive etonogestrel 17β-estradiol (ENG-E2)125/300 μg for three 28-day treatment periods, each treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Participants will receive NuvaRing® (etonogestrel-ethinyl estradiol [ENG-EE] 120/15 μg) for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Outcomes
Primary Outcome Measures
Percentage of Participants With Ovulation Incidence, by Cycle
Ovulation was defined as having 2 or more consecutive progesterone concentrations >16 nmol/L within 5 days, confirmed by ultrasound evidence of ovulation (follicular rupture or preceding presence of a follicle-like structure >15 mm in size).
Percentage of Participants With Progesterone Concentrations >16 Nmol/L, by Cycle
Maximum progesterone (Max P) was defined as the maximum progesterone value. Ovulation was defined as 2 or more consecutive progesterone concentrations >16 nmol/L within 5 days during the 3 treatment cycles, supported by ultrasound evidence of ovulation. The Max P values greater than 16 nmol/L are presented by vaginal ring group and cycle.
Percentage of Participants With Breakthrough Bleeding and/or Spotting During Cycle 3
Breakthrough bleeding and/or spotting (BTB-S) is defined as any bleeding or spotting episode that occurred during the expected non-bleeding period that was neither an early nor a continued withdrawal bleeding. Bleeding = any bloody vaginal discharge that required one or more sanitary pads or tampons per day; Spotting = any bloody vaginal discharge that required no sanitary pads or tampons per day.
Secondary Outcome Measures
Percentage of Participants With Absence of Withdrawal Bleeding and/or Spotting During Cycle 2
Withdrawal bleeding and/or spotting is considered any bleeding or spotting episode that starts during or continues into the expected bleeding period (i.e., when the ring has been removed the last week of the cycle). Absence of withdrawal bleeding is no withdrawal bleeding and/or spotting episodes during an expected bleeding period when the ring has been removed.
Intensity of Withdrawal Bleeding During Cycle 2
Intensity of withdrawal bleeding during Cycle 2 was defined as the ratio of the number of withdrawal bleeding days divided by the number of withdrawal bleeding and/or spotting days. Withdrawal bleeding and/or spotting is considered any bleeding or spotting episode that starts during or continues into the expected bleeding period (i.e., when the ring has been removed the last week of the cycle). Absence of withdrawal bleeding is no withdrawal bleeding and/or spotting episodes during an expected bleeding period when the ring has been removed.
Intensity of Breakthrough Bleeding and/or Spotting During Cycle 3
Intensity of breakthrough bleeding and/or spotting (BTB-S) during Cycle 3 was defined as the ratio of the number of breakthrough bleeding days divided by the number of breakthrough bleeding and/or spotting days. Breakthrough bleeding and/or spotting (BTB-S) is defined as any bleeding or spotting episode that occurred during the expected non-bleeding period that was neither an early nor a continued withdrawal bleeding. Bleeding = any bloody vaginal discharge that required one or more sanitary pads or tampons per day; Spotting = any bloody vaginal discharge that required no sanitary pads or tampons per day.
Percentage of Participants Who Experienced At Least One Adverse Event
An adverse event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug.
Percentage of Participants Who Experienced At Least One Serious Adverse Event
A serious adverse event (SAE) is an AE that results in death, is life threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is a cancer, is associated with an overdose; or is another important medical event deemed such by medical or scientific judgment.
Percentage of Participants Who Experienced At Least One Drug-Related Adverse Event
An adverse event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. A drug-related AE was defined as any AE for which there is reasonable possibility of drug relationship as assessed by the Investigator.
Percentage of Participants With Any Drug-Related Serious Adverse Event
A serious adverse event (SAE) is an AE that results in death, is life threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is a cancer, is associated with an overdose; or is another important medical event deemed such by medical or scientific judgment. A drug-related SAE was defined as any SAE for which there is reasonable possibility of drug relationship as assessed by the Investigator.
Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event
An adverse event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01709318
Brief Title
A Dose-Finding Study to Evaluate Ovarian Function and Vaginal Bleeding in Next Generation Rings (P06109/MK-8175A/MK-8342B-012)
Official Title
A Multicenter, Randomized, Partially-blinded, Phase IIb Dose-finding Study on Ovarian Function, Vaginal Bleeding Pattern, and Pharmacokinetics Associated With the Use of Combined Vaginal Rings Releasing 17β-estradiol Plus Three Different Doses of Either Nomegestrol Acetate or Etonogestrel in Healthy Women Aged 18-35 Years. Protocol MK-8175A/MK-8342B 012
Study Type
Interventional
2. Study Status
Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
December 12, 2012 (Actual)
Primary Completion Date
October 22, 2013 (Actual)
Study Completion Date
October 22, 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Organon and Co
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The primary objective of this trial was to identify at least one next generation ring (NGR) that demonstrates inhibition of ovulation (which was considered confirmed if in the subset of participants ovulation was observed in less than 15% of the participants at any time during the 3 treatment cycles of the study) and cycle control that was non-inferior to NuvaRing®, as judged by the incidence of breakthrough bleeding and/or spotting (BTB-S) during Cycle 3. The primary hypothesis was that at least 1 of the 6 NGRs would show inhibition of ovulation and cycle control during Treatment Cycle 3 that is non-inferior to NuvaRing®, as judged by the incidence of BTB-S.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Contraception
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
666 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Nomegestrol Acetate-17β-Estradiol (NOMAC-E2) 500/300 μg/day
Arm Type
Experimental
Arm Description
Participants will receive nomegestrol acetate 17β-estradiol (NOMAC-E2) 500/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Arm Title
Nomegestrol Acetate-17β-Estradiol (NOMAC-E2) 700/300 μg/day
Arm Type
Experimental
Arm Description
Participants will receive nomegestrol acetate 17β-estradiol (NOMAC-E2) 700/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Arm Title
Nomegestrol Acetate-17β-Estradiol (NOMAC-E2) 900/300 μg/day
Arm Type
Experimental
Arm Description
Participants will receive nomegestrol acetate 17β-estradiol (NOMAC-E2) 900/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Arm Title
Etonogestrel-17β-Estradiol (ENG-E2) 75/300 μg/day
Arm Type
Experimental
Arm Description
Participants will receive etonogestrel 17β-estradiol (ENG-E2) 75/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Arm Title
Etonogestrel-17β-Estradiol (ENG-E2) 100/300 μg/day
Arm Type
Experimental
Arm Description
Participants will receive etonogestrel 17β-estradiol (ENG-E2) 100/300 μg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Arm Title
Etonogestrel-17β-Estradiol (ENG-E2) 125/300 μg/day
Arm Type
Experimental
Arm Description
Participants will receive etonogestrel 17β-estradiol (ENG-E2)125/300 μg for three 28-day treatment periods, each treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Arm Title
NuvaRing®
Arm Type
Active Comparator
Arm Description
Participants will receive NuvaRing® (etonogestrel-ethinyl estradiol [ENG-EE] 120/15 μg) for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
Intervention Type
Drug
Intervention Name(s)
Nomegestrol acetate (NOMAC)
Intervention Description
Daily release of 500, 700, or 900 μg.
Intervention Type
Drug
Intervention Name(s)
Etonogestrel (ENG)
Intervention Description
Daily release of 75, 100, 120 or 125 μg
Intervention Type
Drug
Intervention Name(s)
Ethinyl estradiol (EE)
Intervention Description
Daily release of 15 μg
Intervention Type
Drug
Intervention Name(s)
Estradiol (E2)
Intervention Description
Daily release of 300 μg
Primary Outcome Measure Information:
Title
Percentage of Participants With Ovulation Incidence, by Cycle
Description
Ovulation was defined as having 2 or more consecutive progesterone concentrations >16 nmol/L within 5 days, confirmed by ultrasound evidence of ovulation (follicular rupture or preceding presence of a follicle-like structure >15 mm in size).
Time Frame
Day 1 of Treatment Cycle 1 through Day 28 of Treatment Cycle 3 (Up to ~92 days)
Title
Percentage of Participants With Progesterone Concentrations >16 Nmol/L, by Cycle
Description
Maximum progesterone (Max P) was defined as the maximum progesterone value. Ovulation was defined as 2 or more consecutive progesterone concentrations >16 nmol/L within 5 days during the 3 treatment cycles, supported by ultrasound evidence of ovulation. The Max P values greater than 16 nmol/L are presented by vaginal ring group and cycle.
Time Frame
Day 1 of Treatment Cycle 1 through Day 28 of Treatment Cycle 3 (Up to ~92 days)
Title
Percentage of Participants With Breakthrough Bleeding and/or Spotting During Cycle 3
Description
Breakthrough bleeding and/or spotting (BTB-S) is defined as any bleeding or spotting episode that occurred during the expected non-bleeding period that was neither an early nor a continued withdrawal bleeding. Bleeding = any bloody vaginal discharge that required one or more sanitary pads or tampons per day; Spotting = any bloody vaginal discharge that required no sanitary pads or tampons per day.
Time Frame
Day 1 Cycle 3 through Day 28 Cycle 3 (Up to ~28 days)
Secondary Outcome Measure Information:
Title
Percentage of Participants With Absence of Withdrawal Bleeding and/or Spotting During Cycle 2
Description
Withdrawal bleeding and/or spotting is considered any bleeding or spotting episode that starts during or continues into the expected bleeding period (i.e., when the ring has been removed the last week of the cycle). Absence of withdrawal bleeding is no withdrawal bleeding and/or spotting episodes during an expected bleeding period when the ring has been removed.
Time Frame
Day 1 Cycle 2 through Day 28 Cycle 2 (Up to ~28 days)
Title
Intensity of Withdrawal Bleeding During Cycle 2
Description
Intensity of withdrawal bleeding during Cycle 2 was defined as the ratio of the number of withdrawal bleeding days divided by the number of withdrawal bleeding and/or spotting days. Withdrawal bleeding and/or spotting is considered any bleeding or spotting episode that starts during or continues into the expected bleeding period (i.e., when the ring has been removed the last week of the cycle). Absence of withdrawal bleeding is no withdrawal bleeding and/or spotting episodes during an expected bleeding period when the ring has been removed.
Time Frame
Day 1 Cycle 2 through Day 28 Cycle 2 (Up to ~28 days)
Title
Intensity of Breakthrough Bleeding and/or Spotting During Cycle 3
Description
Intensity of breakthrough bleeding and/or spotting (BTB-S) during Cycle 3 was defined as the ratio of the number of breakthrough bleeding days divided by the number of breakthrough bleeding and/or spotting days. Breakthrough bleeding and/or spotting (BTB-S) is defined as any bleeding or spotting episode that occurred during the expected non-bleeding period that was neither an early nor a continued withdrawal bleeding. Bleeding = any bloody vaginal discharge that required one or more sanitary pads or tampons per day; Spotting = any bloody vaginal discharge that required no sanitary pads or tampons per day.
Time Frame
Day 1 Cycle 3 through Day 28 Cycle 3 (Up to ~ 28 days)
Title
Percentage of Participants Who Experienced At Least One Adverse Event
Description
An adverse event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug.
Time Frame
Up to ~92 days
Title
Percentage of Participants Who Experienced At Least One Serious Adverse Event
Description
A serious adverse event (SAE) is an AE that results in death, is life threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is a cancer, is associated with an overdose; or is another important medical event deemed such by medical or scientific judgment.
Time Frame
Up to ~92 days
Title
Percentage of Participants Who Experienced At Least One Drug-Related Adverse Event
Description
An adverse event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. A drug-related AE was defined as any AE for which there is reasonable possibility of drug relationship as assessed by the Investigator.
Time Frame
Up to ~92 days
Title
Percentage of Participants With Any Drug-Related Serious Adverse Event
Description
A serious adverse event (SAE) is an AE that results in death, is life threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is a cancer, is associated with an overdose; or is another important medical event deemed such by medical or scientific judgment. A drug-related SAE was defined as any SAE for which there is reasonable possibility of drug relationship as assessed by the Investigator.
Time Frame
Up to ~92 days
Title
Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event
Description
An adverse event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug.
Time Frame
Up to ~92 days
Other Pre-specified Outcome Measures:
Title
Number of Participants With Venous or Arterial Thrombotic/Thromboembolic Events
Description
Venous or arterial thrombotic/thrombo-embolic events, (VTEs or ATEs) (e.g., deep venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident) were assessed.
Time Frame
From Cycle 1 Day 1 up to 8 days after Day 28 of Cycle 3 (Up to ~92 days)
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Body mass index (BMI) ≥18 and ≤35
Regular cycles from 24 to 35 days in length, with an intra-individual variation of ±3 days permitted within this range
Good physical and mental health
Exclusion Criteria:
Diabetes mellitus with vascular involvement
Presence of a severe or multiple risk factor(s) for venous or arterial thrombosis
Severe dyslipoproteinemia
Severe hypertension
Presence or history of pancreatitis associated with severe hypertriglyceridaemia
Presence or history of severe hepatic disease
Undiagnosed vaginal bleeding
Known or suspected pregnancy
Participation in another investigational drug study within 30 days prior to screening visit
History of malignancy ≤5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer
Documented abnormal cervical smear result in 6 months prior to screening visit
Sterilization using a fallopian tube occlusion device (e.g., Essure method)
Sex hormone therapy within 2 months prior to screening visit for purpose other than contraception, or injectable hormonal contraception within 6 months prior to screening
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Citations:
PubMed Identifier
30203681
Citation
Duijkers I, Klipping C, Heger-Mahn D, Fayad GN, Frenkl TL, Cruz SM, Korver T. Phase II dose-finding study on ovulation inhibition and cycle control associated with the use of contraceptive vaginal rings containing 17beta-estradiol and the progestagens etonogestrel or nomegestrol acetate compared to NuvaRing. Eur J Contracept Reprod Health Care. 2018 Aug;23(4):245-254. doi: 10.1080/13625187.2018.1506101. Epub 2018 Sep 11.
Results Reference
result
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A Dose-Finding Study to Evaluate Ovarian Function and Vaginal Bleeding in Next Generation Rings (P06109/MK-8175A/MK-8342B-012)
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