A Dose-Finding Study to Evaluate Ovarian Function and Vaginal Bleeding in Next Generation Rings (P06109/MK-8175A/MK-8342B-012)

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

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.

Study Overview

• Status: Completed
• Conditions: Contraception
• Intervention / Treatment: Drug: Nomegestrol acetate (NOMAC); Drug: Estradiol (E2); Drug: Etonogestrel (ENG); Drug: Ethinyl estradiol (EE)

• Study Type: Interventional
• Enrollment (Actual): 666
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nomegestrol Acetate-17β-Estradiol (NOMAC-E2) 500/300 μg/day; 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.	Drug: Nomegestrol acetate (NOMAC); Daily release of 500, 700, or 900 μg.; Drug: Estradiol (E2); Daily release of 300 μg
Experimental: Nomegestrol Acetate-17β-Estradiol (NOMAC-E2) 700/300 μg/day; 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.	Drug: Nomegestrol acetate (NOMAC); Daily release of 500, 700, or 900 μg.; Drug: Estradiol (E2); Daily release of 300 μg
Experimental: Nomegestrol Acetate-17β-Estradiol (NOMAC-E2) 900/300 μg/day; 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.	Drug: Nomegestrol acetate (NOMAC); Daily release of 500, 700, or 900 μg.; Drug: Estradiol (E2); Daily release of 300 μg
Experimental: Etonogestrel-17β-Estradiol (ENG-E2) 75/300 μg/day; 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.	Drug: Estradiol (E2); Daily release of 300 μg; Drug: Etonogestrel (ENG); Daily release of 75, 100, 120 or 125 μg
Experimental: Etonogestrel-17β-Estradiol (ENG-E2) 100/300 μg/day; 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.	Drug: Estradiol (E2); Daily release of 300 μg; Drug: Etonogestrel (ENG); Daily release of 75, 100, 120 or 125 μg
Experimental: Etonogestrel-17β-Estradiol (ENG-E2) 125/300 μg/day; 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.	Drug: Estradiol (E2); Daily release of 300 μg; Drug: Etonogestrel (ENG); Daily release of 75, 100, 120 or 125 μg
Active Comparator: NuvaRing®; 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.	Drug: Etonogestrel (ENG); Daily release of 75, 100, 120 or 125 μg; Drug: Ethinyl estradiol (EE); Daily release of 15 μg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Day 1 of Treatment Cycle 1 through Day 28 of Treatment Cycle 3 (Up to ~92 days)
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.	Day 1 of Treatment Cycle 1 through Day 28 of Treatment Cycle 3 (Up to ~92 days)
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.	Day 1 Cycle 3 through Day 28 Cycle 3 (Up to ~28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 1 Cycle 2 through Day 28 Cycle 2 (Up to ~28 days)
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.	Day 1 Cycle 2 through Day 28 Cycle 2 (Up to ~28 days)
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.	Day 1 Cycle 3 through Day 28 Cycle 3 (Up to ~ 28 days)
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.	Up to ~92 days
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.	Up to ~92 days
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.	Up to ~92 days
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.	Up to ~92 days
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.	Up to ~92 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Venous or Arterial Thrombotic/Thromboembolic Events	Venous or arterial thrombotic/thrombo-embolic events, (VTEs or ATEs) (e.g., deep venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident) were assessed.	From Cycle 1 Day 1 up to 8 days after Day 28 of Cycle 3 (Up to ~92 days)

Collaborators and Investigators

• Sponsor: Organon and Co
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2012
• Primary Completion (Actual): October 22, 2013
• Study Completion (Actual): October 22, 2013

Study Registration Dates

• First Submitted: October 16, 2012
• First Submitted That Met QC Criteria: October 16, 2012
• First Posted (Estimated): October 18, 2012

Study Record Updates

• Last Update Posted (Actual): May 28, 2024
• Last Update Submitted That Met QC Criteria: May 9, 2024
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Uterine Diseases; Hemorrhage; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Uterine Hemorrhage; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Hormonal; Estradiol; Ethinyl Estradiol; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate; Etonogestrel
• Other Study ID Numbers: P06109 (Other Identifier: Schering-Plough); 2012-002459-41 (Other Identifier: EudraCT Number); MK-8175A/MK-8342B-012 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf