Study to assess the efficacy and safety of a new contraceptive vaginal ring containing etonogestrel and estradiol and a marketed oral contraceptive pill containing levonorgestrel and ethinyl-estradiol.

• Register: EUCTR
• Last refreshed on: 31 October 2016
• Main ID: EUCTR2014-002208-26-DK
• Date of registration: 21/09/2015
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc.
• Public title: Study to assess the efficacy and safety of a new contraceptive vaginal ring containing etonogestrel and estradiol and a marketed oral contraceptive pill containing levonorgestrel and ethinyl-estradiol.
• Scientific title: A Phase 3, randomized, active-comparator controlled clinical trial to study the contraceptive efficacy and safety of the MK-8342B (etonogestrel + 17ß-estradiol) vaginal ring and the levonorgestrel-ethinylestradiol (LNG-EE) 150/30 µg combined oral contraceptive (COC) in healthy women 18 years of age and older, at risk for pregnancy. - Assessment of contraceptive efficacy & safety of MK-8342B(ENGE2) vaginal ring & LNG-EE 150/30 µg COC
• Date of first enrolment: 28/01/2016
• Target sample size: 2370
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-002208-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Brazil, Chile, Colombia, Czech Republic, Denmark, Finland, Germany, Guatemala, Hungary, Italy, Mexico, Netherlands, Norway, Peru, Poland, Russian Federation, South Africa, Spain, Sweden

Contacts

• Name: Global Clinical Trials Operations

• Name: Global Clinical Trials Operations

Key inclusion & exclusion criteria

Inclusion criteria:
1. Provide written informed consent for both the trial and for Future Biomedical Research
2. Be a premenopausal female >18 years old at enrollment
3. Be at risk for pregnancy (heterosexual vaginal intercourse at least once per month and not sterilized) and seeking contraception
4. Be willing to use either ENG-E2 contraceptive vaginal ring or LNG-EE COC for up to 13 treatment cycles and not intending to use any other forms of contraception (e.g. condoms, except when specified per protocol)
5. Have body mass index of >18 and <38 Kg/m2. Trial sites may exclude subjects with maximum BMI less than 38 kg/m2 based on local standard of care guidelines for the use of combined hormonal contraceptives.
6. Be in good physical and mental health, based upon the medical judgment of the investigator.
7. Be able and will to adhere to use of the ENG-E2 vaginal ring or the LNG-EE COC and to all the required trial procedures, including trial visits and use of the daily diaries and does not plan to relocate during the trial (such that the subject would not be able to continue participation at the trial site).

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 2370
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Cardiovascular risks and disorders:
1. Has a history of venous thromboembolic events (deep vein thrombosis, pulmonary embolism) or history of arterial thrombotic or thromboembolic events or a history of arterial thrombolic events (myocardial infarction, stroke, or peripheral arterial events), or a history or transient ischemia attack or angina pectoris or claudication
2. Is at a higher risk of VTE event due to recent prolonged immobilization (within 2 weeks of screening due to trauma r other illness markedly limiting mobility), plans for surgery requiring prolonged immobilization or has a hereditary or acquired predisposition or elevated risk for venous or arterial thrombosis. Refer to protocol for complete list
3. Is currently smoking or uses tobacco products and is >35 years of age
4. Has uncontrolled or severe hypertension
5. Has a history of severe dyslipoproteinemia
6. Is >35 years of age and has a history of migraine with aura or focal neurological symptoms or is >35 years of age and has a history of migraines (with or without aura)
7. Has diabetes mellitus with end organ involvement (nephropathy, retinopathy, neuropathy or vascular involvement) or has had diabetes for > 20 years
8. Has multiple cardiovascular risk factors such as older age (>35 years), obesity, BMI >30 Kg/m2), inadequately controlled hypertension, use of tobacco/nicotine, or inadequately controlled diabetes which in the opinion of the nvestigator in the composite pose an unacceptable risk of participation

Gastrointestinal Disorders:
9. Has a history of pancreatitis associated with severe hyper triglyceridemia
10. Has clinically significant liver disease which is now inactive of successfully treated may be enrolled if liver function values (AST, ALT, total bilirubin) have been normal for the past year and are within the normal range (per central lab) at V1
11. History of malabsorptive bariatric surgery (i.e., bileopancreatic diversion or Roux-en-Y bypass). Non-malabsorptive restrictive surgery is acceptable for inclusion (i.e., Gastric banding, partial gastrectomy)
Other Medical Disorders:
12. Has history of malignancy <5years prior to signing informed consent except for treated basal or squamous cell skin cancer or in situ cervical cancer. Subjects with a history or presence of liver tumors (benign or malignant) or sex steroid-influenced malignancies (e.g., of the genital organs or the breasts) are excluded regardless of the timing.
13. Has any disease that may worsen under hormonal treatment, such as disturbances in the bile flow (presence or history of cholestasis, presence of gall stones), systemic lupus erythematosus, pemphigoid gestationis or idiopathic icterus during a previous pregnancy, middle ear deafness, Sydenham chorea, or porphyria. History of cholecystectomy does not exclude a subject.
14. Has a known allergy/sensitivity or contraindication to the investigational products (ENG-E2 vaginal ring or LNG-EE COC) or their excipients).
15. Has a history (current or within the past two years) of drug or alcohol abuse or dependence.
16. Has any clinically relevant abnormal laboratory result at screening as judged by the investigator.
17. Has a history or current evidence of any condition therapy or other circumstance that in the opinion of the investigator might expose the subject to risk by participating in the trial, confound the results of the trial, or interfere with the subject’s participation for the full duration of the trial.

Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Contraception
MedDRA version: 19.0 Level: HLT Classification code 10010812 Term: Contraceptive methods female System Organ Class: 100000004865

Therapeutic area: Body processes [G] - Reproductive physiologi cal processes [G08]

Intervention(s)

Product Name: Etonogestrel/Estradiol (ENG-E2)
Product Code: MK-8342B
Pharmaceutical Form: Vaginal delivery system
INN or Proposed INN: Etonogestrel
CAS Number: 54048-10-1
Current Sponsor code: MK-8342
Other descriptive name: ENG, SCH900342, Org 3236
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 125-
INN or Proposed INN: Estradiol
CAS Number: 50-28-2
Current Sponsor code: MK-9271
Other descriptive name: E2, SCH 900618, Org 2317
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 300-

Trade Name: Microgynon 21
Product Name: Microgynon 21
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Levonorgestrel
Other descriptive name: levonorgestrelum
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 150-
INN or Proposed INN: Ethinylestradiol
Other descriptive name: ethinylestradiolum
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 30-

Primary Outcome(s)

Primary end point(s): The primary efficacy endpoint for this trial is the determination of contraceptive efficacy (the prevention of in-treatment pregnancy) using the PI, as defined as follows:
PI=n/E,
Where n=number of in treatment pregnancies, E= exposure in 100 woman years.

The calculation of the exact 95% confidence interval for the PI will be based on the Poissson distribution using the formulas:

Lower limit 95% CI=(1/2/E) X chi square (0.025,2n), and
Upper limit 95%CI= (1.2E) X chi square (.975,2n+2)
(Chi-square = percentage point of the chi-square distribution)

If no pregnancies occur an upper confidence level of 2.5% will be used

Timepoint(s) of evaluation of this end point: The PI is defined as the number of pregnancies per 100 woman-years of a contraceptive method’s use.

Secondary Objective: 1. To assess the “perfect use” and “typical use” efficacy of the ENG-E2 vaginal ring in women 18-35 years old based on the number of in treatment pregnancies as expressed by the PI in the per protocol set and in the full analysis set, respectively.
2. To assess the efficacy of the ENG-E2 vaginal ring in women 18 and 35 years old based on the number of in treatment pregnancies with documentation that no additional contraception was used a but (in contrast to the rFAS) with additional requirement of affirmed vaginal intercourse.
3. To assess the efficacy of the ENG-E2 vaginal ring in women 18 years and older based on the number of in treatment pregnancies as expressed by the PI in rFAS.
4. To assess the incidence of breakthrough bleeding/spotting and absent withdrawal bleeding in each cycle of the ENG-E2 vaginal ring.
5. To assess and estimate the contraceptive efficacy, cycle control, safety and tolerability of ENG- E2 vaginal ring relative to the LNG-EE COC

Main Objective: 1. To assess the contraceptive efficacy of the ENG-E2 vaginal ring in women 18 and 35 years of age based on the number of in treatment pregnancies as expressed by the Pearl Index (PI) in the restricted full analysis set population (rFAS) which excludes cycles in which back-up contraception was used.
2. To assess the safety and tolerability of the ENG-E2 vaginal ring.

Secondary Outcome(s)

Secondary end point(s): Main vaginal bleeding endpoints for the vaginal bleeding CCA are:
- Incidence of BTB-S (any bleeding/spotting episode that occurred during the ring use tablet interval that is neither an early nor a continued.
- Incidence of AWB (i.e. no bleeding/spotting episodes that began during or continued into the ring free interval or the tablet-free interval).

Timepoint(s) of evaluation of this end point: - For the Secondary analysis of the PI Point estimate along with the 95%CI (18-35 years) use of the supportive approach was done.
- Secondary analysis of the PI – Point estimate along with the 95% CI (subject > 18 years of age)
- Incidence of BTB-S- point estimate along with 95% CI (per treatment cycle)
- Incidence of absence of WB- point estimate along with 95% CI per treatment cycle

P =Primary approach; S= secondary approach; CI= confidence interval BTB= break through bleeding

Secondary ID(s)

MK-8342B-062

2014-002208-26-NO

Source(s) of Monetary Support

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc.