| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
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| E.2.2 | Secondary objectives of the trial |
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 |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
To describe the PK of ENG and assess the concentrations of estrone (E1) and estradiol (E2) in users of the ENG-E2 vaginal ring to support future exploratory population PK analyses.
Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| E.3 | Principal 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).
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| E.4 | Principal 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.
Recent or Current pregnancy:
18. Has a known or suspected pregnancy
19. Has not had at least 2 menstrual cycles or has not completed two 28-day cycles of a hormonal contraceptive (pill, patch or ring) following a recent pregnancy
20. Is breast feeding
If recently stopped breast feeding must have resumed normal menstrual cycles.
Gynecologic conditions:
21. Has gonorrhea, chlamydia, or trichomonas, symptomatic vaginitis/cervicitis. Subjects may be screened 3 weeks after completing treatment for these conditions.
22. Has an abnormal cervical Pap test or positive high risk HPV test at screening or documented within 3 years of screening (i.e. ASCUS-high-risk HPV positive ASC-H, LSIL, HSIL), squamous cell carcinoma or adenocarcinoma (in situ or invasive)
23. Is currently using an intra-uterine device or contraceptive implant.
24. Within the past 6 months, has had undiagnosed (unexplained) abnormal vaginal bleeding or any abnormal bleeding that is expected to recur during the trial (e.g. bleeding from a cervical polyp, recurrent bleeding after sex).
25. Has stage 4 pelvic organ prolapse (1 cm. beyond intoritus) or lesser degrees of prolapse with a history of difficulty retaining tampons, vaginal rings, or other products in the vagina.
Miscellaneous:
26. Is or has an immediate family member who is part of the investigational site of sponsor staff directly involved with this trial.
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| E.5 End points |
| E.5.1 | 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
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| E.5.1.1 | 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. |
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| E.5.2 | 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).
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| E.5.2.1 | 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
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Brazil |
| Chile |
| Colombia |
| Czech Republic |
| Denmark |
| Finland |
| Germany |
| Guatemala |
| Hungary |
| Italy |
| Mexico |
| Netherlands |
| Norway |
| Peru |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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