| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe primary dysmenorrhea |
|
| E.1.1.1 | Medical condition in easily understood language |
| Menstrual pain in the absence of a diagnosed specific known cause |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062851 |
| E.1.2 | Term | Primary dysmenorrhea |
| E.1.2 | System Organ Class | 100000004872 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013934 |
| E.1.2 | Term | Dysmenorrhea |
| E.1.2 | System Organ Class | 100000004872 |
|
| 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 |
In women with moderate to severe primary dysmenorrhea:
1. To evaluate the efficacy of the ENG-E2 vaginal ring relative to placebo in the treatment of dysmenorrhea at Treatment Cycle 2.
2. To assess the safety and tolerability of the ENG-E2 vaginal ring over 4 treatment cycles. |
|
| E.2.2 | Secondary objectives of the trial |
In women with moderate to severe primary dysmenorrhea, to assess the effect of treatment with the ENG-E2 vaginal ring relative to placebo at Treatment Cycle 2 on:
1. The change from baseline in the peak pelvic pain score.
2. The number of days with no impact of dysmenorrhea (score = 0) on each of the following DysDD items separately: work/school, physical activities, and social or leisure activities.
3. The proportion of subjects with no or minimal pain (i.e. peak pelvic pain score of “0” or “1”) and no use of ibuprofen tablets.
4. The proportion of subjects with a ≥3 point reduction in peak pelvic pain score and a decrease in the number of ibuprofen tablets as compared to baseline.
5. The change from baseline in the mean pelvic pain score. |
|
| 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 |
| Merck will conduct Future Biomedical Research on DNA (from buccal swabs) 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. |
|
| E.3 | Principal inclusion criteria |
In order to be eligible for participation in this trial, the subject must:
1. Provide written informed consent/assent for the trial. Provide consent/assent if agreeing to participate in sample collection for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be a post-menarcheal female, age ≤50 years.
3. Have a history of moderate to severe primary dysmenorrhea for the past 3 months or longer, and no history of recurrent non-menstrual pelvic pain intermittently or continuously throughout the month, and no history of dysmenorrhea secondary to structural pelvic pathology (e.g., endometriosis, fibroids, pelvic inflammatory disease, adenomyosis). Subjects with a history of mid-cycle discomfort with ovulation (mittelschmerz) may participate.
4. Have a body mass index (BMI) of ≥18 and <38 kg/m2.
5. If heterosexually active, agrees to consistently use male condoms as the contraceptive method starting the day of Visit 1, and during the entire treatment period (until 14 days after removal of the last study ring) unless her partner is surgically sterilized. Sporadic use of an emergency contraceptive (EC) is not an exclusion; however, the
investigator should carefully assess subject’s ability to comply with the protocol requirements for condom use.
6. Has a history of regular menstrual cycles with a cycle length between 24 and 32 days (inclusive) for the past three months.
7. Be in good physical and mental health, based upon the medical judgment of the investigator
8. Be able and willing (in the opinion of the investigator) to adhere to use of the vaginal ring and to all required trial procedures, including study visits and use of daily eDiary, and not planning to relocate during the study (such that the subject would not be able to continue participation at the trial site).
9. Be willing to use the rescue medication ibuprofen at the study recommended dose (provided by the study site) and no other pain medication for treatment of dysmenorrhea.
Additional inclusion criteria to be verified at Visit 3:
10. Have demonstrated a menstrual cycle length between 24 and 32 days (inclusive) in the eDiary during the screening period (1st spontaneous menses during screening period (SM1) to 2nd spontaneous menses during screening period (SM2)).
11. Have demonstrated moderate to severe dysmenorrhea during the screening period as defined by a peak menstrual cramping pain score ≥6 on item #2 of the Dysmenorrhea Daily Diary during both SM1 and SM2.
12. Have no more than 3 days with incomplete eDiary entries during the screening period and no more than one day with incomplete entries during SM2.
13. Have demonstrated compliance with taking only the study provided ibuprofen tablets for dysmenorrhea during SM1 and SM2 as evidence in the eDiary. |
|
| E.4 | Principal exclusion criteria |
- Has a personal history of VTE (deep vein thrombosis, pulmonary embolism) or history of ATE events (i.e., myocardial infarction, stroke, or peripheral arterial), or history of transient ischemic attack or angina pectoris or claudication.
- Is at a higher risk of VTE events due to recent prolonged immobilization (within 2 weeks prior to screening, e.g., due to trauma, surgery, or other illness markedly limiting mobility, planned surgery limiting mobilization, or has a hereditary or acquired predisposition or elevated risk for venous or arterial thrombosis, such as APC (activated protein C) resistance, antithrombin-III-deficiency, protein C
deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant) or has thrombogenic cardiac valve or rhythm abnormalities of the heart associated with thromboembolism (e.g., atrial fibrillation).
- Is currently smoking or uses tobacco/nicotine containing products and is ≥35 years of age.
- Has a history of severe dyslipoproteinemia.
- 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 or focal neurologic symptoms).
- Has diabetes mellitus with end-organ involvement (nephropathy, retinopathy, neuropathy or other vascular involvement) or has had diabetes for >20 years duration.
- Has multiple cardiovascular risk factors such as older age (>35 years), obesity (BMI >30 kg/m2), inadequately controlled hypertension, use of tobacco/ nicotine products, or inadequately controlled diabetes which, in the opinion of the investigator, in composite pose an unacceptable risk of study participation. The investigator should consider the severity of each risk factor in determining whether study participation is appropriate.
- Has a known or suspected pregnancy.
- Has been pregnant or breastfeeding within the past 2 months.
- Has used hormonal contraceptives (pill, patch, ring, implant, intrauterine system) within the past 3 months.
- Current use of non-hormonal intrauterine device (IUD). To qualify, device must be discontinued before V1 and the diagnosis of primary dysmenorrhea must have preceded IUD insertion.
- Within the past 6 months has had undiagnosed (unexplained) abnormal vaginal bleeding or any other abnormal bleeding that is expected to recur during the study (e.g., bleeding from a cervical polyp, recurrent bleeding after intercourse).
- Currently has gonorrhea, chlamydia, or trichomonas or symptomatic vaginitis/cervicitis. Subjects may be rescreened 3 weeks after completing treatment for these conditions.
- Has an abnormal cervical smear or positive high-risk human papilloma virus (HPV) test at screening or documented within 3 years of screening.
- Has Stage 4 pelvic organ prolapse (1 cm beyond introitus) or lesser degrees of prolapse with a history of difficulty retaining tampons, vaginal rings, or other products within the vagina.
- Has a history of pancreatitis associated with severe hypertriglyceridemia.
- Has clinically significant liver disease, including active viral hepatitis or cirrhosis.
Subjects with a prior history of liver disease which is now inactive or 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.
- Has history of conditions of the gastrointestinal or urologic tract which may cause pelvic pain (i.e. inflammatory bowel disease, interstitial cystitis).
- Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell 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 interval since the history of the malignancy.
- Has any disease that may worsen under hormonal treatment such as disturbances in the bile flow (presence of or history of cholestasis, presence of gallstones), systemic lupus erythematosus, pemphigoid gestationis or idiopathic icterus during a previous pregnancy, middle-ear deafness (otosclerosis), Sydenham chorea, or porphyria. History of cholecystectomy does not exclude a subject.
- Has received or must continue to receive any treatment listed in the table in the protocol more recently than the last allowable use as indicated in the table. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is a composite responder endpoint defined as the proportion of subjects with a reduction in peak pelvic pain score of at least 3 points (item #2 of the Dysmenorrhea Daily Diary, and no increase in the use of rescue pain relief medication (total number of ibuprofen 400 mg tablets taken) at Treatment Cycle 2 as compared to baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The main assessment of the primary endpoint is performed at Treatment cycle 2. |
|
| E.5.2 | Secondary end point(s) |
1. Change from baseline cycle in the peak pelvic pain score.
2. Change from baseline cycle in the number of days with no impact (score = 0) of dysmenorrhea on each of the DysDD items, separately:
physical activities, social or leisure activities, and work/school.
3. Proportion of subjects with pelvic pain score of "0" or "1" and no use of ibuprofen tablets.
4. Proportion of subjects with reduction in peak pelvic pain score of at least 3 points and a decrease in number of ibuprofen tablets taken.
5. Change from baseline cycle in the mean pelvic pain score. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The main assessment of the secondary endpoints are performed at Treatment cycle 2. |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Chile |
| Guatemala |
| Italy |
| Poland |
| Puerto Rico |
| Russian Federation |
| South Africa |
| Sweden |
| United States |
|
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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