| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Investigation of ovulation inhibition for indication of contraception in healthy subjects |
|
| E.1.1.1 | Medical condition in easily understood language |
| Investigation of ovulation inhibition for indication of contraception in healthy subjects |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073728 |
| E.1.2 | Term | Hormonal contraception |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 |
| To determine the inhibition of ovulation of different dosages and dose regimens of MR-130A-01 in two 28-day treatment cycles in healthy pre-menopausal women with BMI <30.0 or ≥30.0 kg/m2 |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of this clinical trial are:
• To assess the ovarian activity during treatment with MR-130A-01
• To assess the corpus luteum function during treatment with MR-130A-01
• To assess the effects of MR-130A-01 on follicle-like structure (FLS) diameter and endometrial thickness
• To assess the effects of MR-130A-01 on cervical mucus
• To assess the effects of MR-130A-01 on sexual hormones
• To characterize systemic exposure under treatment with MR-130A-01 containing transdermal therapeutic systems of different dosages
• To assess patch adhesion
• To assess overall safety and tolerability of MR-130A-01 as well as local tolerability of the transdermal therapeutic system
• To assess the bleeding pattern during treatment with MR-130A-01 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Healthy, post-menarcheal and premenopausal women of age 18 to 35 years (inclusive).
2. BMI ≥18.0 kg/m2 at screening examination
3. Subjects must be in good physical and mental health as determined by vital signs, medical history, and physical and gynecological examination, as assessed by the investigator.
4. Written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the subject participating in the clinical trial.
5. Status at least 3 months after a delivery, abortion, and stopping lactation, if applicable, before screening.
6. Has regular menstrual cycles that are between 21 and 35 days in duration as reported by the subject during anamnesis, with an intact uterus and ovaries. If the subject uses hormonal birth control at screening, historic data should be used to evaluate this criterion.
7. Both ovaries must be visible on TVUS examination during screening.
8. Ovulatory pre-treatment cycle, as confirmed by a progesterone concentration >10.0 nmol/L.
9. Subjects must consent to use reliable non-hormonal contraceptive methods (male condoms, diaphragm, or heterosexual abstinence) throughout the study, unless the subject has a history of female sterilization or sterilization of the sexual partner. |
|
| E.4 | Principal exclusion criteria |
1. Known hypersensitivity or intolerance to any ingredient of the investigational product
2. History or presence of dermal sensitivity to medicated patches or to topical applications including bandages, surgical tape
3. Pregnancy or a positive serum beta human chorionic gonadotropin (β-hCG) pregnancy test at screening
4. Clinically relevant abnormal findings from serum biochemistry and hematology and HBsAg and Hepatitis C virus/human immunodeficiency virus (HIV) serology as evaluated by the investigator
5. ASAT > 20 % ULN, ALAT > 10 % ULN, bilirubin > 20% ULN (except in case of existing Morbus Gilbert-Meulengracht deduced from anamnesis/medical history) and creatinine > 0.1 mg/dL ULN (limit of > 0.1 mg/dL corresponds to > 9 µmol/l ULN)
6. Use of a non-hormonal intra-uterine device within the pre-treatment cycle or any hormonal contraception as follows:
• Short-acting hormonal contraceptives such as oral, patch, ring or intra-uterine systems within the menstrual cycle prior to the pre-treatment cycle
• Injectable (intramuscularly or subcutaneously) within 10 months (three-month treatment duration), 6 months (two-month treatment duration) or 3 months (one-month treatment duration) prior to the start of pre-treatment cycle or implants within the menstrual cycle prior to the pre-treatment cycle
7. Known or suspected malignancy or history thereof
8. Has unexplained vaginal bleeding within the past 6 months suspicious for serious condition, or any abnormal bleeding which is expected to recur during the study (eg. bleeding from cervical polyp, recurrent bleeding after sex)
9. History or presence of ischemic heart disease, coronary artery disease, myocardial infarction, stroke, other cerebrovascular diseases including transient ischemic attacks (TIAs)
10. Known dyslipidemias with other known cardiovascular risk factors
11. History or presence of hypertension (including adequately controlled hypertension) or hypertension with vascular disease or elevated BP defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg, measured in sitting position after at least 5 minutes of rest (a single reading of blood pressure level is not sufficient to classify a woman as hypertensive)
12. Pulse rate < 50 bpm or > 90 bpm
13. Presence of deep vein thrombosis/pulmonary embolism
14. Has any comorbid condition that may require major surgery with prolonged immobilization during the study period
15. History or presence of migraine with aura
16. Presence of liver disease including severe (decompensated) cirrhosis, benign (e.g., hepatocellular adenoma) or malignant liver tumors
17. Chronic disease potentially necessitating organ transplantation during the anticipated course of the study
18. Subjects having any other known contraindication to progestin only contraception as defined by category 3 or 4 conditions per World Health Organization Medical eligibility criteria for contraceptive use, 2015 or Centers for Disease Control and Prevention (CDC) US Medical Eligibility Criteria (US MEC) for Contraceptive Use, 2016 (WHO 2015, Curtis KM et al., 2016)
• Multiple risk factors for arterial cardiovascular disease (such as older age [35 years at screening or during the study], smoking, diabetes, hypertension and known dyslipidemias)
• History or presence of systemic lupus erythematosus with positive (or unknown) antiphospholipid antibodies
• History (even with no evidence of current disease for 5 years) or presence of or suspected carcinoma of breast
• Has diabetes mellitus with nephropathy, retinopathy, neuropathy, or other vascular disease or diabetes of >20 years’ duration
• Subject has requirement to be on treatment with medications prohibited during the study (phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine) or rifampin or rifabutin therapy, see section 13.2.1 for additional information on prohibited medications)
19. Presence or history of acute or chronic diseases especially of the skin, which could affect dermal absorption or metabolism, which may interfere with the bioavailability and /or the pharmacokinetics of the IMP based on assessment of the investigator
20. Skin abnormality (e.g., tattoo or scar) at all possible application sites (at least two different applications sites with normal skin situation are required)
21. History of clinically significant depression, as per investigator’s judgment
22. Any condition that, in the opinion of the investigator may jeopardize the subject safety or trial conduct according to the protocol
23. Participation in another clinical trial at same time or within the preceding 30 days (calculated from the date of the last IMP intake)
24. Recent history (within prior 12 months) of drug or alcohol abuse or at the Investigator’s discretion, history greater than 12 months prior and at risk for noncompliance.
25. Any cervical infection which will impair the cervical assessment during the trial, as per investigator’s judgment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Proportion of responder overall (subjects with no ovulation in both treatment cycles)
• Proportion of responder in cycle (subjects with no ovulation in one of the treatment cycles) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Ovarian activity (via Hoogland and Skouby score)
• Landgren criterion
• Dominant FLS diameter (FLSdom)
• Pituitary (FSH, LH) and ovarian (E2, P) hormones
• Endometrial thickness
• Cervical mucus evaluation (Insler score)
• Bleeding pattern
• Concentrations of NGMN and norgestrel
• TEAEs
• Safety clinical laboratory parameters
• Application site reactions / local patch tolerability
• Adhesion performance as measured by adhesion scores |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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