| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| This is the dose-finding study on ovarian function, vaginal bleeding pattern, and pharmacokinetics associated with the use of combined vaginal rings in healthy women |
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| E.1.1.1 | Medical condition in easily understood language |
| This is the dose-finding study on ovarian function, vaginal bleeding associated with the use of combined vaginal rings in healthy women |
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| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046883 |
| E.1.2 | Term | Vaginal bleeding |
| 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 |
1. Inhibition of ovulation, which is considered confirmed if in the subset of subjects for whom the test will be performed, ovulation is observed in less than 15% of the subjects at any time during the 3 treatment cycles of the study. Ovulation is defined as two or more consecutive progesterone concentrations >16 nmol/L within 5 days, supported by ultrasound evidence of ovulation. NOTE: Ultrasound evidence of ovulation is defined as either follicular rupture, or the preceding presence of a follicular-like structure >15 mm in size.
2. Cycle control that is non-inferior to NuvaRing®, as judged by the incidence of BTB-S during Treatment Cycle 3. |
|
| E.2.2 | Secondary objectives of the trial |
1. Assessment of safety and tolerability of NGRs compared with NuvaRing®
2. Assessment of effects of NGRs on pharmacodynamic parameters; endometrial thickness as measured by transvaginal ultrasound, and cervical mucus properties
3. Measurement of PD parameters; follicle-stimulating hormone, luteinizing hormone, and progesterone levels
4. Pharmacokinetic assessments including levels of estradiol, estrone, and estrone sulfate, as well as ENG, NOMAC, and SHBG levels, to characterize their PK profile
5. Assessment of scheduled (withdrawal) bleeding incidence, length and intensity with the NGRs compared with NuvaRing® during Treatment Cycle 2, to explore whether at least one NGR can be identified that induces shorter and/or lighter withdrawal bleeding episodes than NuvaRing®
6. Assessment of additional cycle control parameters, including duration and intensity of unscheduled (breakthrough) bleeding and spotting with the NGRs compared with NuvaRing® during Treatment Cycle 3
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject must be willing and able to provide written informed consent for the trial.
2. Subject must be female.
3. Subject must be ≥18 to ≤ 35 years of age.
4. Subject must have a body mass index (BMI) ≥18 and ≤35.
5. Subject must have regular cycles from 24 to 35 days in length, with an intraindividual variation of ±3 days permitted.
6. Each non-sterilized sexually active subject of child-bearing potential must agree to use condoms for contraception during the screening period, treatment period, and post-treatment period until the final study visit (see Section 7.4.1.3.2 for more details).
7. Subject using a hormonal contraceptive (combined or progestin-only), or a nonhormonal IUD, at the screening visit must agree to stop using that method.
8. Subject must be in good physical and mental health, based upon the medical judgment of the investigator.
9. Subject must be able to adhere to dose and visit schedules, and does not plan to relocate during the study.
10.To participate in the pharmacogenetic analysis, the subject must be willing to give written informed consent for the pharmacogenetic testing and able to adhere to the study’s dose and visit schedules. NOTE: A subject unwilling to sign the informed consent for pharmacogenetic testing may be included in the trial; however, pharmacogenetic samples must not be obtained.
11.Subject continues to meet all of the inclusion criteria completed at the screening visit.
12.Subject is not pregnant. At the randomization visit, the subject has had a negative urine pregnancy test at Visit 2 in the clinic prior to being randomized. |
|
| E.4 | Principal exclusion criteria |
1. Subject has any of the following contraindications to the use of contraceptive
steroids:
- Presence or a history of venous or arterial thrombotic/thromboembolic events (e.g. deep venous thrombosis,
pulmonary embolism, myocardial infarction) or of a cerebrovascular accident;
- Presence or history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris);
- History of migraine with focal neurological symptoms;
- Diabetes mellitus with vascular involvement;
- The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis (to be judged by the (sub)-investigator).
e.g. increasing age; smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age); a positive family history (i.e. venous or arterial thromboembolism ever in a sibling or parent at a relatively early age); obesity (body mass index over 30 kg/m2); migraine, valvular heart disease, atrial fibrillation; prolonged immobilization, major surgery, any surgery to the legs, or major trauma (in these situations it is advisable to discontinue the COC use and not to resume until two weeks after full remobilization); systemic lupus erythematosus; haemolytic uraemic syndrome; chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis); sickle cell disease;
- Severe dyslipoproteinemia
- Severe hypertension
- Hereditary or acquired predisposition for venous or arterial thrombosis, such as known APC resistance, known antithrombin-IIIdeficiency, known protein C deficiency, known protein S deficiency, known hyperhomocysteinaemia and known antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
- Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia;
- Presence or history of severe hepatic disease as long as liver function values have not returned to normal;
- Presence or history of liver tumors (benign or malignant);
- Known or suspected sex steroid-influenced malignancies (e.g. of the genital organs or the breasts);
- Undiagnosed vaginal bleeding;
- Known or suspected pregnancy;
- Hypersensitivity to the active substances or to any of the excipients of the investigational product.
2. The subject has not had spontaneous menstruation following a delivery or abortion at the screening visit.
3. The subject is breastfeeding or has not had spontaneous menstruation following completion of breastfeeding at the screening visit.
4. The subject has participated in an investigational drug study within the past 30 days prior to the screening visit.
5. Subject has a history of malignancy ≤5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
6. The subject had a documented abnormal cervical smear result within 6 months prior to the screening visit
7. The subject is a user of recreational or illicit drugs, or has had any recent history of drug abuse.
8. Subject routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking. NOTE: (1) One alcoholic drink is defined as 5 oz (150 mL) of wine, or 12 oz (350 mL) of beer, or 1.5 oz (50 mL) of 80-proof liquor. NOTE: (2) Binge drinking is defined as a pattern of 5 or more alcoholic drinks (male), or 4 or more alcoholic drinks (female) in about 2 hours.
9. The subject has an allergy/sensitivity to the investigational products or their excipients.
10.The subject has been sterilized using a fallopian tube occlusion device (e.g., the Essure method). NOTE: Subjects who have been surgically sterilized and with intact ovarian function are eligible for this study.
11.The subject or a family member is among the personnel of the investigational or Sponsor staff directly involved with this trial.
12.The subject is receiving, or has received, within 2 months prior to the screening visit, sex hormones for any purpose other than contraception, or injectable hormonal contraception within 6 months prior to screening.
13.The subject has received any treatment listed in Table 2 more recently than the indicated washout period, or must continue to receive any treatment listed in Table 2 during the current trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Ovulation inhibition, based on progesterone concentration and ultrasound evidence of follicular rupture (in a subset of subjects in whom the testing will be performed) during the 3 treatment cycles of the study, and
2. The occurrence of breakthrough bleeding and/or spotting during Treatment Cycle 3 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Ovarian suppression, based on the maximum follicular diameter reached during each cycle
2. Absence of withdrawal bleeding during Treatment Cycle 2
3. Number of withdrawal bleeding days during Treatment Cycle 2
4. Number of withdrawal bleeding-spotting days during Treatment Cycle 2
5. Intensity of withdrawal bleeding during Treatment Cycle 2
6. Number of BT bleeding days during Treatment Cycle 3
7. Number of BTB-S days during Treatment Cycle 3
8. Intensity of BTB-S during Treatment Cycle 3
9. In a subset of subjects, PD assessments, including endometrial thickness, cervical mucus properties, and levels of FSH, LH, and progesterone, and PK assessments including levels of E2, E1, E1 sulfate, ENG, NOMAC, and SHBG. |
|
| 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 | Yes |
| 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) | 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 | 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 | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 7 |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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