| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| As the clinical trial is intended to investigate a new contraceptive medicinal product, the trial subjects included are not characterized by a specific medical condition. |
|
| E.1.1.1 | Medical condition in easily understood language |
| As the clinical trial is intended to investigate a new contraceptive medicinal product, the trial subjects included are not characterized by a specific medical condition. |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065589 |
| E.1.2 | Term | Male 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 |
| The primary objective of the study is to determine contraceptive efficacy for a couple provided by daily application by the male partner of a gel containing testosterone (T) and Nestorone (NES) for a period of 52 weeks (about 12 months). |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to assess the safety and acceptability of the NES 8 mg/day + T 62 mg/day (NES-8/T-62) gel and the NES 8 mg/day + T 74 mg/day (NES-8/T-74) gel. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male Partner – Inclusion Criteria
1. Good health as confirmed by medical history, physical examination, and clinical laboratory tests of blood and urine at the time of screening;
2. 18 to 50 years of age, at the enrollment visit;
3. BMI < 33 kg/m2;
4. No history of androgen use in the six months prior to the first screening visit;
5. Agreement to use an effective method of contraception with his female partner during the suppression and recovery phases and then only use the experimental method during the efficacy phase of the study;
6. In the opinion of the investigator, the male subject is willing and able to comply with the protocol;
7. The subject is legally competent, has been informed of the nature, the scope and the relevance of the study, voluntarily agrees to participation and the study’s provisions and has duly signed the informed consent form (ICF);
8. Sexually active with a female partner (as specified below) with whom he has been in a stable, mutually monogamous relationship for at least 1 year prior to screening and with whom he intends to remain in a relationship for the duration of the study;
9. No known infertility;
10. Normal reproductive state as demonstrated by:
• Sperm concentration ≥15 million/mL in two semen samples and with no gross abnormalities of sperm motility and morphology on at least one semen sample assessment;
• Screening Testosterone within the study site’s local lab normal reference range for adult men;
11. Willingness to accept a low but unknown risk of conceiving a pregnancy for the duration of the trial.
Female Partner – Inclusion Criteria:
1. Good general health with no chronic medical conditions that result in periodic exacerbations which require significant medical care or are known to affect fertility;
2. Aged between 18 and 34 years, inclusive, at the enrollment visit;
3. Have regular menstrual cycles of 21-35 days in duration, per patient report, when not using hormonal contraception. If hormonal contraception has been used, the following applies:
a. If recently used intramuscular Depo-Provera must have had last injection at least 3 months prior enrollment;
b. If using an IUD or an implant, she is planning to have this removed for purposes unrelated to enrollment in the study prior to entering the efficacy phase;
c. Completion of her last pack of oral contraceptives or completion of effectiveness period for a monthly injection, patch or ring if any has been used prior to entering the efficacy phase;
4. Have intact uterus and at least one ovary;
5. The subject is legally competent, has been informed of the nature, the scope and the relevance of the study, voluntarily agrees to participation and the study’s provisions and has duly signed the informed consent form (ICF);
6. Consistent use of effective contraception during the preceding cycle prior to enrolling;
7. No known infertility;
8. Intends to remain in a monogamous relationship with male study partner (as specified above). (Note: this study will not provide her contraception for intercourse with any other male partners);
9. Be at risk for pregnancy with participating male partner (heterosexual vaginal intercourse at least once per cycle and not sterilized);
10. Have a negative pregnancy test at enrollment;
11. Willingness to accept a low but unknown risk of pregnancy and able to understand the need for follow-up in case of pregnancy;
12. No medical contraindication to pregnancy; |
|
| E.4 | Principal exclusion criteria |
Male Partner – Exclusion Criteria:
1. Men participating in another clinical trial involving an investigational drug within the last 30 days (or within five half-lives of the investigational drug, whichever is longer) prior to the first screening visit.
2. Men not living in the catchment’s area of the study site or within a reasonable distance from the site.
3. Clinically significant abnormal findings at screening per the Investigator’s medical judgment.
4. PSA levels ≥ 4 ng/mL.
5. Abnormal serum chemistry values that may indicate clinically significant liver or kidney dysfunction.
6. Use of androgens or other anabolic steroids that may suppress gonadotropins within 6 months prior to the first screening visit.
7. Diastolic blood pressure (DBP) ≥ 85 and Systolic blood pressure (SBP) ≥ 135 mm Hg; (BP will be taken three times at approximately 5 minute intervals and the mean of the last two of the three measurements will be used to determine eligibility).
8. History of hypertension, including hypertension controlled with treatment.
9. Known history of primary testicular disease or disorders of the hypothalamic-pituitary axis.
10. Known hypersensitivity to progestins or testosterone or any excipient of the investigational product.
11. History of prostate, testicular or breast carcinoma.
12. Significant prostatic symptoms (IPSS > 15).
13. Known history of reproductive dysfunction including vasectomy or infertility.
14. Known history of significant cardiac, renal, hepatic or prostatic disease.
15. History of thromboembolic disease.
16. A serious systemic disease such as diabetes mellitus (including diabetes controlled with treatment), or HIV.
17. Current active or ongoing hepatitis infection.
18. History of untreated sleep apnea.
19. Known or suspected current alcohol dependence syndrome, chronic marijuana use, or any illicit drug use that may affect metabolism/transformation of steroid hormones and study treatment compliance.
20. Any skin condition that might interfere with absorption of gel.
21. Couples desiring fertility within the study participation
22. PHQ9 score ≥15 or history of severe depression or other serious mental health disorder, including ongoing use of an anti-depressant.
23. Men participating in competitive sports where drug screening for prohibited substances (including anabolic steroids) is routine. Exclusion is due to the potential of testing positive for androgens that may occur from their study participation coupled with the unknown efficacy (i.e. duration of positive testing) of a single application.
24. Use of sex steroids or medications which might interfere with steroid metabolism (i.e. ketoconazole, finasteride, oral corticosteroids, dutasteride and statins).
25. Use of anticoagulants.
26. Use of medications that will interfere or interact with Nestorone or Testosterone.
27. Use of oily cosmetic skin gels/products that would prevent absorption of steroids.
28. Previous participation in this clinical trial.
29. Any site staff member with delegated study responsibilities or a family member of a site staff member with delegated study responsibilities.
30. Have issues or concerns (in the judgment of the investigator) that may compromise the safety of the subject or confound the reliability of compliance and information acquired in this study.
Female Partner – Exclusion Criteria:
1. Desire to become pregnant during the study.
2. Breastfeeding.
3. Known or suspected current alcoholism or drug abuse.
4. Participation in another clinical trial involving an investigational drug within the last 30 days prior to the first screening visit.
5. Currently pregnant.
6. Known hypersensitivity to progestins or testosterone.
7. Previous participation in this clinical trial.
8. Any site staff member with delegated study responsibilities or a family member of a site staff member with delegated study responsibilities.
9. Have issues or concerns (in the judgment of the investigator) that may compromise the safety of the subject or confound the reliability of compliance and information acquired in this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Twelve-month (365 days) cumulative contraceptive efficacy in couples, during the efficacy portion of the study, in which the male partner uses the product daily to suppress sperm production and the couple uses the method as their sole contraceptive method is the primary endpoint for this study. Kaplan-Meier methods will be used to estimate the twelve-month cumulative pregnancy probability (through day 365) (and 95% CI) in the typical use population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. For the efficacy portion of the study, the Pearl Index at 12 months (with 95% confidence intervals(CI));
2. The level and rate of suppression of spermatogenesis induced by daily administration of NES-8/T-62 gel or NES-8/T-74 gel, as evaluated by the number and proportion of male participants who are rendered azoospermic (no sperm) and/or severely oligozoospermic (sperm concentration ≤1 million/mL) during the suppression phase of the study;
3. The maintenance of suppression of spermatogenesis induced by daily administration of NES-8/T-62 gel or NES-8/T-74 gel, as evaluated by the number and proportion of men who remain azoospermic (no sperm) or severely oligo-zoospermic (sperm concentration ≤1 million/mL) during the 52-week efficacy phase of the study.
4. The average length of time to recovery of spermatogenesis for all male participants who complete the efficacy phase and enter the recovery phase.
5. The alterations in circulating concentrations of gonadotropins, T, free T, NES, and sex hormone binding globulin (SHBG) as a result of administration of the investigational medicinal product (IMP).
6. The safety of the IMP as evaluated by number and frequency of reported adverse events (AE), number and frequency of abnormal safety laboratory test results and change in behavioral monitoring questionnaires when the male participants are using daily NES-8/T-62 gel or NES-8/T-74 gel.
7. The safety of the IMP as evaluated by the health of pregnancies, which will be followed up to one year post delivery in cases of contraceptive failure.
8. General safety recorded as AEs and SAEs.
9. The safety of the IMP as evaluated by changes in sexual function, prostate and mood.
10. The acceptability of this method as a contraceptive among both male participants and their participating female partners. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Study Week 76
2. Study Weeks 4, 8, 10, 12, 14, 16, 18, 20
3. Study Weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76
4. Study Weeks 80, 84, 88, 92, 96, 100, 104
5. Study Weeks 4, 8, 12, 16, 20
6. Study Weeks 0, 4, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104
7. Whenever applicable
8. Continuously thoroughout the clinical trial
9. Study Weeks 20, 28, 40, 52, 64, 76, 88, 104
10. Study Weeks 0, 24, 48, 76, 80 |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| 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 | No |
| 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 | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
| Italy |
| Kenya |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of the study will occur when the last male subject to be enrolled has completed his Exit Visit and all data is entered on the appropriate CRF pages. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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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