Clinical Evaluation of Daily Application of Nestorone? (NES) and Testosterone (T) Combination Gel for Male Contraception

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Description

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the Population Council (PC) have a mission to develop safe and effective contraceptives for both men and women. Many women cannot use hormonal contraception and decide to rely on their male partner to protect them from unplanned pregnancy. Current contraceptive methods available for men are limited to vasectomy and condoms. A majority of men surveyed internationally are interested and willing to use male contraceptive methods (Martin et al., 2000; Heinemann et al., 2005; Dorman and Bishai, 2012) and female partners support male involvement (Glasier et al. 2000). Unfortunately, no safe, highly effective, reversible method is available to men. Development of effective male contraceptive regimens remains a challenge for the field. Furthermore, the success of hormonal male contraception depends on the near complete suppression of spermatogenesis with minimal effects on libido or other androgen-dependent functions. The steady-state delivery of a progestin and an androgen by transdermal gel application would be a user-controlled delivery method as compared to injectable or implant approaches. Several studies using testosterone (T) ester IM injections or T implants plus a long acting progestin (depo–Medroxyprogesterone acetate) have validated the efficacy, safety and reversibility of male hormonal contraceptive strategies (Gu et al., 2009; Gu et al., 2003; Turner et al., 2003; WHO Task Force, 1990; WHO Task Force, 1996, Behre et al, 2016). Testosterone alone is not as efficacious as T plus a progestin both in the rate and extent of suppression of spermatogenesis (Liu et al., 2008). The mechanism whereby progestin therapies exert a contraceptive effect is due to inhibition of gonadotropin secretion by a negative feedback mechanism not involving androgen receptors (e.g. putative progesterone receptors) and they may have a direct action at the testes to inhibit local T production. Male hormonal contraceptive strategies have relied on combinations of T (e.g. T ester injections, T implants, T patches) with oral, injections and implants of mainly 19-nortestosterone derived progestins (e.g. levonorgestrel, etonogestrel, norethisterone enanthate). To achieve azoospermia by exogenously administered hormones, endogenous T production is suppressed; therefore, part of the purpose of the T supplementation in the male hormonal contraceptive is to restore serum T levels to the normal range. Nestorone? (NES, 16-methylen-17α-acetoxy-19-norpregn-4-ene-3, 20-dione) (international nonproprietary name segesterone acetate) is the first 19-norprogesterone-derived progestin to be used for contraception in men and has been extensively studied in women. It has been FDA-approved in a first contraceptive system for women (Annovera?). NES is a synthetic progestin structurally related to progesterone that does not have any androgenic, estrogenic or glucocorticoid activity at therapeutic doses (Sitruk-Ware, 2006) and does not interact with GABA-Receptors (Kumar et al, 2017). It is therefore not expected to have some of the undesirable side effects of levonorgestrel or DMPA such as weight gain or mood changes. A pilot study using T and NES transdermal gels (8mg of NES and 100mg T in 1 % T gel) (CCN005) in healthy men for 20 days showed dose-dependent gonadotropin suppression without any significant adverse events (Mahabadi et al., 2009). More recently we have studied NES gel (0, 8, or 12 mg/day) in addition to testosterone (T) gel (100 mg T in 1% T gel per day) (CCN007), both applied transdermally in healthy male volunteers to suppress sperm production (Ilani et al., 2012). In this study, efficacy data analyses were performed on 56 male subjects who adhered to the protocol and completed at least 20 weeks of treatment. The percentage of men whose sperm concentration was suppressed to 

Details
Age

Adult

Eligibility

Male Partner Inclusion Criteria: Men who meet all the following criteria will be eligible for enrollment in the trial: 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 (refer to Appendix 11 for acceptable forms of contraception) 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, understand and sign an informed consent and HIPAA form; 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&#8217;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: a. Sperm concentration &#8805;15 million/mL in two semen samples with and no gross abnormalities of sperm motility and morphology on at least one semen sample assessment; b. Screening Testosterone within the study site&#8217;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; 10.1.2 Female Partner Inclusion Criteria: Females who meet all the following criteria are eligible for participation in the trial: 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 to 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&#8217;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

Male Partner Inclusion Criteria: Men who meet all the following criteria will be eligible for enrollment in the trial: 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 (refer to Appendix 11 for acceptable forms of contraception) 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, understand and sign an informed consent and HIPAA form; 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: a. Sperm concentration ≥15 million/mL in two semen samples with and no gross abnormalities of sperm motility and morphology on at least one semen sample assessment; b. 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; 10.1.2 Female Partner Inclusion Criteria: Females who meet all the following criteria are eligible for participation in the trial: 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 to 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

Type of Study

Outcomes Research

Locations

Comprehensive Women's Health Center

Principal Investigator
Photograph of Aaron Lazorwitz,  MD, MSCS

Aaron Lazorwitz, MD, MSCS

Study ID

Protocol Number: 21-3956

More information available at ClinicalTrials.gov: NCT03452111

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