Injectable DMAU for Male Contraception in Healthy Male Volunteers (CCN015)

This single dose, dose-ranging study will be conducted in two centers: the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and the University of Washington.

Single doses of DMAU in castor oil/benzyl benzoate injections intramuscularly (IM) (80 mg, 240 mg, 480 mg, and 800 mg) or administered subcutaneously (SC) (50 mg, 100 mg and 200 mg) were selected for this dose-escalating study. Twelve subjects will complete this study at each of the DMAU doses (10 on DMAU and 2 on placebo injections) yielding a total of 84 completed subjects (70 on DMAU and 14 on placebo) across both sites. Safety will be assessed in all subjects and recovery will be assessed in two subjects receiving lower doses, either IM or SC, before additional men receive higher doses of IM or SC of DMAU. In addition to safety and tolerability, suppression of serum T, E2, gonadotropins, and SHBG will be assessed as secondary pharmacodynamic (PD) endpoints. PK of DMAU and DMA will be assessed through blood draws done at each visit. Suppression of spermatogenesis will be assessed with semen analysis.

DMAU injections will be administered at the study site by research nurses or physicians. For intramuscular injections, the staff will inject DMAU in castor oil into the gluteal region following standard procedures for intramuscular steroid injection. Abdominal subcutaneous injections will follow standard subcutaneous procedures. The subject will be observed for at least 30 minutes before release from the study site.

Inclusion criteria

Men who meet all the following criteria are eligible for enrollment in the trial:

• Male volunteers in good health as confirmed by physical examination, medical history, and clinical laboratory tests of blood and urine at the time of screening.
• 18 to 50 years of age (inclusive) at the time of the enrollment visit.
• BMI ≤ 33 calculated as weight in kg/ (height in m2).
• Weight ≥60 kg.
• No history of hormonal therapy use in the three months prior to the first screening visit.
• Agree to use a recognized effective method of contraception with any female partner (i.e. at a minimum, barrier plus an additional method of contraception) during the course of the study treatment and recovery phases until recovery is confirmed and study exit occurs.
• Subjects will refrain from donating blood or plasma during the study period.
• Subjects will be advised to refrain from excessive alcoholic consumption during the study period. (No more than 15 drinks per week and no alcohol consumption within 24 hours of a study visit.)
• No 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.
• In the opinion of the investigator, subject is able to comply with the protocol, understand and sign an informed consent and HIPAA form.

• Subjects will be advised to refrain from major changes in their level of exercise during the study period.

Exclusion criteria

Men who meet any of the following criteria are NOT eligible for enrollment in the trial:

• Men participating in another clinical trial involving an investigational drug within the 30 days prior to the first screening visit.
• Men not living in the catchment area of the clinic or within a reasonable distance from the study site.
• Clinically significant abnormal physical and laboratory findings at screening.
• Elevated PSA (levels ≥ 2.5 ng/mL) at screening, according to local laboratory normal values.
• Abnormal serum chemistry values at screening, according to local laboratory reference ranges that indicate liver or kidney dysfunction or that may be considered clinically significant. In addition, the following upper limits will be observed: fasting bilirubin less than 2 mg/dL, cholesterol less than 221 mg/dL, and fasting triglycerides less than 201 mg/dL.
• Abnormal semen analyses or abnormal semen concentration as defined by the WHO semen manual.
• Use of androgens within 3 months before first screening visit except for long acting testosterone injections (e.g. Testosterone undecanoate) which will require a wash out period of 6 months prior to screening.
• Ongoing use of body building substances including nutritional supplements.
• Systolic BP > 130 mm Hg and Diastolic blood pressure BP > 80 and mm Hg; Blood pressure (BP) will be taken 3 times at 5 - minute intervals and the mean of all measurements be used to determine eligibility).
• Clinically significant abnormal EKG or a QTc interval of > 450 msec.
• PHQ-9 score of 15 or above.
• History of hypertension, including hypertension controlled with treatment.
• Known history of primary testicular disease or disorders of the hypothalamic-pituitary axis.
• Benign or malignant liver tumors; active liver disease.
• History of breast carcinoma.
• Known history of androgen deficiency due to hypothalamic-pituitary or testicular disease.
• Known history of cardiovascular, renal, hepatic or prostatic disease or significant psychiatric illness.
• Positive serology for active Hepatitis (not immunization-related serology) or HIV at screening visit.
• A serious systemic disease such as diabetes mellitus or obesity (body weight greater than BMI >33 kg/m2 as above).
• History of known, untreated sleep apnea.

• Partner is known to be pregnant. 23. Men desiring fertility within the first seven months of study participation.

• 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) from a single injection.

• Use of sex steroids or medications which might interfere with steroid metabolism (i.e. ketoconazole, finasteride, oral corticosteroids, dutasteride and statins).

• Use of medications that will interfere or interact with DMAU.