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

Study Overview
=================
Brief Summary
-----------------
This is a Phase I multicenter, double-blind, single dose, dose-ranging study, in healthy men to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of Dimethandrolone Undecanoate (DMAU) administered as an intramuscular or subcutaneous injection.

Detailed Description
-----------------
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.

Official Title
-----------------
Injectable DMAU for Male Contraception: Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of Single IM or SC DMAU Injection Dose Escalation Study in Healthy Male Volunteers

Conditions
-----------------
Healthy Men, Male Contraception

Intervention / Treatment
-----------------
* Drug: Dimethandrolone Undecanoate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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. 12. 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. 22. Partner is known to be pregnant. 23. Men desiring fertility within the first seven months of study participation. 24. 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. 26. Use of sex steroids or medications which might interfere with steroid metabolism (i.e. ketoconazole, finasteride, oral corticosteroids, dutasteride and statins). 27. Use of medications that will interfere or interact with DMAU.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo injections that look like the DMAU injections but with no active ingredients | Drug: Placebo<br>* Placebo injections that look like the DMAU injections but with no active ingredients<br>|
| Experimental: Dimethandrolone Undecanoate<br>Single doses of DMAU administered via injection intramuscularly (IM - 80 mg, 240 mg, 480 mg, and 800 mg) or administered subcutaneously (SC - 50 mg, 100 mg and 200 mg) | Drug: Dimethandrolone Undecanoate<br>* 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).<br>* Other names: DMAU;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in sexual function (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) using the psychosexual daily questionnaire |  | 5-7 months | 
| Changes from baseline in mood (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) using the Patient Health Questionnaire-9 |  | 5-7 months | 
| Changes from baseline in sodium (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in potassium (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in chloride (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in bicarbonate (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in fasting glucose (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in blood urea nitrogen (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in creatinine (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in calcium (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in total bilirubin (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in alkaline phosphatase (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in alanine aminotransferase (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in aspartate transaminase (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in albumin (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in blood pressure (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in pulse (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in respiratory rate (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 
| Changes from baseline in body mass index (safety and tolerability) with a single IM or SC injection of escalating doses of Dimethandrolone Undecanoate (DMAU) |  | 5-7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of DMAU and DMA using AUC (0-t, where t is the last time-point with measurable concentration) |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of serum Testosterone (T) using mean values at each visit |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of Dihydrotestosterone (DHT) using mean values at each visit |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of Estradiol (E2) using mean values at each visit |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of Follicle Stimulating Hormone (FSH) using mean values at each visit |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of Luteinizing Hormone (LH) using mean values at each visit |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of Sex Hormone Binding Globulin (SHBG) using mean values at each visit |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of serum T using number of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of serum T using percentage of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of DHT using number of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of DHT using percentage of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of E2 using number of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of E2 using percentage of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of FSH using number of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of FSH using of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of LH using number of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of LH using percentage of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of SHBG using number of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Pharmacodynamics of DMAU by assessing the suppression of SHBG using percentage of subjects with FSH and LH ≤ 1.0 IU/L |  | 5-7 months | 
| Suppression of spermatogenesis as assessed by semen analyses using number of subjects with sperm concentration <1 million (M)/mL |  | 5-7 months | 
| Suppression of spermatogenesis as assessed by semen analyses using percentage of subjects with sperm concentration <1 million (M)/mL |  | 5-7 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Healthy Men, Male Contraception, Androgen, Dimethandrolone