Single Dose, Dose-Ranging Study of 11-β Methyl Nortestosterone Dodecylcarbonate (11β-MNTDC) in Healthy Men

Healthy Men Clinical Trial

— CCN014  

Official title:

Single Dose, Dose-Ranging Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics Study of 11-β Methyl Nortestosterone Dodecylcarbonate (11β-MNTDC) in Healthy Men

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02754687
• Other study ID #: CCN014
• Secondary ID: HHSN275201200002
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: April 2016
• Est. completion date: January 2020

Study information

• Verified date: August 2019
• Source: Health Decisions
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The long term objective is to develop a new male hormone 11-β Methyl Nortestosterone Dodecylcarbonate (11β-MNTDC) as a male hormonal contraceptive.

Description:

This is a Phase I multicenter, double-blind, single dose, dose-ranging study, in healthy men followed on an inpatient basis to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of 11β-methyl nortestosterone dodecylcarbonate (11β-MNTDC).

This single dose, dose-ranging study of 4 escalating doses will be conducted in two centers.

Initially, 12 men will be enrolled in total, 6 men at each center, with a goal of having a minimum of 12 healthy male subjects completing this study (10 active drugs and 2 placebos) both in the fed and fasting states at each dose.

Each of the 4 doses of 11β-MNTDC will be administered first fasting and then fed. Each of the doses of 11β-MNTDC will be administered about 28 days apart +/- 14 days with the time interval between the fasting and fed dosing will be approximately 7 days (-2/+9 days) and a 7 to 14 day washout will occur before dose escalation.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 12
• Est. completion date: January 2020
• Est. primary completion date: January 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

1. 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.

2. 18 to 50 years of age (inclusive).

3. BMI = 33 calculated as weight in kg/ (height in m2).

4. No history of hormonal therapy use in the last three months prior to the first screening visit.

5. Subject agrees to use a recognized effective method of contraception with any female partner (i.e. at a minimum, use barrier plus and additional method of contraception) during the course of the study treatment and recovery phase.

6. Subjects will refrain from donating blood or plasma during the study period.

7. Subjects will be advised to refrain/abstain from alcoholic beverages and grapefruit juice during the study period.

8. Subjects will not use cannabis or any recreational drugs at least 2 weeks before completing screening and during the study.

9. In the opinion of the investigator, subject is able to comply with the protocol, understand and sign an informed consent and HIPAA form.

10. Does not meet any of the exclusion criteria.

Exclusion Criteria:

1. Men participating in another clinical trial involving an investigational drug within the last 30 days prior to the first screening visit.

2. Men not living in the catchment area of the clinic or within a reasonable distance from the study site.

3. Clinically significant abnormal physical and laboratory findings at screening.

4. Elevated PSA (levels = 2.5 ng/mL), according to local laboratory normal values.

5. Abnormal serum chemistry values, according to local laboratory reference ranges that indicate liver or kidney dysfunction or that may be considered clinically significant except for: an upper limit for fasting bilirubin less than 2 mg/dL, upper limit for cholesterol less than 221 mg/dL, or upper limit for fasting triglycerides less than 201 mg/dL.

6. Use of androgens within 2 months before first screening visit.

7. Ongoing use of body building nutritional supplements.

8. Systolic BP > 135 mm Hg and Diastolic blood pressure BP > 85 and mm Hg; ((BP) Blood pressure will be taken 3 times at 5 - minute intervals and the mean of all measurements be considered).

9. Clinically significant abnormal EKG or a QTc interval of > 450 msec.

10. History of hypertension, including hypertension controlled with treatment.

11. Benign or malignant liver tumors; active liver disease.

12. History of breast carcinoma.

13. Known history of androgen deficiency due to hypothalamic-pituitary or testicular disease.

14. Known history of cardiovascular, renal, hepatic or prostatic disease or significant psychiatric illness.

15. Positive serology for active Hepatitis (not immunization-related serology) or HIV at screening visit.

16. A serious systemic disease such as diabetes mellitus or obesity (body weight greater than BMI >33 kg/m2 as above).

17. History of known, untreated sleep apnea.

18. Known or suspected alcoholism or drug abuse that may affect metabolism/transformation of steroid hormones or study treatment compliance.

19. Partner is known to be pregnant.

20. Men desiring fertility within the first 24 weeks of study participation.

21. Men participating in competitive sports where drug screening for prohibited substances (including anabolic steroids) is routine will be advised of the relative and temporary hazards that participating in this study may have for their sporting status.

Related Conditions & MeSH terms

• Healthy Men
• Male Contraception

Intervention

Drug:
• Placebo
Placebo with capsules that look like the 11ß-MNTDC capsules but with no active ingredients
• 11ßmethyl nortestosterone dodecylcarbonate
Escalating doses of 100, 200, 400, and 800 mg 11ß-MNTDC

Locations

Country	Name	City	State
United States	University of Washington	Seattle	Washington
United States	Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center	Torrance	California

Sponsors (4)

Lead Sponsor	Collaborator
Health Decisions	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Los Angeles Biomedical Research Institute, University of Washington

Country where clinical trial is conducted

United States, 

References & Publications (33)

Amory JK, Anawalt BD, Bremner WJ, Matsumoto AM. Daily testosterone and gonadotropin levels are similar in azoospermic and nonazoospermic normal men administered weekly testosterone: implications for male contraceptive development. J Androl. 2001 Nov-Dec;22(6):1053-60. — View Citation

Amory JK, Bremner WJ. Oral testosterone in oil plus dutasteride in men: a pharmacokinetic study. J Clin Endocrinol Metab. 2005 May;90(5):2610-7. Epub 2005 Feb 15. — View Citation

Anderson RA, Wallace AM, Wu FC. Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. III. Higher 5 alpha-reductase activity in oligozoospermic men administered supraphysiological doses of testosterone. J Clin Endocrinol Metab. 1996 Mar;81(3):902-8. — View Citation

Attardi BJ, Engbring JA, Gropp D, Hild SA. Development of dimethandrolone 17beta-undecanoate (DMAU) as an oral male hormonal contraceptive: induction of infertility and recovery of fertility in adult male rabbits. J Androl. 2011 Sep-Oct;32(5):530-40. doi: 10.2164/jandrol.110.011817. Epub 2010 Dec 16. — View Citation

Attardi BJ, Hild SA, Koduri S, Pham T, Pessaint L, Engbring J, Till B, Gropp D, Semon A, Reel JR. The potent synthetic androgens, dimethandrolone (7a,11ß-dimethyl-19-nortestosterone) and 11ß-methyl-19-nortestosterone, do not require 5a-reduction to exert their maximal androgenic effects. J Steroid Biochem Mol Biol. 2010 Oct;122(4):212-8. doi: 10.1016/j.jsbmb.2010.06.009. Epub 2010 Jun 25. — View Citation

Attardi BJ, Hild SA, Reel JR. Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity. Endocrinology. 2006 Jun;147(6):3016-26. Epub 2006 Feb 23. — View Citation

Attardi BJ, Marck BT, Matsumoto AM, Koduri S, Hild SA. Long-term effects of dimethandrolone 17ß-undecanoate and 11ß-methyl-19-nortestosterone 17ß-dodecylcarbonate on body composition, bone mineral density, serum gonadotropins, and androgenic/anabolic activity in castrated male rats. J Androl. 2011 Mar-Apr;32(2):183-92. doi: 10.2164/jandrol.110.010371. Epub 2010 Aug 26. — View Citation

Attardi BJ, Pham TC, Radler LC, Burgenson J, Hild SA, Reel JR. Dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11beta-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase. J Steroid Biochem Mol Biol. 2008 Jun;110(3-5):214-22. doi: 10.1016/j.jsbmb.2007.11.009. — View Citation

Bagchus WM, Hust R, Maris F, Schnabel PG, Houwing NS. Important effect of food on the bioavailability of oral testosterone undecanoate. Pharmacotherapy. 2003 Mar;23(3):319-25. — View Citation

Behre H M, Wang C, Handelsman D J & Nieschlag E. (2004) Pharmacology of Testosterone Preparations. In: Testosterone, Vol. Third (eds E Nieschlag & H M Behre), pp. 405-444. Cambridge University Press, Cambridge.

Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet. 1990 Oct 20;336(8721):955-9. — View Citation

Cook CE, Kepler JA. 7alpha,11beta-Dimethyl-19-nortestosterone: a potent and selective androgen response modulator with prostate-sparing properties. Bioorg Med Chem Lett. 2005 Feb 15;15(4):1213-6. — View Citation

Friedl KE, Hannan CJ Jr, Jones RE, Plymate SR. High-density lipoprotein cholesterol is not decreased if an aromatizable androgen is administered. Metabolism. 1990 Jan;39(1):69-74. — View Citation

Gooren LJ. A ten-year safety study of the oral androgen testosterone undecanoate. J Androl. 1994 May-Jun;15(3):212-5. — View Citation

Gu Y, Liang X, Wu W, Liu M, Song S, Cheng L, Bo L, Xiong C, Wang X, Liu X, Peng L, Yao K. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab. 2009 Jun;94(6):1910-5. doi: 10.1210/jc.2008-1846. Epub 2009 Mar 17. — View Citation

Heckel M J. (1939) Production of oliogspermia in a man by the use of testosterone propionate. Exl. Biol. Med. 40, 658-659.

Hild SA, Attardi BJ, Koduri S, Till BA, Reel JR. Effects of synthetic androgens on liver function using the rabbit as a model. J Androl. 2010 Sep-Oct;31(5):472-81. doi: 10.2164/jandrol.109.009365. Epub 2010 Apr 8. — View Citation

Houwing NS, Maris F, Schnabel PG, Bagchus WM. Pharmacokinetic study in women of three different doses of a new formulation of oral testosterone undecanoate, Andriol Testocaps. Pharmacotherapy. 2003 Oct;23(10):1257-65. — View Citation

McLachlan RI, Robertson DM, Pruysers E, Ugoni A, Matsumoto AM, Anawalt BD, Bremner WJ, Meriggiola C. Relationship between serum gonadotropins and spermatogenic suppression in men undergoing steroidal contraceptive treatment. J Clin Endocrinol Metab. 2004 Jan;89(1):142-9. — View Citation

Nieschlag E, Mauss J, Coert A, Kicovic P. Plasma androgen levels in men after oral administration of testosterone or testosterone undecanoate. Acta Endocrinol (Copenh). 1975 Jun;79(2):366-74. — View Citation

Piotrowska K, Wang C, Swerdloff RS, Liu PY. Male hormonal contraception: hope and promise. Lancet Diabetes Endocrinol. 2017 Mar;5(3):214-223. doi: 10.1016/S2213-8587(16)00034-6. Epub 2016 Feb 23. Review. — View Citation

Qoubaitary A, Swerdloff RS, Wang C. Advances in male hormone substitution therapy. Expert Opin Pharmacother. 2005 Aug;6(9):1493-506. Review. — View Citation

Roth MY, Page ST, Bremner WJ. Male hormonal contraception: looking back and moving forward. Andrology. 2016 Jan;4(1):4-12. doi: 10.1111/andr.12110. Epub 2015 Oct 9. Review. — View Citation

Rothman MS, Carlson NE, Xu M, Wang C, Swerdloff R, Lee P, Goh VH, Ridgway EC, Wierman ME. Reexamination of testosterone, dihydrotestosterone, estradiol and estrone levels across the menstrual cycle and in postmenopausal women measured by liquid chromatography-tandem mass spectrometry. Steroids. 2011 Jan;76(1-2):177-82. doi: 10.1016/j.steroids.2010.10.010. Epub 2010 Nov 9. — View Citation

Skakkebaek NE, Bancroft J, Davidson DW, Warner P. Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clin Endocrinol (Oxf). 1981 Jan;14(1):49-61. — View Citation

Surampudi P, Page ST, Swerdloff RS, Nya-Ngatchou JJ, Liu PY, Amory JK, Leung A, Hull L, Blithe DL, Woo J, Bremner WJ, Wang C. Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive. Andrology. 2014 Jul;2(4):579-587. doi: 10.1111/j.2047-2927.2014.00216.x. Epub 2014 May 2. — View Citation

Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Longstreth J, Berman N. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab. 2000 Dec;85(12):4500-10. — View Citation

Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999 Oct;84(10):3666-72. — View Citation

von Eckardstein S, Noe G, Brache V, Nieschlag E, Croxatto H, Alvarez F, Moo-Young A, Sivin I, Kumar N, Small M, Sundaram K; International Committee for Contraception Research, The Population Council. A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men. J Clin Endocrinol Metab. 2003 Nov;88(11):5232-9. — View Citation

Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab. 2004 Feb;89(2):534-43. — View Citation

Wang C, Shiraishi S, Leung A, Baravarian S, Hull L, Goh V, Lee PW, Swerdloff RS. Validation of a testosterone and dihydrotestosterone liquid chromatography tandem mass spectrometry assay: Interference and comparison with established methods. Steroids. 2008 Dec 12;73(13):1345-52. doi: 10.1016/j.steroids.2008.05.004. Epub 2008 May 21. Erratum in: Steroids. 2018 Jul;135:108. — View Citation

Wang C, Swerdloff R, Kipnes M, Matsumoto AM, Dobs AS, Cunningham G, Katznelson L, Weber TJ, Friedman TC, Snyder P, Levine HL. New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. J Clin Endocrinol Metab. 2004 Aug;89(8):3821-9. — View Citation

World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996 Apr;65(4):821-9. Erratum in: Fertil Steril 1996 Jun;65(6):1267. — View Citation

* Note: There are 33 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and tolerability of single dose oral administration of up to 4 escalating doses of 11-ß methyl nortestosterone dodecylcarbonate (11ß-MNTDC) as measured by adverse events	As by adverse events	12-20 weeks
Primary	Safety and tolerability of single dose oral administration of up to 4 escalating doses of 11-ß methyl nortestosterone dodecylcarbonate (11ß-MNTDC) as measured by changes from baseline in vital signs	As by changes from baseline in vital signs	12-20 weeks
Primary	Safety and tolerability of single dose oral administration of up to 4 escalating doses of 11-ß methyl nortestosterone dodecylcarbonate (11ß-MNTDC) as measured by changes from baseline in electrocardiogram (EKG)	As by changes from baseline in EKG	12-20 weeks
Primary	Safety and tolerability of single dose oral administration of up to 4 escalating doses of 11-ß methyl nortestosterone dodecylcarbonate (11ß-MNTDC) as measured by changes from baseline in physical exams	As by changes from baseline in physical exams	12-20 weeks
Primary	Safety and tolerability of single dose oral administration of up to 4 escalating doses of 11-ß methyl nortestosterone dodecylcarbonate (11ß-MNTDC) as measured by changes from baseline in lab tests	As by changes from baseline in lab tests	12-20 weeks
Secondary	Pharmacokinetics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose using area under the curve (AUC)	11ß-MNTDC PK levels at various time points through the 112 days of treatment using AUC	112 days
Secondary	Pharmacokinetics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose using maximum concentration (Cmax)	11ß-MNTDC PK levels at various time points through the 112 days of treatment using Cmax	112 days
Secondary	Pharmacokinetics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose using Time to Reach Maximum Concentration (Tmax)	11ß-MNTDC PK levels at various time points through the 112 days of treatment using Tmax	112 days
Secondary	Pharmacodynamics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Luteinizing Hormone (LH)	11ß-MNTDC PD levels at various time points through the 112 days of treatment	112 days
Secondary	Pharmacodynamics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Follicle Stimulating Hormone (FSH)	11ß-MNTDC PD levels at various time points through the 112 days of treatment	112 days
Secondary	Pharmacodynamics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Testosterone (T)	11ß-MNTDC PD levels at various time points through the 112 days of treatment	112 days
Secondary	Pharmacodynamics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by free Testosterone (free T)	11ß-MNTDC PD levels at various time points through the 112 days of treatment	112 days
Secondary	Pharmacodynamics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Dihydrotestosterone (DHT)	11ß-MNTDC PD levels at various time points through the 112 days of treatment	112 days
Secondary	Pharmacodynamics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by estradiol (E2)	11ß-MNTDC PD levels at various time points through the 112 days of treatment	112 days
Secondary	Pharmacodynamics of 11ß-MNTDC after 4 escalating oral doses of 11ß-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Sex Hormone Binding Globulin (SHBG)	11ß-MNTDC PD levels at various time points through the 112 days of treatment	112 days
Secondary	Effect of food on the pharmacokinetics of orally administered 11ß-MNTDC using Average Concentration (Cavg)	Comparison of pharmacokinetic measures among the single dose periods and comparison of PK parameters in the fed and fasting states will be performed with mixed model repeated measures analysis of variance (ANOVA). Evidence of lack of food effect will be concluded if ANOVA-estimated PK parameters (Cavg) after food are within 80 to 125% of those obtained at the fasting state.	112 days
Secondary	Effect of food on the pharmacokinetics of orally administered 11ß-MNTDC using the area under the curve from 0-24 hours (AUC 0-24h)	Comparison of pharmacokinetic measures among the single dose periods and comparison of PK parameters in the fed and fasting states will be performed with mixed model repeated measures analysis of variance (ANOVA). Evidence of lack of food effect will be concluded if ANOVA-estimated PK parameters (AUC0-24h) after food are within 80 to 125% of those obtained at the fasting state.	112 days
Secondary	Effect of food on the pharmacokinetics of orally administered 11ß-MNTDC using maximum concentration (Cmax)	Comparison of pharmacokinetic measures among the single dose periods and comparison of PK parameters in the fed and fasting states will be performed with mixed model repeated measures analysis of variance (ANOVA). Evidence of lack of food effect will be concluded if ANOVA-estimated PK parameters (Cmax) after food are within 80 to 125% of those obtained at the fasting state.	112 days