PROS-1-Male Hormonal Contraceptive Regimens on Prostate Tissue

NCT00490555 | Completed Phase 2 Results

• 3 other identifiers: 31434-ARFA-HD-06-014;06-4795-A 01
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators propose to examine the in vivo responses to hormonal manipulation at the molecular level directly in the tissue of interest (prostate). As in the investigators' previous, pilot study, the investigators will use the novel approach of procuring tissue specimens from normal, healthy men who might be chose to use a male hormonal contraceptive regimen were it available. The investigators will employ state of the art techniques such as laser capture microdissection (LCM) and cDNA microarrays to determine the tissue-specific consequences of male hormonal contraceptive regimens on the prostate. The results will help guide the design, safety monitoring, and selection of male hormonal contraceptive agents and provide valuable insights into prostate human prostate biology. The investigators will test the hypothesis that exogenous T administration that results in increased circulating T and dihydrotestosterone (DHT) levels will increase intraprostatic concentrations of T and its metabolite DHT. The investigators will test the hypothesis that the addition of a potent 5α-reductase inhibitor, dutasteride, or the progestin, Depomedoxyprogesterone (IM DMPA), to T administration in young and middle aged men will decrease intraprostatic DHT and increase intraprostatic T concentrations compared to T alone. The investigators will test the hypothesis that the addition of a 5α-reductase inhibitor dutasteride or the progestin IM DMPA to exogenous T, by reducing intraprostatic DHT, will decrease prostate epithelial proliferation, assessed by Ki-67 labeling index (Ki-67LI), and increase apoptosis, assessed by caspase-3 expression, and decrease androgen-regulated protein expression such as prostate specific antigen (PSA). The investigators will test the hypothesis that the addition of a 5α-reductase inhibitor or the progestin IM DMPA to exogenous T, by modifying the intraprostatic hormonal milieu, will alter prostate epithelial gene expression. Specifically, the investigators expect that the addition of the 5α-reductase inhibitor dutasteride or the progestin IM DMPA to exogenous T, will result in decreased expression of androgen-regulated genes such as PSA.

Conditions

Healthy

Keywords

Male Contraception; Testosterone; Testis; Contraception; Prostate

Outcome Measures

Primary Outcomes (3)

• Prostate-specific Antigen (PSA)

  PSA level week 10 end of treatment

  10 weeks

• Testosterone Concentration

  10 weeks

• Dihydrotestosterone (DHT) Concentration

  10 weeks

Secondary Outcomes (2)

• Androstenedione (AED)

  10 weeks

• Dehydroepiandrosterone (DHEA)

  10 weeks

Study Arms (4)

1

PLACEBO COMPARATOR

Placebo gel + Placebo pill + placebo injection

Other: Placebo Testosterone gel; Other: Placebo dutasteride; Other: Placebo DMPA

2

ACTIVE COMPARATOR

Testosterone 1% transdermal gel 10 g + placebo pill + placebo injection

Drug: Testosterone gel

3

ACTIVE COMPARATOR

Testosterone 1% transdermal gel 10 g + dutasteride 0.5 mg Orally + placebo injection

Drug: Testosterone gel; Drug: Dutasteride

4

ACTIVE COMPARATOR

Testosterone 1% transdermal gel 10 g + placebo pill + DMPA 300 mg injection (IM)

Drug: Testosterone gel; Drug: Depo-Medroxyprogesterone (DMPA); Other: Placebo dutasteride

Interventions

Testosterone gel DRUG

Testosterone gel 10 g

Also known as: Testim

2; 3; 4

Dutasteride DRUG

dutasteride 0.5 mg orally

Also known as: Avodart

3

Depo-Medroxyprogesterone (DMPA) DRUG

300 mg DMPA injection on Day 0 IM (into the muscle)

Also known as: Depo-Provera

4

Placebo Testosterone gel OTHER

Place gel applied daily for 12 weeks

1

Placebo dutasteride OTHER

placebo pill for 12 weeks

1; 4

Placebo DMPA OTHER

placebo DMPA injection Once

1

Eligibility Criteria

• Age: 25 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Men in good health, and without a history of chronic androgen therapy or known history of gonadal or prostate abnormalities.
• PSA ≤ 2.
• Age 25-55 years
• Ability to understand the study,study procedures and provide consent
• Normal serum total T, LH, FSH, urine analyses, and sperm count \> or equal to 15million/ml
• International Prostate Symptom Score (IPSS) \< 10
• Normal seminal fluid analysis (\>20 million sperm/ml)
• Agree not to donate blood during the treatment and recovery periods

You may not qualify if:

• A history or evidence of prostate or breast cancer
• History of invasive therapy for BPH
• History of acute urinary retention
• Current or past treatment with a 5α-reductase inhibitor
• History of anti/androgenic drugs or drugs that interfere with steroid metabolism within past 3 months
• Severe systemic illness (renal, liver, cardiac, lung disease, cancer, poorly controlled diabetes)
• Known untreated obstructive sleep apnea
• Hematocrit \> 52%
• Skin disease that might interfere with T gel absorption
• Hypersensitivity to any of the drugs used in the study
• History of a bleeding disorder or anticoagulation
• History of drug or alcohol abuse within 12 months
• History of infertility or desire for fertility within 12 months, or current pregnant partner
• A first-degree relative (i.e. father, brother) with a history of prostate cancer
• Abnormal digital rectal examination or prostate ultrasound

Sponsors & Collaborators

• University of Washington: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

University of Washington

Seattle, Washington, 98195, United States

Location

Related Publications (15)

• Amory JK, Page ST, Bremner WJ. Drug insight: Recent advances in male hormonal contraception. Nat Clin Pract Endocrinol Metab. 2006 Jan;2(1):32-41. doi: 10.1038/ncpendmet0069.

  PMID: 16932251 BACKGROUND

• Brady BM, Amory JK, Perheentupa A, Zitzmann M, Hay CJ, Apter D, Anderson RA, Bremner WJ, Pollanen P, Nieschlag E, Wu FC, Kersemaekers WM. A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive. Hum Reprod. 2006 Jan;21(1):285-94. doi: 10.1093/humrep/dei300. Epub 2005 Sep 19.

  PMID: 16172147 BACKGROUND

• Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol. 2004 Apr;190(4 Suppl):S5-22. doi: 10.1016/j.ajog.2004.01.061.

  PMID: 15105794 BACKGROUND

• Jacobsen SJ, Girman CJ, Lieber MM. Natural history of benign prostatic hyperplasia. Urology. 2001 Dec;58(6 Suppl 1):5-16; discussion 16. doi: 10.1016/s0090-4295(01)01298-5.

  PMID: 11750242 BACKGROUND

• Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43.

  PMID: 17237035 BACKGROUND

• Wilson JD, George FW. The Physiology of Reproduction. Raven Press, 1994

  BACKGROUND

• Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994;63:25-61. doi: 10.1146/annurev.bi.63.070194.000325. No abstract available.

  PMID: 7979239 BACKGROUND

• Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003 Jul 17;349(3):215-24. doi: 10.1056/NEJMoa030660. Epub 2003 Jun 24.

  PMID: 12824459 BACKGROUND

• Geller J. Effect of finasteride, a 5 alpha-reductase inhibitor on prostate tissue androgens and prostate-specific antigen. J Clin Endocrinol Metab. 1990 Dec;71(6):1552-5. doi: 10.1210/jcem-71-6-1552.

  PMID: 1699965 BACKGROUND

• Geller J, Albert J. Effects of castration compared with total androgen blockade on tissue dihydrotestosterone (DHT) concentration in benign prostatic hyperplasia (BPH). Urol Res. 1987;15(3):151-3. doi: 10.1007/BF00254427.

  PMID: 3629749 BACKGROUND

• Mohler JL, Gregory CW, Ford OH 3rd, Kim D, Weaver CM, Petrusz P, Wilson EM, French FS. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004 Jan 15;10(2):440-8. doi: 10.1158/1078-0432.ccr-1146-03.

  PMID: 14760063 BACKGROUND

• Forti G, Salerno R, Moneti G, Zoppi S, Fiorelli G, Marinoni T, Natali A, Costantini A, Serio M, Martini L, et al. Three-month treatment with a long-acting gonadotropin-releasing hormone agonist of patients with benign prostatic hyperplasia: effects on tissue androgen concentration, 5 alpha-reductase activity and androgen receptor content. J Clin Endocrinol Metab. 1989 Feb;68(2):461-8. doi: 10.1210/jcem-68-2-461.

  PMID: 2465302 BACKGROUND

• Habib FK, Ross M, Tate R, Chisholm GD. Differential effect of finasteride on the tissue androgen concentrations in benign prostatic hyperplasia. Clin Endocrinol (Oxf). 1997 Feb;46(2):137-44. doi: 10.1046/j.1365-2265.1997.950908.x.

  PMID: 9135694 BACKGROUND

• Page ST, Lin DW, Mostaghel EA, Hess DL, True LD, Amory JK, Nelson PS, Matsumoto AM, Bremner WJ. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab. 2006 Oct;91(10):3850-6. doi: 10.1210/jc.2006-0968. Epub 2006 Aug 1.

  PMID: 16882745 BACKGROUND

• Page ST, Amory JK, Anawalt BD, Irwig MS, Brockenbrough AT, Matsumoto AM, Bremner WJ. Testosterone gel combined with depomedroxyprogesterone acetate is an effective male hormonal contraceptive regimen and is not enhanced by the addition of a GnRH antagonist. J Clin Endocrinol Metab. 2006 Nov;91(11):4374-80. doi: 10.1210/jc.2006-1411. Epub 2006 Aug 29.

  PMID: 16940442 BACKGROUND

MeSH Terms

Interventions

Testosterone; Dutasteride; N,N-dimethyl-4-anisidine; Medroxyprogesterone Acetate

Intervention Hierarchy (Ancestors)

Androstenols; Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Testosterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Azasteroids; Steroids, Heterocyclic; Medroxyprogesterone; Hydroxyprogesterones; Progesterone; Pregnenediones; Pregnenes; Pregnanes

Results Point of Contact

• Title: Dr. Stephanie Page
• Organization: University of Washington

page@u.washington.edu

2066160483

Study Officials

• Stephanie T Page, MD, PhD

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: June 20, 2007
• First Posted: June 22, 2007
• Study Start: January 1, 2009
• Primary Completion: January 1, 2012
• Study Completion: March 1, 2012
• Last Updated: November 15, 2013
• Results First Posted: November 15, 2013

Record last verified: 2013-09

Locations

US (1)