RA-2 13-cis Retinoic Acid (Isotretinoin)

NCT02061384 | Completed Phase 2 Results

• 1 other identifier: STUDY00000564
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Men with infertility and normal hormone levels have few options for fertility treatment. Previous research work has suggested that men with infertility may have low levels of the active form of Vitamin A, called retinoic acid, in their testes. We think that giving men with low sperm counts retinoic acid may increase their sperm counts and improve their chances of fathering a pregnancy. We want to see if retinoic acid administration over twenty weeks can increase sperm production and help infertile men become fathers without the need for In vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). We also want to see if adding calcitriol with retinoic acid will improve sperm motility in a sub-set of subjects.

Conditions

Male Infertility; Klinefelter's Syndrome; Y-chromosome Microdeletions

Keywords

Infertility

Outcome Measures

Primary Outcomes (1)

• Millions of Sperm Per Ejaculate

  Millions of sperm per ejaculate in men treated with 13-cis retinoic acid

  Up to 20-weeks

Study Arms (2)

13-cis retinoic acid

EXPERIMENTAL

20mg 13-cis retinoic acid twice daily (BID) with meals for 20 weeks

Drug: 13-cis retinoic acid

Calcitriol 0.25 mcg

EXPERIMENTAL

oral calcitriol 025 mcg BID subjects 11-20 for 20 weeks

Drug: 13-cis retinoic acid; Drug: Calcitriol

Interventions

13-cis retinoic acid DRUG

Accutane is used for the treatment of severe acne

Also known as: Accutane, Isotretinoin

13-cis retinoic acid; Calcitriol 0.25 mcg

Calcitriol DRUG

Calcitriol is a form of vitamin D given twice daily (BID)

Also known as: 1,25-dihydroxyvitamin D3

Calcitriol 0.25 mcg

Eligibility Criteria

• Age: 21 Years - 60 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Subjects will be infertile men (no pregnancy with partner with normal cycles and normal hysterosalpingogram despite \>1 year of unprotected intercourse).
• Abnormal sperm analyses with a total, motile sperm count of less than 10 million sperm as assessed by semen analysis on two occasions separated by one week.
• In the opinion of the investigator, is able to comply with the protocol, understand and sign an informed consent and HIPAA (Health Insurance Portability and Accountability Act ) form.

You may not qualify if:

• Men participating in another clinical trial
• Men not living in the catchment area of the clinic
• Clinically significant abnormal findings at screening
• Known genetic infertility (e.g. Klinefelter syndrome or Y-chromosome microdeletions),
• Hypogonadotropic hypogonadism (that might respond to gonadotropin injections),
• The use of anabolic steroids, illicit drugs, or the consumption of more than 4 alcoholic beverages daily
• Severe mental health problems requiring medications
• Current therapy with retinoic acid (e.g. Accutane) or vitamin A.
• Score of greater than 15 on the Patient health questionnaire (PHQ9).
• Men with a personal history of serious psychiatric disorders
• Men currently receiving tetracycline containing medications
• Men currently receiving phenytoin
• Men with a history of inflammatory bowel disease
• Men with a history of bone disease
• Men who have used isotretinoin within eight weeks of the start of dosing

Sponsors & Collaborators

• University of Washington: lead

Study Sites (1)

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Related Publications (25)

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  PMID: 8102079 BACKGROUND

• de Kretser DM. Male infertility. Lancet. 1997 Mar 15;349(9054):787-90. doi: 10.1016/s0140-6736(96)08341-9. No abstract available.

  PMID: 9074589 BACKGROUND

• Schlegel PN. Nonobstructive azoospermia: a revolutionary surgical approach and results. Semin Reprod Med. 2009 Mar;27(2):165-70. doi: 10.1055/s-0029-1202305. Epub 2009 Feb 26.

  PMID: 19247918 BACKGROUND

• Napoli JL. Retinoic acid: its biosynthesis and metabolism. Prog Nucleic Acid Res Mol Biol. 1999;63:139-88. doi: 10.1016/s0079-6603(08)60722-9.

  PMID: 10506831 BACKGROUND

• Center for Disease Control. Infertility Facts,m accessed at http://www.ede.gov/nchs/fastats/fertile.htm (June 3, 2013)

  BACKGROUND

• Doyle TJ, Braun KW, McLean DJ, Wright RW, Griswold MD, Kim KH. Potential functions of retinoic acid receptor A in Sertoli cells and germ cells during spermatogenesis. Ann N Y Acad Sci. 2007 Dec;1120:114-30. doi: 10.1196/annals.1411.008. Epub 2007 Sep 28.

  PMID: 17905941 BACKGROUND

• Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2474-9. doi: 10.1073/pnas.0510813103. Epub 2006 Feb 6.

  PMID: 16461896 BACKGROUND

• Anderson EL, Baltus AE, Roepers-Gajadien HL, Hassold TJ, de Rooij DG, van Pelt AM, Page DC. Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14976-80. doi: 10.1073/pnas.0807297105. Epub 2008 Sep 17.

  PMID: 18799751 BACKGROUND

• Chung SS, Wang X, Wolgemuth DJ. Expression of retinoic acid receptor alpha in the germline is essential for proper cellular association and spermiogenesis during spermatogenesis. Development. 2009 Jun;136(12):2091-100. doi: 10.1242/dev.020040.

  PMID: 19465599 BACKGROUND

• Dufour JM, Kim KH. Cellular and subcellular localization of six retinoid receptors in rat testis during postnatal development: identification of potential heterodimeric receptors. Biol Reprod. 1999 Nov;61(5):1300-8. doi: 10.1095/biolreprod61.5.1300.

  PMID: 10529278 BACKGROUND

• Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P. Function of retinoic acid receptor gamma in the mouse. Cell. 1993 May 21;73(4):643-58. doi: 10.1016/0092-8674(93)90246-m.

  PMID: 8388780 BACKGROUND

• Lufkin T, Lohnes D, Mark M, Dierich A, Gorry P, Gaub MP, LeMeur M, Chambon P. High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7225-9. doi: 10.1073/pnas.90.15.7225.

  PMID: 8394014 BACKGROUND

• Kastner P, Mark M, Leid M, Gansmuller A, Chin W, Grondona JM, Decimo D, Krezel W, Dierich A, Chambon P. Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev. 1996 Jan 1;10(1):80-92. doi: 10.1101/gad.10.1.80.

  PMID: 8557197 BACKGROUND

• Ghyselinck NB, Vernet N, Dennefeld C, Giese N, Nau H, Chambon P, Viville S, Mark M. Retinoids and spermatogenesis: lessons from mutant mice lacking the plasma retinol binding protein. Dev Dyn. 2006 Jun;235(6):1608-22. doi: 10.1002/dvdy.20795.

  PMID: 16586441 BACKGROUND

• Hoting VE, Schutte B, Schirren C. [Isotretinoin treatment of acne conglobata. Andrologic follow-up]. Fortschr Med. 1992 Aug 20;110(23):427-30. German.

  PMID: 1398387 BACKGROUND

• Vogt HJ, Ewers R. [13-cis-Retinoic acid and spermatogenesis. Spermatological and impulse cytophotometric studies]. Hautarzt. 1985 May;36(5):281-6. German.

  PMID: 3159708 BACKGROUND

• Torok L, Kadar L, Kasa M. Spermatological investigations in patients treated with etretinate and isotretinoin. Andrologia. 1987 Nov-Dec;19(6):629-33. doi: 10.1111/j.1439-0272.1987.tb01915.x.

  PMID: 3481225 BACKGROUND

• Nya-Ngatchou JJ, Arnold SL, Walsh TJ, Muller CH, Page ST, Isoherranen N, Amory JK. Intratesticular 13-cis retinoic acid is lower in men with abnormal semen analyses: a pilot study. Andrology. 2013 Mar;1(2):325-31. doi: 10.1111/j.2047-2927.2012.00033.x. Epub 2012 Nov 29.

  PMID: 23413144 BACKGROUND

• WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction

  BACKGROUND

• Christiansen C, Christensen MS, Rodbro P, Hagen C, Transbol I. Effect of 1,25-dihydroxy-vitamin D3 in itself or combined with hormone treatment in preventing postmenopausal osteoporosis. Eur J Clin Invest. 1981 Aug;11(4):305-9. doi: 10.1111/j.1365-2362.1981.tb02121.x.

  PMID: 6795047 BACKGROUND

• Riggs BL, Nelson KI. Effect of long term treatment with calcitriol on calcium absorption and mineral metabolism in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1985 Sep;61(3):457-61. doi: 10.1210/jcem-61-3-457.

  PMID: 3926808 BACKGROUND

• Falch JA, Odegaard OR, Finnanger AM, Matheson I. Postmenopausal osteoporosis: no effect of three years treatment with 1,25-dihydroxycholecalciferol. Acta Med Scand. 1987;221(2):199-204. doi: 10.1111/j.0954-6820.1987.tb01267.x.

  PMID: 3035879 BACKGROUND

• Caniggia A, Nuti R, Lore F, Martini G, Turchetti V, Righi G. Long-term treatment with calcitriol in postmenopausal osteoporosis. Metabolism. 1990 Apr;39(4 Suppl 1):43-9. doi: 10.1016/0026-0495(90)90272-e.

  PMID: 2325571 BACKGROUND

• Ott SM, Chesnut CH 3rd. Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med. 1989 Feb 15;110(4):267-74. doi: 10.7326/0003-4819-110-4-267.

  PMID: 2913914 BACKGROUND

• Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab. 2001 Aug;86(8):3618-28. doi: 10.1210/jcem.86.8.7703.

  PMID: 11502787 BACKGROUND

MeSH Terms

Conditions

Infertility, Male; Klinefelter Syndrome; Male sterility due to Y-chromosome deletions; Infertility

Interventions

Isotretinoin; Calcitriol

Condition Hierarchy (Ancestors)

Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Male Urogenital Diseases; Sex Chromosome Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Sex Chromosome Disorders; Chromosome Disorders; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Gonadal Disorders; Endocrine System Diseases; Hypogonadism

Intervention Hierarchy (Ancestors)

Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors; Dihydroxycholecalciferols; Hydroxycholecalciferols; Cholecalciferol; Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids

Results Point of Contact

• Title: Dr. John Amory
• Organization: University of Washington School of Medicine

jamory@uw.edu

2066161727

Study Officials

• John K Amory, MD, MPH

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, General Internal Medicine

Study Record Dates

• First Submitted: February 10, 2014
• First Posted: February 12, 2014
• Study Start: August 1, 2014
• Primary Completion: December 1, 2018
• Study Completion: December 1, 2018
• Last Updated: August 2, 2021
• Results First Posted: July 30, 2021

Record last verified: 2021-06

Locations

US (1)