RA-4: 13-cis Retinoic Acid for Treatment of Men With Azoospermia

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT03323801
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 10
• Location: 1
• Arm: 1
• Actual Duration (Months): 22.2
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Men with infertility and normal hormone levels have few options for fertility treatment. Previous research suggests that men with infertility may have low levels of the active form of Vitamin A, called retinoic acid, in their testes. In a pilot study of 20 men with low numbers of sperm (<10 million motile sperm), roughly half the men showed improvement in sperm production. Thus, we want to see if retinoic acid administration to men with azoospermia (no sperm present) can initiate sperm production.

Condition or Disease	Intervention/Treatment	Phase
Male Infertility, Azoospermia	Drug: 13-cis retinoic acid	Phase 2

Detailed Description

Twenty men with infertility, aged 21 - 60, due to azoospermia (no apparent sperm in the ejaculate on two separate occasions) will be enrolled in a single-arm pilot trial of daily oral therapy of 20 mg twice daily of 13-cis retinoic acid for 32 weeks. The impact of treatment on the appearance of sperm in the ejaculate will be determined by monthly semen analyses.

Note: The outcome measure of serum and seminal plasma 13-cis-retinoic acid concentrations was entered in error and not intended to be reported for this study. Information on these levels is available in our earlier study of 13-cis-retinoic acid in men with sub-fertility. Amory et al. Andrology 2017 5:1115-1123.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: 20 mg 13-cis retinoic acid twice daily (BID) with meals for 32 weeks20 mg 13-cis retinoic acid twice daily (BID) with meals for 32 weeks
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Trial of 13-cis Retinoic Acid (Isotretinoin) for the Treatment of Men With Azoospermia
• Actual Study Start Date: Jul 25, 2017
• Actual Primary Completion Date: May 16, 2019
• Actual Study Completion Date: May 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 13-cis retinoic acid 20 mg 13-cis retinoic acid twice daily (BID) with means for 32 weeks	Drug: 13-cis retinoic acid; Accutane is used for the treatment of severe acne; Other Names: Accutane, Isotretinoin

Outcome Measures

Primary Outcome Measures

1. Total Motile Sperm [up to 32 weeks]

   Number of participants with undetectable or detectable sperm in their ejaculates.

2. Total Sperm and Percentage of These Sperm That Were Motile [32 weeks]

   Number of total sperm in ejaculate and percentage of these sperm that were motile

Secondary Outcome Measures

1. Serious and Non-Serious Adverse Effects [32 weeks]

   Number of participants with Serious and Non-Serious Adverse effects associated with treatment with 13-cis retinoic acid

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 60 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria: Infertile men with azoospermia on at least two semen analyses separated by at least one week, and no pregnancy with partner with normal cycles and normal hysterosalpingogram despite >1 year of unprotected intercourse.

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Exclusion Criteria: hypogonadotropic hypogonadism (that might respond to gonadotropin injections); use of anabolic steroids,illicit drugs, or consumption of more than 4 alcoholic beverages daily; current therapy with retinoic acid (eg Accutane) or vitamin A- of use of isotretinoin within eight weeks of start of dosing;phenytoin, or medication containing tetracycline; personal history of serious psychiatric disorders, score of greater than 15 on the PHQ9 (mood) questionnaire; elevated serum serum triglycerides or other abnormal serum chemistry values; history of inflammatory bowel disease or bone disease; not living within catchment area; participation in another clinical trial

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Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Washington Medical Center	Seattle	Washington	United States	98195

Sponsors and Collaborators

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

Investigators

• Principal Investigator: John K Amory, MD, University of Washington

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 12, 2017
• Informed Consent Form - May 23, 2017

More Information

Additional Information:

• Center for Disease Control, Infertility Facts, on June 3rd, 2013

Publications

• 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.
• 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.
• de Kretser DM. Male infertility. Lancet. 1997 Mar 15;349(9054):787-90. Review.
• 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. Epub 2007 Sep 28.
• 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.
• 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.
• Hoting VE, Schütte B, Schirren C. [Isotretinoin treatment of acne conglobata. Andrologic follow-up]. Fortschr Med. 1992 Aug 20;110(23):427-30. German.
• Jequier AM, Holmes SC. Primary testicular disease presenting as azoospermia or oligozoospermia in an infertility clinic. Br J Urol. 1993 Jun;71(6):731-5.
• 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. Epub 2006 Feb 6.
• 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.
• 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.
• Napoli JL. Retinoic acid: its biosynthesis and metabolism. Prog Nucleic Acid Res Mol Biol. 1999;63:139-88. Review.
• 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.
• 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. Review.
• Török L, Kádár L, Kása M. Spermatological investigations in patients treated with etretinate and isotretinoin. Andrologia. 1987 Nov-Dec;19(6):629-33.
• Vogt HJ, Ewers R. [13-cis-Retinoic acid and spermatogenesis. Spermatological and impulse cytophotometric studies]. Hautarzt. 1985 May;36(5):281-6. German.

• Responsible Party: John Amory, Professor, School of Medicine, General Internal Medicine, University of Washington
• ClinicalTrials.gov Identifier: NCT03323801
• Other Study ID Numbers: STUDY00001055; K24HD082231
• First Posted: Oct 27, 2017
• Last Update Posted: Oct 26, 2021
• Last Verified: Sep 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by John Amory, Professor, School of Medicine, General Internal Medicine, University of Washington: Infertility
• Additional relevant MeSH terms: Infertility; Infertility, Male; Azoospermia; Tretinoin; Isotretinoin

Study Results

Participant Flow

Arm/Group Title	13-cis Retinoic Acid
Arm/Group Description	20 mg 13-cis retinoic acid twice daily (BID) with means for 32 weeks 13-cis retinoic acid: Accutane is used for the treatment of severe acne
Period Title: Overall Study
STARTED	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	13-cis Retinoic Acid
Arm/Group Description	20 mg 13-cis retinoic acid twice daily (BID) with means for 32 weeks 13-cis retinoic acid: Accutane is used for the treatment of severe acne
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 100%
>=65 years	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	36
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	10 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 20%
Not Hispanic or Latino	8 80%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 20%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	8 80%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Total Motile Sperm
Description	Number of participants with undetectable or detectable sperm in their ejaculates.
Time Frame	up to 32 weeks

Outcome Measure Data

Analysis Population Description

Men had idiopathic azoospermia, without evidence of obstruction or know genetic causes of azoospermia, although one man had known AZFc deletion

Arm/Group Title	Accutane-13-cis Retinoic Acid
Arm/Group Description	20 mg 13-cis retinoic acid twice daily (BID) with means for 32 weeks 13-cis retinoic acid: Accutane is used for the treatment of severe acne
Measure Participants	9
undetectable	8 80%
detectable motile sperm	1 10%

2. Primary Outcome

Title	Total Sperm and Percentage of These Sperm That Were Motile
Description	Number of total sperm in ejaculate and percentage of these sperm that were motile
Time Frame	32 weeks

Outcome Measure Data

Analysis Population Description

Only man who developed sperm in ejaculate on treatment

Arm/Group Title	13-cis Retinoic Acid
Arm/Group Description	20 mg 13-cis retinoic acid twice daily (BID) with means for 32 weeks 13-cis retinoic acid: Accutane is used for the treatment of severe acne
Measure Participants	1
Measure Total sperm in the ejaculate	32500
Number [Percent of sperm that were motile]	20

3. Secondary Outcome

Title	Serious and Non-Serious Adverse Effects
Description	Number of participants with Serious and Non-Serious Adverse effects associated with treatment with 13-cis retinoic acid
Time Frame	32 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Accutane-13-cis Retinoic Acid
Arm/Group Description	20 mg 13-cis retinoic acid twice daily (BID) with means for 32 weeks 13-cis retinoic acid: Accutane is used for the treatment of severe acne
Measure Participants	10
Count of Participants [Participants]	1 10%

Adverse Events

Time Frame	32 weeks
Arm/Group Title	Accutane-13-cis Retinoic Acid
Arm/Group Description	20 mg 13-cis retinoic acid twice daily (BID) with means for 32 weeks 13-cis retinoic acid: Accutane is used for the treatment of severe acne
All Cause Mortality
	Accutane-13-cis Retinoic Acid
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Serious Adverse Events
	Accutane-13-cis Retinoic Acid
	Affected / at Risk (%)	# Events
Total	1/10 (10%)
Gastrointestinal disorders
nephrotic syndrome	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Accutane-13-cis Retinoic Acid
	Affected / at Risk (%)	# Events
Total	1/10 (10%)
Musculoskeletal and connective tissue disorders
cramps	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.