CClinicalTrials.gg
CompletedNCT03323801Updated Oct 26, 2021Results posted

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

A Phase 2 interventional study of 13-cis retinoic acid in Male Infertility, Azoospermia, sponsored by University of Washington. Completed at 1 site in United States. Open to male participants aged 21 Years to 60 Years. Per ClinicalTrials.gov, last updated 2021-10-26.

Sponsored by University of Washington · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
10
Allocation
Not applicable
Ages
21 Years to 60 Years
Sex
Male
01

Study 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.

Read the 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.

02

Conditions studied

  • Male Infertility, Azoospermia

Keywords

  • Infertility
03

Who can participate

Ages eligible
21 Years to 60 Years
Sexes eligible
Male
Accepts healthy volunteers
No

Eligibility criteria

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

-

04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
10 participants (actual)

Study arms

  • Experimental
    13-cis retinoic acid

    20 mg 13-cis retinoic acid twice daily (BID) with means for 32 weeks

    Drug: 13-cis retinoic acid

Interventions

  • Drug13-cis retinoic acid

    Accutane is used for the treatment of severe acne

    Also known as: Accutane, Isotretinoin

05

What researchers measure

Primary outcomes

  1. Total Motile Sperm

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

    Time frame: up to 32 weeks

  2. Total Sperm and Percentage of These Sperm That Were Motile

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

    Time frame: 32 weeks

Secondary outcomes

  1. Serious and Non-Serious Adverse Effects

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

    Time frame: 32 weeks

06

Results

Posted Oct 26, 2021

Participant flow

Participant flow — Overall Study
Milestone13-cis Retinoic Acid
Started10
Completed10
Not completed0

Outcome measures

PrimaryTotal Motile Sperm

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

Time frame:
up to 32 weeks
Reported as:
Count of participants · Participants
Total Motile Sperm
ParticipantsAccutane-13-cis Retinoic Acid
undetectable8
detectable motile sperm1
PrimaryTotal Sperm and Percentage of These Sperm That Were Motile

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

Time frame:
32 weeks
Reported as:
Number · Percent of sperm that were motile
Total Sperm and Percentage of These Sperm That Were Motile
Percent of sperm that were motile13-cis Retinoic Acid
Total Sperm and Percentage of These Sperm That Were Motile20
SecondarySerious and Non-Serious Adverse Effects

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

Time frame:
32 weeks
Reported as:
Count of participants · Participants
Serious and Non-Serious Adverse Effects
ParticipantsAccutane-13-cis Retinoic Acid
Serious and Non-Serious Adverse Effects1

Adverse events

Collected over 32 weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Accutane-13-cis Retinoic Acid0/10 (0%)1/10 (10%)1/10 (10%)
Most frequent serious events
Most frequent serious events
EventAccutane-13-cis Retinoic Acid
nephrotic syndromeGastrointestinal disorders1/10
Most frequent other events
Most frequent other events
EventAccutane-13-cis Retinoic Acid
crampsMusculoskeletal and connective tissue disorders1/10

Baseline characteristics

Men with infertility due to azoospermia

Age, Categorical
Age, Categorical(Participants)13-cis Retinoic Acid
<=18 years0
Between 18 and 65 years10
>=65 years0
Age, Continuous
Age, Continuous(years)13-cis Retinoic Acid
Median36 (31 to 42)
Sex: Female, Male
Sex: Female, Male(Participants)13-cis Retinoic Acid
Female0
Male10
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)13-cis Retinoic Acid
Hispanic or Latino2
Not Hispanic or Latino8
Unknown or Not Reported0
Race (NIH/OMB)
Race (NIH/OMB)(Participants)13-cis Retinoic Acid
American Indian or Alaska Native0
Asian2
Native Hawaiian or Other Pacific Islander0
Black or African American0
White8
More than one race0
Unknown or Not Reported0
Region of Enrollment
Region of Enrollment(participants)13-cis Retinoic Acid
United States10
07

Study locations

1 site
  • University of Washington Medical Center
    Seattle, Washington 98195, United States
08

References and documents

Publications

  • 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. doi: 10.1111/j.1464-410x.1993.tb16075.x. PubMed 8102079 ↗
  • de Kretser DM. Male infertility. Lancet. 1997 Mar 15;349(9054):787-90. doi: 10.1016/s0140-6736(96)08341-9. No abstract available. PubMed 9074589 ↗
  • 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. PubMed 19247918 ↗
  • 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. PubMed 10506831 ↗
  • 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. PubMed 17905941 ↗
  • 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. PubMed 16461896 ↗
  • 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. PubMed 18799751 ↗
  • 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. PubMed 19465599 ↗
  • 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. PubMed 10529278 ↗
  • 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. PubMed 8388780 ↗
  • 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. PubMed 8394014 ↗
  • 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. PubMed 16586441 ↗
  • Hoting VE, Schutte B, Schirren C. [Isotretinoin treatment of acne conglobata. Andrologic follow-up]. Fortschr Med. 1992 Aug 20;110(23):427-30. German. PubMed 1398387 ↗
  • Vogt HJ, Ewers R. [13-cis-Retinoic acid and spermatogenesis. Spermatological and impulse cytophotometric studies]. Hautarzt. 1985 May;36(5):281-6. German. PubMed 3159708 ↗
  • 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. PubMed 3481225 ↗
  • 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. PubMed 23413144 ↗

Study documents

  • Protocol and statistical analysis plan · Jan 12, 2017
  • Informed consent form · May 23, 2017

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03323801
Lead sponsor
University of Washington
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Responsible party
John Amory (Professor, School of Medicine, General Internal Medicine, University of Washington) — Principal investigator
First posted
Oct 27, 2017
Start date
Jul 25, 2017
Primary completion
May 16, 2019
Completion
May 31, 2019
Results posted
Oct 26, 2021
Last update
Oct 26, 2021

Study contacts

John K Amory, MD
principal investigator · University of Washington

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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