- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02061384
RA-2 13-cis Retinoic Acid (Isotretinoin) (RA-2)
July 29, 2021 updated by: John Amory, University of Washington
A Pilot Trial of 13-cis Retinoic Acid (Isotretinoin) for the Treatment of Men With Oligoasthenoteratozoospermia
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.
Study Overview
Status
Completed
Intervention / Treatment
Detailed Description
This is a 20 week, unblinded, two-arm pilot study to determine the impact of therapy with 13-cis retinoic acid and calcitriol on sperm indices in infertile men.
Twenty infertile men, ages 21-60 with abnormal sperm analyses will be enrolled for 20-week and given 20 mg 13-cis retinoic acid, twice daily.
Subjects#11-#20 will also be administered calcitriol to see if adding calcitriol with Accutane will improve sperm motility.
All subjects will be closely followed for side effects related to treatment.
The impact of treatment on indices of spermatogenesis will be determined by monthly seminal fluid analyses.
Study Type
Interventional
Enrollment (Actual)
20
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Washington
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Seattle, Washington, United States, 98195
- University of Washington Medical Center
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
19 years to 58 years (Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
Male
Description
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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).
- Abnormal serum chemistry values according to local laboratory normal values which indicate liver or kidney dysfunction. Other abnormal lab values may also be exclusionary, at the discretion of the investigator
- 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
- Men with elevated serum triglycerides
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 13-cis retinoic acid
20mg 13-cis retinoic acid twice daily (BID) with meals for 20 weeks
|
Accutane is used for the treatment of severe acne
Other Names:
|
Experimental: Calcitriol 0.25 mcg
oral calcitriol 025 mcg BID subjects 11-20 for 20 weeks
|
Accutane is used for the treatment of severe acne
Other Names:
Calcitriol is a form of vitamin D given twice daily (BID)
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Millions of Sperm Per Ejaculate
Time Frame: Up to 20-weeks
|
Millions of sperm per ejaculate in men treated with 13-cis retinoic acid
|
Up to 20-weeks
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General 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.
- de Kretser DM. Male infertility. Lancet. 1997 Mar 15;349(9054):787-90. doi: 10.1016/s0140-6736(96)08341-9. No abstract available.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Hoting VE, Schutte B, Schirren C. [Isotretinoin treatment of acne conglobata. Andrologic follow-up]. Fortschr Med. 1992 Aug 20;110(23):427-30. German.
- Vogt HJ, Ewers R. [13-cis-Retinoic acid and spermatogenesis. Spermatological and impulse cytophotometric studies]. Hautarzt. 1985 May;36(5):281-6. German.
- 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.
- 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.
- Center for Disease Control. Infertility Facts,m accessed at http://www.ede.gov/nchs/fastats/fertile.htm (June 3, 2013)
- 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.
- WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
August 1, 2014
Primary Completion (Actual)
December 1, 2018
Study Completion (Actual)
December 1, 2018
Study Registration Dates
First Submitted
February 10, 2014
First Submitted That Met QC Criteria
February 10, 2014
First Posted (Estimate)
February 12, 2014
Study Record Updates
Last Update Posted (Actual)
August 2, 2021
Last Update Submitted That Met QC Criteria
July 29, 2021
Last Verified
June 1, 2021
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Endocrine System Diseases
- Gonadal Disorders
- Disorders of Sex Development
- Urogenital Abnormalities
- Congenital Abnormalities
- Genetic Diseases, Inborn
- Chromosome Disorders
- Sex Chromosome Disorders
- Sex Chromosome Disorders of Sex Development
- Hypogonadism
- Infertility
- Infertility, Male
- Klinefelter Syndrome
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antineoplastic Agents
- Dermatologic Agents
- Micronutrients
- Membrane Transport Modulators
- Vitamins
- Bone Density Conservation Agents
- Calcium-Regulating Hormones and Agents
- Keratolytic Agents
- Vasoconstrictor Agents
- Calcium Channel Agonists
- Tretinoin
- Isotretinoin
- Calcitriol
- Dihydroxycholecalciferols
Other Study ID Numbers
- STUDY00000564
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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