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RA-2 13-cis Retinoic Acid (Isotretinoin) (RA-2)

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02061384
First Posted: February 12, 2014
Last Update Posted: May 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
John Amory, University of Washington
  Purpose
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.

Condition Intervention Phase
Male Infertility Klinefelter's Syndrome Y-chromosome Microdeletions Drug: 13-cis retinoic acid Drug: Calcitriol Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Trial of 13-cis Retinoic Acid (Isotretinoin) for the Treatment of Men With Oligoasthenoteratozoospermia

Resource links provided by NLM:


Further study details as provided by John Amory, University of Washington:

Primary Outcome Measures:
  • Total motile sperm [ Time Frame: Up to 20-weeks ]
    Total motile sperm count in men treated with 13-cis retinoic acid


Secondary Outcome Measures:
  • 13-cis retinoic acid serum level [ Time Frame: 20-weeks ]
    Concentration level of 13-cis retinoic acid in the serum of treated men

  • Number of Participants with Serious and Non-Serious Adverse effects associated with treatment with 13-cis retinoic acid [ Time Frame: 20-weeks ]
    Number of adverse effects per subject associated with treatment with 13-cis retinoic acid

  • 13-cis retinoic acid Seminal Plasma Concentration [ Time Frame: Up to 20-weeks ]
    13-cis retinoic acid concentration in semen of treated men

  • To determine if the additions of calcitriol with 13-cis retinoic acid can improve sperm motility [ Time Frame: 20 weeks ]
    improved sperm motility


Estimated Enrollment: 20
Study Start Date: August 2014
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 13-cis retinoic acid
20mg 13-cis retinoic acid twice daily (BID) with meals for 20 weeks
Drug: 13-cis retinoic acid
Accutane is used for the treatment of severe acne
Other Names:
  • Accutane
  • Isotretinoin
Experimental: Calcitriol 0.25 mcg
oral calcitriol 025 mcg BID subjects 11-20 for 20 weeks
Drug: Calcitriol
Calcitriol is a form of vitamin D given twice daily (BID)
Other Name: 1,25-dihydroxyvitamin D3

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.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 60 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02061384


Locations
United States, Washington
University of Washington Medical Center
Seattle, Washington, United States, 98195
Sponsors and Collaborators
University of Washington
Investigators
Principal Investigator: John K Amory, MD, MPH University of Washington
  More Information

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.
de Kretser DM. Male infertility. Lancet. 1997 Mar 15;349(9054):787-90. Review.
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.
Napoli JL. Retinoic acid: its biosynthesis and metabolism. Prog Nucleic Acid Res Mol Biol. 1999;63:139-88. Review.
Center for Disease Control. Infertility Facts,m accessed at http://www.ede.gov/nchs/fastats/fertile.htm (June 3, 2013)
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.
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.
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.
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.
Kastner P, Mark M, Leid M, Gansmuller A, Chin W, Grondona JM, Décimo D, Krezel W, Dierich A, Chambon P. Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev. 1996 Jan 1;10(1):80-92.
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.
Vogt HJ, Ewers R. [13-cis-Retinoic acid and spermatogenesis. Spermatological and impulse cytophotometric studies]. Hautarzt. 1985 May;36(5):281-6. German.
Török L, Kádár L, Kása M. Spermatological investigations in patients treated with etretinate and isotretinoin. Andrologia. 1987 Nov-Dec;19(6):629-33.
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.
Lieberman LS. WHO laboratory manual for the examination of human semen and sperm-cervicle mucus interaction, 3rd edition. By WHO Special Programme of Research, Development and Research Training in Human Reproduction. viii + 107 pp. Cambridge: Cambridge University Press, 1992. $29.95 (paper). Am J Hum Biol. 1993;5(5):594-595. doi: 10.1002/ajhb.1310050517.
Christiansen C, Christensen MS, Rødbro P, Hagen C, Transbøl 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.
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.
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.
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.
Ott SM, Chesnut CH 3rd. Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med. 1989 Feb 15;110(4):267-74.
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.

Responsible Party: John Amory, Professor, General Internal Medicine, University of Washington
ClinicalTrials.gov Identifier: NCT02061384     History of Changes
Other Study ID Numbers: STUDY00000564
First Submitted: February 10, 2014
First Posted: February 12, 2014
Last Update Posted: May 30, 2017
Last Verified: May 2017

Keywords provided by John Amory, University of Washington:
Infertility

Additional relevant MeSH terms:
Infertility
Infertility, Male
Klinefelter Syndrome
Chromosome Deletion
Sex Chromosome Aberrations
Sex Chromosome Disorders of Sex Development
Genital Diseases, Male
Genital Diseases, Female
Disorders of Sex Development
Urogenital Abnormalities
Sex Chromosome Disorders
Chromosome Disorders
Congenital Abnormalities
Genetic Diseases, Inborn
Gonadal Disorders
Endocrine System Diseases
Hypogonadism
Monosomy
Aneuploidy
Chromosome Aberrations
Pathologic Processes
Calcitriol
Dihydroxycholecalciferols
Tretinoin
Isotretinoin
Calcium Channel Agonists
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasoconstrictor Agents
Vitamins


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