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Interest of Clomiphene Citrate in Patients With Non-obstructive Azoospermia on the Quantity of Sperm Cells (CLOMINOA)

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ClinicalTrials.gov Identifier: NCT03615547
Recruitment Status : Not yet recruiting
First Posted : August 6, 2018
Last Update Posted : August 29, 2018
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

Brief Summary:

In the absence of sperm in the semen (azoospermia), there is no chance of natural paternity. It is found in about 1% of men and is either due to an obstruction of the seminal tracks (obstructive azoospermia (OA)) in 1/3 of the cases, or a spermatogenic failure (non-obstructive azoospermia (NOA)) in 2/3 of the cases. To date, no medical treatment had proved its efficiency to induce spermatogenesis in case of NOA.

The development of Intracytoplasmic sperm injection (ICSI) in 1992 allowed to obtain pregnancies from a small number of spermatozoa. The next year, testicular sperms were extracted from testicular tissue obtained surgically in cases of OA , allowing paternity for azoospermic men. In case of NOA, TESE allowed to obtain few sperms in an unexpected number of cases. It was shown that spermatogenesis remains active in rare portions of seminiferous tubules, a phenomenon called focal spermatogenesis, which allows to extract testicular sperms with an average SRR of 50%, and to obtain pregnancy by ICSI. Thus, TESE-ICSI revolutionized the prognosis of NOA, however, half of the cases of NOA had no sperm extracted and remained sterile . Since sperm donation and adoption are unacceptable for several of these couples, there is a real demand for additional treatment.

Two ways to improve chances of paternity in case of NOA are currently discussed:

  1. Proceed to a second attempt of TESE. Since the first attempt could have missed a focus of active spermatogenesis, the chance for a positive second TESE is not null even. Reviewing the few articles published on this issue , the SRR for the second attempt, after a first negative attempt averaged 25%.
  2. Based upon the decrease of testosterone production within the testis in case of NOA and the potential increased of the focal spermatogenesis by gonadotropins, few reports of hormonal therapy in case of NOA have been published and suggested a positive effect of hormonal therapy.

This prompted us to develop this clinical trial to investigate the effect of Clomiphene Citrate versus placebo on the results of a second TESE in NOA.

Results of hormonal therapy in case of NOA were heterogeneous and of poor methodological quality, none was randomized versus placebo: Anti-aromatases or Gonadotropins administered before the first TESE or the second TESE gave positive results. Hussein at al in 2013, suggested a positive effect of Clomiphene citrate (CC), administrated before the first TESE (57% of the CC treated group versus 33.6% in not treated group) but with drop out of patient positive to sperm analysis. However, in these positive studies, sample sizes were small or selected patients on hormonal status or histology criteria suggesting subgroup of favourable NOA. Thus, there is no strong evaluation of the interest of hormonal treatment in NOA, after a negative first TESE.

The investigators decided to evaluate the effect of the CC, the most convincing and convenient hormonal treatment, in patients with negative first TESE for NOA. It is of main interest to known if CC could enhance the SRR of a second TESE, that is the ultimate possibility to have their own child for these patients.


Condition or disease Intervention/treatment Phase
Azoospermia, Nonobstructive Drug: Clomifene Citrate Other: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 128 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Interest of Clomiphene Citrate (CC) Associated With a Second Testicular Sperm Extraction (TESE) in Patients With Non-obstructive Azoospermia (NOA) After Failure of a First TESE, on the Quantity of Sperm Cells Available for Intracytoplasmic Sperm Injection (ICSI). Randomized Double Blind Trial Versus Placebo.
Estimated Study Start Date : January 2019
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Clomifene citrate group
a daily dose of 50mg of Clomifene Citrate per os during 9 months
Drug: Clomifene Citrate

After randomization, the andrologist will give a prescription with the first three months of treatment (Clomifene Citrate or placebo) to be collected to the local hospital pharmacy. The andrologist will be blind of the treatment arm.

Treatment unit and their shipment to local pharmacy will be provided and organized by the East group pharmacy of the Hospices Civils of Lyon which is the coordination pharmacy for this study. Prescription and delivery will be renewed for three months at the 3 month and 6 months visit.

The experimental treatment consists in a daily dose of 50mg of Clomifene Citrate per os during 9 months followed by a second TESE if no spermatozoid has been obtained from semen. The dose level was set according to Chua et al 2013 (cf 1.2.2). One capsule containing 50 mg of CC will be orally administered in the morning every day.


Experimental: Placebo group
a daily dose of 50mg per os of placebo (lactose monohydrate) during 9 months.
Other: Placebo
The placebo treatment consists in a daily dose of 50mg of lactose monohydrate per os during 9 months followed by a second TESE if no spermatozoid has been obtained from semen. The capsule containing the placebo will have the exact same size, weight, color, taste and will be delivered in the exact same condition as the experimental treatment capsule.




Primary Outcome Measures :
  1. presence of sperm cells point of view [ Time Frame: 9 months ]
    Evaluate, versus placebo, the interest of 9 months treatment by 50 mg of Clomiphene citrate to increase the proportion of patient for which at least one sperm cell can be isolated either from the semen at 9 months of treatment or, in case of persistent azoospermia, from a second TESE attempt performed at 9 months of treatment


Secondary Outcome Measures :
  1. number of sperm cells point of view [ Time Frame: 9 months ]
    Evaluate, versus placebo, the interest of 9 months treatment by 50 mg of Clomiphene citrate to increase the number of spermatozoa obtained, from the semen at 9 months of treatment or, in case of persistent azoospermia, from a second TESE attempt performed at 9 months of treatment

  2. Follicle Stimulating Hormone (FSH) level evolution [ Time Frame: 9 months ]
    Evaluate the evolution of FSH in both groups

  3. testosterone level evolution [ Time Frame: 9 months ]
    Evaluate the evolution of testosterone in both groups

  4. Luteinizing hormone (LH) level evolution [ Time Frame: 9 months ]
    Evaluate the evolution of LH in both groups

  5. Sex Hormone-Binding Globulin (SHBG) level evolution [ Time Frame: 9 months ]
    Evaluate the evolution of SHBG in both groups

  6. Bioavailable testosterone Inhibin B level evolution [ Time Frame: 9 months ]
    Evaluate the evolution of bioavailable testosterone Inhibin B in both groups

  7. number spermatogonia [ Time Frame: 9 months ]
    Evaluate Hypospermatogenesis status

  8. number of spermatocytes, [ Time Frame: 9 months ]
    Evaluate Hypospermatogenesis status

  9. number of round elongated spermatids [ Time Frame: 9 months ]
    Evaluate Hypospermatogenesis status

  10. prevalence of Sertoli cell only syndrome [ Time Frame: 9 months ]
    Evaluate Sertoli cell only syndrome status

  11. prevalence of maturation arrest [ Time Frame: 9 months ]
    Evaluate maturation arrest status

  12. number of Clomiphene citrate capsules [ Time Frame: 9 months ]
    Compliance will be measured by counting the number of Clomiphene citrate capsules remaining in the brought back at each visit

  13. number of adverse events [ Time Frame: 9 months ]
    Evolution of Clomiphene citrate proportion of side effects

  14. proportion of complications at the second TESE [ Time Frame: 9 months ]
  15. proportion of Pregnancies [ Time Frame: 9 months ]
    proportion of pregnancies after Intracytoplasmic sperm injection

  16. proportion of Miscarriages [ Time Frame: 9 months ]
    proportion of Miscarriages after ICSI

  17. number of Newborn [ Time Frame: 9 months ]
    proportion of Newborn after ICSI



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient aged from 18-55
  • Body Mass Index lower than 35
  • Patients with confirmed diagnostic of Non Obstructive Azoospermia based on
  • 2 negative spermogram with centrifugation (three month in between)
  • Failure of detecting spermatozoid at first testicular sperm extraction (TESE)
  • Patients without sperm cells at semen analysis
  • Signed informed consent
  • Patients benefiting from a social insurance system or a similar system

Exclusion Criteria:

  • Patients with grade 2 or 3 varicocele, persistant after cure of the varicocele.
  • Patients with current or history of testicular tumor detected on a less than 3 months' ultrasound.
  • Patients with history of any other cancer of less than 5 years.
  • Patient with Klinefelter or karyotype abnormalities
  • Yq micro-deletions
  • First TESE conducted under hormonal treatment (Clomifene, Tamoxifen, gonadotrophins or anti-aromatase)
  • Patients receiving a treatment known to alter male fertility (see RCP of the treatment, colchicine, methotrexate, ….) in the 6 months before inclusion.
  • Patients receiving treatment know to modify the gonadotroph axis activity (FSH, TESTO, DHT, HCG…)
  • Hypogonadotropic Hypogonadism
  • Persistant bilateral abdominal cryptorchidism
  • Patient unable to understand the purpose of the trial or refusing to follow treatment and post-treatment instructions
  • Patients with history of psychiatric disorder
  • Participation to another trial that would interfere with this trial
  • Patients under legal protection

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): NCT03615547


Contacts
Contact: Hervé LEJEUNE, MD, PhD 4 72 12 94 12 ext +33 herve.lejeune@chu-lyon.fr
Contact: Julien BERTHILLER 4 27 85 63 01 ext +33 julien.berthiller@chu-lyon.fr

Locations
France
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant Not yet recruiting
Bron, France
Contact: Hervé LEJEUNE       herve.lejeune@chu-lyon.fr   
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
Principal Investigator: Hervé LEJEUNE, MD, PhD Hospices Civils de Lyon

Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT03615547     History of Changes
Other Study ID Numbers: 69HCL18_0033
First Posted: August 6, 2018    Key Record Dates
Last Update Posted: August 29, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hospices Civils de Lyon:
azoospermia
clominophene

Additional relevant MeSH terms:
Infertility, Male
Infertility
Azoospermia
Genital Diseases, Male
Citric Acid
Clomiphene
Enclomiphene
Zuclomiphene
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators