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

NCT03615547 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: 69HCL18_0033
• Study Type: interventional
• Target: 128
• Locations: 1 country
• Sites: 1

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. 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. 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.

Conditions

Azoospermia, Nonobstructive

Keywords

azoospermia; clominophene

Outcome Measures

Primary Outcomes (1)

• presence of sperm cells point of view

  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

  9 months

Secondary Outcomes (17)

• number of sperm cells point of view

  9 months

• Follicle Stimulating Hormone (FSH) level evolution

  9 months

• testosterone level evolution

  9 months

• Luteinizing hormone (LH) level evolution

  9 months

• Sex Hormone-Binding Globulin (SHBG) level evolution

  9 months

Study Arms (2)

Clomifene citrate group

EXPERIMENTAL

a daily dose of 50mg of Clomifene Citrate per os during 9 months

Drug: Clomifene Citrate

Placebo group

EXPERIMENTAL

a daily dose of 50mg per os of placebo (lactose monohydrate) during 9 months.

Other: Placebo

Interventions

Clomifene Citrate DRUG

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.

Clomifene citrate group

Placebo OTHER

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.

Placebo group

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Patient aged from 18-55
• Body Mass Index lower than 35
• Patients with confirmed diagnostic of Non Obstructive Azoospermia based on
• 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

You may not qualify if:

• 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 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

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (1)

Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant

Bron, France

Location

MeSH Terms

Conditions

Azoospermia, Nonobstructive; Azoospermia

Interventions

Clomiphene

Condition Hierarchy (Ancestors)

Infertility, Male; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Infertility; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Plotton Ingrid

  Hospices Civils de Lyon

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Plotton Ingrid

CONTACT

4 72 12 96 35; ingrid.plotton@chu-lyon.fr

Julien BERTHILLER

CONTACT

4 27 85 63 01; julien.berthiller@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 20, 2018
• First Posted: August 6, 2018
• Study Start: January 1, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029
• Last Updated: September 9, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)