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

Azoospermia, Nonobstructive Clinical Trial

— CLOMINOA  

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.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03615547
• Other study ID #: 69HCL18_0033
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: January 2023
• Est. completion date: January 2026

Study information

• Verified date: July 2022
• Source: Hospices Civils de Lyon
• Contact: Hervé LEJEUNE, MD, PhD
• Phone: 4 72 12 94 12
• Email: herve.lejeune[@]chu-lyon.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 128
• Est. completion date: January 2026
• Est. primary completion date: January 2026
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Azoospermia
• Azoospermia, Nonobstructive

Intervention

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.

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.

Locations

Country	Name	City	State
France	Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant	Bron

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	number of sperm cells point of view	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	9 months
Secondary	Follicle Stimulating Hormone (FSH) level evolution	Evaluate the evolution of FSH in both groups	9 months
Secondary	testosterone level evolution	Evaluate the evolution of testosterone in both groups	9 months
Secondary	Luteinizing hormone (LH) level evolution	Evaluate the evolution of LH in both groups	9 months
Secondary	Sex Hormone-Binding Globulin (SHBG) level evolution	Evaluate the evolution of SHBG in both groups	9 months
Secondary	Bioavailable testosterone Inhibin B level evolution	Evaluate the evolution of bioavailable testosterone Inhibin B in both groups	9 months
Secondary	number spermatogonia	Evaluate Hypospermatogenesis status	9 months
Secondary	number of spermatocytes,	Evaluate Hypospermatogenesis status	9 months
Secondary	number of round elongated spermatids	Evaluate Hypospermatogenesis status	9 months
Secondary	prevalence of Sertoli cell only syndrome	Evaluate Sertoli cell only syndrome status	9 months
Secondary	prevalence of maturation arrest	Evaluate maturation arrest status	9 months
Secondary	number of Clomiphene citrate capsules	Compliance will be measured by counting the number of Clomiphene citrate capsules remaining in the brought back at each visit	9 months
Secondary	number of adverse events	Evolution of Clomiphene citrate proportion of side effects	9 months
Secondary	proportion of complications at the second TESE		9 months
Secondary	proportion of Pregnancies	proportion of pregnancies after Intracytoplasmic sperm injection	9 months
Secondary	proportion of Miscarriages	proportion of Miscarriages after ICSI	9 months
Secondary	number of Newborn	proportion of Newborn after ICSI	9 months