Clinical trial NCT03615547: Interest of Clomiphene Citrate in Patients With Non-obstructive Azoospermia on the Quantity of Sperm Cells
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.
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Azoospermia, Nonobstructive
Keywords: azoospermia
clominophene
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2018-08-06
Enrollment: 128
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: presence of sperm cells point of view
timeFrame: 9 months
Secondary outcomes:
measure: number of sperm cells point of view
timeFrame: 9 months
measure: Follicle Stimulating Hormone (FSH) level evolution
timeFrame: 9 months
measure: testosterone level evolution
timeFrame: 9 months
measure: Luteinizing hormone (LH) level evolution
timeFrame: 9 months
measure: Sex Hormone-Binding Globulin (SHBG) level evolution
timeFrame: 9 months
measure: Bioavailable testosterone Inhibin B level evolution
timeFrame: 9 months
measure: number spermatogonia
timeFrame: 9 months
measure: number of spermatocytes,
timeFrame: 9 months
measure: number of round elongated spermatids
timeFrame: 9 months
measure: prevalence of Sertoli cell only syndrome
timeFrame: 9 months
measure: prevalence of maturation arrest
timeFrame: 9 months
measure: number of Clomiphene citrate capsules
timeFrame: 9 months
measure: number of adverse events
timeFrame: 9 months
measure: proportion of complications at the second TESE
timeFrame: 9 months
measure: proportion of Pregnancies
timeFrame: 9 months
measure: proportion of Miscarriages
timeFrame: 9 months
measure: number of Newborn
timeFrame: 9 months
Other outcomes:
Locations:
city: Bron
country: France
facility: Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant
Study officials:
affiliation: Hospices Civils de Lyon
name: Hervé LEJEUNE, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: