Interest of Clomiphene Citrate in Patients With Non-obstructive Azoospermia on the Quantity of Sperm Cells (CLOMINOA)
Primary Purpose
Azoospermia, Nonobstructive
Status
Not yet recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Clomifene Citrate
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Azoospermia, Nonobstructive focused on measuring azoospermia, clominophene
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
Sites / Locations
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Clomifene citrate group
Placebo group
Arm Description
a daily dose of 50mg of Clomifene Citrate per os during 9 months
a daily dose of 50mg per os of placebo (lactose monohydrate) during 9 months.
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
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
Follicle Stimulating Hormone (FSH) level evolution
Evaluate the evolution of FSH in both groups
testosterone level evolution
Evaluate the evolution of testosterone in both groups
Luteinizing hormone (LH) level evolution
Evaluate the evolution of LH in both groups
Sex Hormone-Binding Globulin (SHBG) level evolution
Evaluate the evolution of SHBG in both groups
Bioavailable testosterone Inhibin B level evolution
Evaluate the evolution of bioavailable testosterone Inhibin B in both groups
number spermatogonia
Evaluate Hypospermatogenesis status
number of spermatocytes,
Evaluate Hypospermatogenesis status
number of round elongated spermatids
Evaluate Hypospermatogenesis status
prevalence of Sertoli cell only syndrome
Evaluate Sertoli cell only syndrome status
prevalence of maturation arrest
Evaluate maturation arrest status
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
number of adverse events
Evolution of Clomiphene citrate proportion of side effects
proportion of complications at the second TESE
proportion of Pregnancies
proportion of pregnancies after Intracytoplasmic sperm injection
proportion of Miscarriages
proportion of Miscarriages after ICSI
number of Newborn
proportion of Newborn after ICSI
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03615547
Brief Title
Interest of Clomiphene Citrate in Patients With Non-obstructive Azoospermia on the Quantity of Sperm Cells
Acronym
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.
Study Type
Interventional
2. Study Status
Record Verification Date
July 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
January 2023 (Anticipated)
Primary Completion Date
January 2026 (Anticipated)
Study Completion Date
January 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospices Civils de Lyon
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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:
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%.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Azoospermia, Nonobstructive
Keywords
azoospermia, clominophene
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
128 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Clomifene citrate group
Arm Type
Experimental
Arm Description
a daily dose of 50mg of Clomifene Citrate per os during 9 months
Arm Title
Placebo group
Arm Type
Experimental
Arm Description
a daily dose of 50mg per os of placebo (lactose monohydrate) during 9 months.
Intervention Type
Drug
Intervention Name(s)
Clomifene Citrate
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
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 Measure Information:
Title
presence of sperm cells point of view
Description
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
Time Frame
9 months
Secondary Outcome Measure Information:
Title
number of sperm cells point of view
Description
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
Time Frame
9 months
Title
Follicle Stimulating Hormone (FSH) level evolution
Description
Evaluate the evolution of FSH in both groups
Time Frame
9 months
Title
testosterone level evolution
Description
Evaluate the evolution of testosterone in both groups
Time Frame
9 months
Title
Luteinizing hormone (LH) level evolution
Description
Evaluate the evolution of LH in both groups
Time Frame
9 months
Title
Sex Hormone-Binding Globulin (SHBG) level evolution
Description
Evaluate the evolution of SHBG in both groups
Time Frame
9 months
Title
Bioavailable testosterone Inhibin B level evolution
Description
Evaluate the evolution of bioavailable testosterone Inhibin B in both groups
Time Frame
9 months
Title
number spermatogonia
Description
Evaluate Hypospermatogenesis status
Time Frame
9 months
Title
number of spermatocytes,
Description
Evaluate Hypospermatogenesis status
Time Frame
9 months
Title
number of round elongated spermatids
Description
Evaluate Hypospermatogenesis status
Time Frame
9 months
Title
prevalence of Sertoli cell only syndrome
Description
Evaluate Sertoli cell only syndrome status
Time Frame
9 months
Title
prevalence of maturation arrest
Description
Evaluate maturation arrest status
Time Frame
9 months
Title
number of Clomiphene citrate capsules
Description
Compliance will be measured by counting the number of Clomiphene citrate capsules remaining in the brought back at each visit
Time Frame
9 months
Title
number of adverse events
Description
Evolution of Clomiphene citrate proportion of side effects
Time Frame
9 months
Title
proportion of complications at the second TESE
Time Frame
9 months
Title
proportion of Pregnancies
Description
proportion of pregnancies after Intracytoplasmic sperm injection
Time Frame
9 months
Title
proportion of Miscarriages
Description
proportion of Miscarriages after ICSI
Time Frame
9 months
Title
number of Newborn
Description
proportion of Newborn after ICSI
Time Frame
9 months
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hervé LEJEUNE, MD, PhD
Phone
4 72 12 94 12
Ext
+33
Email
herve.lejeune@chu-lyon.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Julien BERTHILLER
Phone
4 27 85 63 01
Ext
+33
Email
julien.berthiller@chu-lyon.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hervé LEJEUNE, MD, PhD
Organizational Affiliation
Hospices Civils de Lyon
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant
City
Bron
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hervé LEJEUNE
Email
herve.lejeune@chu-lyon.fr
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Interest of Clomiphene Citrate in Patients With Non-obstructive Azoospermia on the Quantity of Sperm Cells
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