Future of Spermatogenesis in Men With Sickle Cell Disease Medically Treated

Drepanocytic Men Treated by Hydroxyurea for the First Time Clinical Trial

— HYDREP  

Official title:

Future of Spermatogenesis in Men With Sickle Cell Disease Medically Treated.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01609192
• Other study ID #: P 081227
• Secondary ID: AOM 09154
• Status: Completed
• Phase: Phase 4
• First received: April 25, 2012
• Last updated: August 6, 2013
• Start date: April 2010
• Est. completion date: February 2013

Study information

• Verified date: August 2013
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: French Data Protection Authority
• Study type: Interventional

Clinical Trial Summary

The project's background: Sickle cell disease is, at present in France, the most frequent genetic illness. Recent progress in its treatment, in particular the use of hydroxyurea, has considerably modified the prognosis of this disease. Many more patients now reach reproductive age and do consider fathering. Exceptional studies have reported the potential impact of this medical treatment on the sperm parameters and fertility of male patients. In a retrospective analysis, the investigators found that the observed alterations of semen parameters due to sickle cell disease seem to be exacerbated by hydroxyurea treatment.

The study hypothesis: A large prospective study is essential to assess the potential adverse impact of the medical treatment of sickle cell disease on spermatogenesis and consider the advisability of proposing sperm cryopreservation before this treatment is started.

Primary purpose of the protocol: evaluate the impact of a treatment by hydroxyurea (20-30 mg/kg/day), 6 months after its beginning, in 34 men with sickle cell disease (18-60 years old). The main trial criterion will be the average difference of the concentration of spermatozoa s (millions/ml) in the ejaculate, before and after 6 months of medical treatment.

Description:

Purpose of the study

Sickle cell disease is, at present in France, the most frequent genetic illness. Recent progress in its treatment, in particular the use of hydroxyurea, has considerably modified the prognosis of this disease. Many more patients now reach reproductive age and do consider fathering. Exceptional studies have reported the potential impact of this medical treatment on the sperm parameters and fertility of male patients. In a retrospective analysis, the investigators found that the observed alterations of semen parameters due to sickle cell disease seem to be exacerbated by hydroxyurea treatment. Moreover, after hydroxyurea cessation, while global results in 30 patients were not statistically different before and after hydroxyurea treatment, in four individuals follow-up sperm parameters did not seem to recover quickly and the total number of spermatozoa per ejaculate fell below the normal range in about half the cases.

Therefore, a large prospective study is essential to assess the potential adverse impact of the medical treatment of sickle cell disease on spermatogenesis and consider the advisability of proposing sperm cryopreservation before this treatment is started.

Main outcomes

Evaluate the impact of a treatment by hydroxyurea (20-30 mg/kg/day), 6 months after its beginning, in 34 men with sickle cell disease (18-60 years old). The primary outcome will be the average difference of the concentration of spermatozoa s (millions/ml) in the ejaculate, before and after 6 months of medical treatment. Six months represent 2 complete cycles of spermatogenesis.

The secondary outcomes will be the other sperm parameters: vitality, mobility, motility, morphology of spermatozoa and the assessment of sperm nuclear DNA fragmentation by TUNEL assay (terminal deoxynucleotidyl transferase dUTP nick end labelling).

This prospective, multicenter, cohort study should allow evaluating the impact of a treatment by hydroxyurea on spermatogenesis in men with sickle cell anemia.

With the hypothesis of a five time reduction in spermatozoa concentration (38 millions ± 43 before treatment), at least 34 analyzable patients are required (aged 18 to 60 years old) who have never received any compound known to be toxic for spermatogenesis.

Protocol

Drepanocytic men who are eligible for a first treatment by hydroxyurea will be sent to the CECOS (center for the study and cryopreservation of oocytes and spermatozoa) at Tenon, Cochin or Jean Verdier hospitals. Their medical history will be recorded and sperm parameters will be analyzed according to WHO criteria. Part of the ejaculate will be fixed and stored (- 20°C) for further DNA fragmentation assay. The rest of the semen could be cryopreserved, according to the patients' will, in case of a potential deleterious effect of the medical treatment on male fertility. Six months after the beginning of the treatment by hydroxyurea, another sperm recovery will be required for the same analysis and the already described parameters will be evaluated and compared to initial results.

Prospects

The study should bring valuable data on the effects of hydroxyurea on human spermatogenesis. If any significant impairment is observed, it would be recommended to perform sperm cryopreservation before the treatment's start.

The study could also help to distinguish between the detrimental effects due to the acute adverse events of sickle cell disease itself and those linked to the administration of hydroxyurea.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: February 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Men from 18 to 60 years old

• Patients diagnosed with sickle-cell anemia homozygote or S beta thal

• Patients for whom a treatment by hydroxyurea is prescribed for the first time.

• Patients having signed the informed consent

• Patients with social security

Exclusion Criteria:

• Patients already subjected to a treatment potentially sterilizing

• Patients under supervision or guardianship

• Patients that must begin or stop(arrest) a transfusional program between the beginning of the hydroxyurea and the spermogram in 6 months of treatment.

• Rate of ferritin > 2500 µg/l

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Drepanocytic Men Treated by Hydroxyurea for the First Time

Intervention

Drug:
• Hydrea® (hydroxyurea )
treatment by hydroxyurea (20-30 mg/kg/day) for 6 months

Locations

Country	Name	City	State
France	Department of biology of reproduction (TENON Hospital- AP-HP)	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary outcomes will be the average difference of the concentration of spermatozoa in the ejaculate measured before treatment and after 6 months of treatment.		6 months	No
Secondary	the average difference of the sperm DNA fragmentation in the ejaculate measured before treatment and after 6 months of treatment.		6 months	No
Secondary	the average difference of the mobility of spermatozoa in the ejaculate measured before treatment and after 6 months of treatment.		6 months	No
Secondary	the average difference of the vitality of spermatozoa in the ejaculate measured before treatment and after 6 months of treatment.		6 months	No
Secondary	the average difference of the morphology of spermatozoa in the ejaculate measured before treatment and after 6 months of treatment.		6 months	No