Drepanocytic Men Treated by Hydroxyurea for the First Time Clinical Trial
Official title:
Future of Spermatogenesis in Men With Sickle Cell Disease Medically Treated.
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.
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.
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Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment