A Trial for Prevention of Recurrent Ischemic Priapism in Men With Sickle Cell Disease: A Pilot Study (PIN)

Description

Sickle cell disease (SCD) is one of the commonest genetic diseases in the world. Approximately 300,000 newborns are born with SCD every year, with 50% of the birth being in Nigeria alone. This huge burden makes Nigeria critical to any intervention that seeks to address the challenges of individuals with SCD. Men with SCD experience many complications, which can even affect their sexuality and reproductive health. One of the most common, but often neglected complications of SCD in men is priapism. Priapism is defined as a painful, purposeless, and sustained erection. In men with SCD, priapism tends to be recurrent and devastating. The prevalence of priapism was 42% in Jamaican men with SCD. Researchers reported the incidence of priapism in SCD to be very low before the age of 10 years, but the cumulative incidence rose to 32.7% by the age of 20 years. Researchers reported the prevalence of priapism in SCD to be 35%, out of which 72% was recurrent ischemic priapism (lasting <4 hours). The majority of the individuals with SCD experienced their first episode of priapism before the age of 20 years, with a mean age of onset being 15 years. In a cross-sectional study of 353 men with SCD, conducted by our team in Kano, Nigeria, the prevalence of priapism was approximately 32%; out of which 74% was recurrent ischemic priapism. In the same study, the prevalence of priapism in men without SCD (n=250) was 2%. The results from focus groups (3 in Nigeria and 3 in the U.S.) our team conducted revealed men with SCD who experienced recurrent ischemic priapism struggled with embarrassment, shame, anxiety and depression, and declining sexual function.

The prevention and treatment of ischemic priapism in SCD is still inadequate. Researchers used a combination of preventive oral etilefrine and self-administered intracavernosal injection of etilefrine for breakthrough priapism lasting >1 hour. Sixty-six percent (4 of 6) had no recurrence of priapism while the remaining two used intracavernosal injection of etilefrine. In a non-RCT study, Researchers reported a good response to oral etilefrine; which was shown to have reduced the frequency of recurrent ischemic priapism in SCD (mean difference 5.78); P < 0.0001.(21) However, in the only RCT for this drug, etilefrine was found to have no efficacy over placebo. Researchers showed that in 35 patients on graded doses of finasteride (5-alpha reductase inhibitor), priapism recurrences were reduced from an average of 22.7 to 2.1 at the end of the 120-day follow-up. A combination of oral ketoconazole with prednisolone showed a promising result in case-series reported by researchers. However, an RCT (n=40) showed no efficacy of ketoconazole (81.25% and 83% in both arms still having post-operative painful erections). In another study, hydroxyurea was shown to have decreased priapism recurrences in 4 of 5 men treated with a high dose. Nonetheless, stopping hydroxyurea heralded relapse of priapism. Researchers reported that sildenafil has controlled priapism experiences in 6 of 7 men observed. Non-RCT designs, small sample sizes, or adverse effects of the trial medications limit most of these studies.

This conceptual framework is based on the synergistic effect of tadalafil (PDE-5 inhibitor, which increases the bioavailability of cGMP), and hydroxyurea (NO donor). In SCD there is chronic hemolysis causing depletion of NO and dysregulation of PDE-5, which underpin the molecular basis of priapism. Chronic dosing of low-dose tadalafil inhibits PDE-5 to paradoxically restore the normal homeostatic mechanism of the NO-cGMP-PDE-5 pathway. Restored PDE-5 function helps prevent recurrent ischemic priapism. Despite the need, all prior priapism studies did not provide sufficient evidence for practice-based outcomes. Several reasons exist for the lack of any substantial progress for secondary prevention of ischemic priapism, the foremost of which is that SCD is a rare disease in high-income settings where most of the studies have been conducted. To overcome these limitations, the investigators propose an internal pilot trial to assess the feasibility trial in a setting where there are over 5000 men available to be enrolled in one city, Kano Nigeria. The trial will also build on the infrastructures and workflow established by NIH-funded pre-existing SCD stroke prevention trials conducted at the same hospitals in Kano.

The aims are 1) To conduct a randomized internal pilot trial and possible complete a phase III trial for the prevention of recurrent ischemic priapism (hydroxyurea + tadalafil vs hydroxyurea + placebo), referred to as the Priapism in Nigeria (PIN) trial, and 2) To assess the tolerability of moderate-dose hydroxyurea and its effect on spermatogenesis.

Trained study personnel will approach the eligible participants for consenting. After obtaining signed informed consent and ensuring they have fulfilled inclusion criteria, the participants will be randomized 1:1 to the treatment and placebo arms. The primary study statistician will be supported by a local statistician in Nigeria to perform the randomization process. After the random allocation, all study personnel and participants will be blinded to the treatment. The treatment arm will include tadalafil, given orally initially at a low-dose of 2.5 mg daily for four weeks. If tolerated very well during the four weeks, the dose will be increased to 5.0 mg daily as the final dose. Tadalafil and the identical placebo will be purchased from a local pharmaceutical company, Bond Chemical Nigerian Limited, which is licensed to produce tadalafil and hydroxyurea in Nigeria. Participants will be instructed to take tadalafil or placebo in the morning for this trial. Chronic morning dosing with tadalafil will allow the drug to be metabolized and is unlikely to be associated with sleep-related erections. Both treatment and placebo arms will be on hydroxyurea as standard care. Hydroxyurea will be given orally at a moderate-dose of 20mg/kg/day and is also produced by the Bond Chemical Nigerian Limited. The moderate-dose of hydroxyurea is found to be effective, with minimal adverse effects, in the preliminary data of stroke prevention in Nigeria (1R01NS094041) trial just recently completed in Kano, Nigeria. Both arms of the trial will be followed for one year; afterward, the trial will go into the open-label phase. The participant can select whether they want to continue either therapy or start a new treatment. At the baseline, demographic and clinical data from medical records of the participants will be collected. The data will include but are not limited to: co-morbidities (hypertension, diabetes, etc.), drug history (antihypertensives, aphrodisiacs, hormonal shots, alpha receptor agonists, antipsychotics, etc.), pain history, and blood transfusions history. The investigators will use internationally validated questionnaires (International Index of Erectile Function [IIEF],(24) PROMIS Erectile function,(25) sexual activity, and satisfaction with sex life) to evaluate erectile and sexual functions of the participants at baseline and subsequent follow-ups.

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