Pruritus (itch) is one of the most frequently identified signs and symptoms of uremia. This clinical condition is known as uremic pruritus, a common, disturbing symptom among dialysis patients. According to a multinational, cross-sectional study of dialysis patients, the Dialysis Observation and Practice Patterns Study (DOPPS), the prevalence of moderate to extreme uremic pruritus in dialysis patients was 42% and with a prevalence in the U.S. of 40% (Pisoni 2006). Uremic pruritus has been shown to be associated with significant, deleterious impairment of the patient quality of life based on QoL measures such as sleep disruption, social functioning and affective disturbances (Mathur 2010 and Pisoni 2006) as well as increased mortality (Pisoni 2006 and Narita 2006). Pisoni concluded that the higher mortality rate associated with moderate to extreme pruritus may be explained in large part by the presence of pruritus leading to a sleep disturbance, which ultimately is associated with increased mortality risk.
While the etiology of uremic pruritus is unknown, it is hypothesized that circulating molecules in the uremic milieu activate central itch pathways through opioid receptors (the “opioid hypothesis”).
Trevi has conducted the largest-to-date controlled study in uremic pruritus. It was a Phase 2/3 Randomized, Double-Blind, Placebo-Controlled, Parallel, 3-Arm Study of the Safety and Anti-Pruritic Efficacy of Nalbuphine HCl ER Tablets in Hemodialysis Patients with Uremic Pruritus. This study dosed twiced-daily at 60 mg and 120 mg in approximately 370 patients on hemodialysis in the United States and Europe. Patients with a wide range of mean moderate-to-severe itch intensity, ranging from 4.5 to 10 on the ten-point Numerical Rating Score (NRS) scale, were enrolled to evaluate efficacy across a representative patient population for this chronic indication. This study consisted of a titration period of two weeks, followed by a six-week blinded period on a fixed dose of drug or placebo and a wash-out period. At the end of the wash-out period, patients were eligible to roll over into a six-month open label extension study.
Patients receiving 120 mg of Nalbuphine® ER (n=120) experienced a 3.5 point reduction in itch intensity from baseline, resulting in a highly statistically significant mean reduction in itch intensity as compared to placebo (p-value=0.017). A statistically significant mean reduction for Nalbuphine® ER compared to placebo was observed as early as one week following titration to the Nalbuphine® ER fixed dose, and there was a statistically significant separation from placebo throughout the remaining blinded period. Severe itch patients (those with an NRS score greater than or equal to 7) experienced on average an NRS score reduction of 4.5 points from baseline, (p-value-0.007). The 60 mg dose showed a numerically favorable reduction over placebo, but did not achieve statistical significance. The secondary endpoints, the Skindex-10 Disease Domain and the Itch MOS Sleep index, provided confirmatory evidence of a favorable Nalbuphine® ER effect on itching compared to placebo.
Trevi conducted a six-month open label extension study in hemodialysis patients with uremic pruritus. This was a multi-center, open-label, single-arm study that was the extension of a randomized controlled trial in which patients were treated for 8 weeks. The parent study met its primary efficacy endpoint, demonstrating that NAL 120mg resulted in a significant reduction in itching intensity as compared with placebo. The conclusions of the study were that long-term treatment with Nalbuphine® ER was associated with significant and sustained reductions in itch intensity and improve itch-related sleep disruption and quality of life.
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