Phase 4 Pharmacovigilance Trial of Paromomycin Injection for the Treatment of Visceral Leishmaniasis in India

Background. A phase 3 study demonstrated the safety and efficacy of paromomycin (paromomycin IM injection) for treatment of VL in an inpatient setting. Methods. This phase 4 study was conducted to assess the safety and efficacy of paromomycin in children and adults in an outpatient setting in Bihar, India. Results. This study enrolled 506 adult and pediatric patients. Of the 494 patients in the intent-to-treat (ITT) population, 98% received a full course of treatment. The overall study completion rate was 94% (462/494) for the ITT population and 96% (461/479) for the efficacy-evaluable (EE) population. Initial clinical cure was 99.6%, and final clinical cure 6 months after treatment was 94.2%. Grade 3 or 4 adverse events occurred in 5% of patients; events with a frequency of ≥1% were increases in alanine aminotransferase and aspartate aminotransferase. Conclusions. This study confirms the safety and efficacy of paromomycin to treat VL in an outpatient setting. 1. Introduction Safe, effective, affordable, and accessible treatments are urgently needed for underserved populations in developing nations who are afflicted with one of the most neglected diseases: visceral leishmaniasis (VL), or kala-azar in South Asia. VL is endemic in 68 countries, primarily in the developing world, with an estimated at-risk population of 200 million [1]. As a systemic disease, VL causes chronic and irregular fever, weight loss, splenomegaly, hepatomegaly (less frequently), and anemia. If left untreated, VL is almost always fatal. New drugs are required for the treatment of VL partly because of the expansion of drug-resistant organisms [2–5]. Antimonials, which were historically the therapeutic mainstay for treating VL, have decreased effectiveness, especially in Bihar, India, where, in some cases, up to 65% of patients are estimated to fail antimonial treatment [3]. Pentamidine is toxic and has lost its initially high level of efficacy; it is no longer a recommended alternative treatment for VL [6]. The oral drug miltefosine is expensive and teratogenic, requiring the coadministration of oral contraceptives for 3 months in women of child-bearing age [7]. Although highly effective, amphotericin B is expensive, must be infused IV over 6 hours, is associated with fever, chills, and rigor, can be nephrotoxic, and requires close clinical and laboratory monitoring with hospitalization. Studies with lipid formulations of amphotericin B, such as AmBisome or Abelcet, have shown excellent results both in terms of safety and efficacy. A recent study showed that AmBisome (liposomal