Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India

PLoS Negl Trop Dis. 2018 Oct 22;12(10):e0006830. doi: 10.1371/journal.pntd.0006830. eCollection 2018 Oct.


Background: In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions.

Methods: This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891.

Results: Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related.

Conclusion: All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India.

Trial registration: Clinical trial is registered at Clinical trial registry of India (CTRI/2012/08/002891, Registered on 16/08/2012, Trial Registered Prospectively).

Publication types

  • Clinical Trial, Phase IV
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amphotericin B / administration & dosage
  • Amphotericin B / adverse effects
  • Antiprotozoal Agents / administration & dosage*
  • Antiprotozoal Agents / adverse effects*
  • Child
  • Child, Preschool
  • Drug Therapy, Combination / adverse effects*
  • Drug Therapy, Combination / methods*
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Female
  • Humans
  • India
  • Leishmaniasis, Visceral / drug therapy*
  • Male
  • Middle Aged
  • Paromomycin / administration & dosage
  • Paromomycin / adverse effects
  • Phosphorylcholine / administration & dosage
  • Phosphorylcholine / adverse effects
  • Phosphorylcholine / analogs & derivatives
  • Prospective Studies
  • Treatment Outcome
  • Young Adult


  • Antiprotozoal Agents
  • liposomal amphotericin B
  • Phosphorylcholine
  • miltefosine
  • Paromomycin
  • Amphotericin B

Associated data

  • CTRI/CTRI/2012/08/002891

Grant support

This study was funded by Bill & Melinda Gates Foundation, USA (Grant Number OPP1017832); UK Aid; Dutch Ministry of Foreign Affairs (DGIS), the Netherlands; and Médecins Sans Frontières. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.