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

• Published in: PLoS neglected tropical diseases 2018-10, Vol.12 (10), p.e0006830
• Main Authors: Goyal, Vishal, Mahajan, Raman, Pandey, Krishna, Singh, Shambhu Nath, Singh, Ravi Shankar, Strub-Wourgaft, Nathalie, Alves, Fabiana, Rabi Das, Vidya Nand, Topno, Roshan Kamal, Sharma, Bhawna, Balasegaram, Manica, Bern, Caryn, Hightower, Allen, Rijal, Suman, Ellis, Sally, Sunyoto, Temmy, Burza, Sakib, Lima, Nines, Das, Pradeep, Alvar, Jorge
• Format: Article
• Language: English
• Subjects: Biology and Life Sciences; Clinical medicine; Clinical trials; Drug dosages; Drugs; Funding; Health care facilities; Health risk assessment; Health services; Hospital facilities; Hospitals; Internet; Library cataloging; Medical research; Medicine; Medicine and Health Sciences; Miltefosine; Parasitic diseases; Paromomycin; Patients; People and Places; Profiles; Public health; R&D; Research & development; Research and Analysis Methods; Safety; Tropical climate; Tropical diseases; Vector-borne diseases; Visceral leishmaniasis
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0006830

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