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Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India.
PLoS Negl Trop Dis. 2018 10; 12(10):e0006830.PN

Abstract

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).

Authors+Show Affiliations

Drugs for Neglected Diseases initiative (DNDi), New Delhi, India.Médecins Sans Frontières (MSF), New Delhi, India.Division of Clinical Medicine, Rajendra Memorial Research Institute of Medical Sciences (RMRI), New Delhi, India.Sadar Hospital Chapra, Saran, India.Sadar Hospital Chapra, Saran, India.Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.Division of Clinical Medicine, Rajendra Memorial Research Institute of Medical Sciences (RMRI), New Delhi, India.Division of Clinical Medicine, Rajendra Memorial Research Institute of Medical Sciences (RMRI), New Delhi, India.Drugs for Neglected Diseases initiative (DNDi), New Delhi, India.Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco CA, United States of America.Independent consultant, Bangkok, Thailand.Drugs for Neglected Diseases initiative (DNDi), New Delhi, India.Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.Médecins Sans Frontières (MSF), New Delhi, India.Médecins Sans Frontières (MSF), New Delhi, India.Médecins Sans Frontières (MSF), Barcelona, Spain.Division of Clinical Medicine, Rajendra Memorial Research Institute of Medical Sciences (RMRI), New Delhi, India.Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.

Pub Type(s)

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

Language

eng

PubMed ID

30346949

Citation

Goyal, Vishal, et al. "Field Safety and Effectiveness of New Visceral Leishmaniasis Treatment Regimens Within Public Health Facilities in Bihar, India." PLoS Neglected Tropical Diseases, vol. 12, no. 10, 2018, pp. e0006830.
Goyal V, Mahajan R, Pandey K, et al. Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India. PLoS Negl Trop Dis. 2018;12(10):e0006830.
Goyal, V., Mahajan, R., Pandey, K., Singh, S. N., Singh, R. S., Strub-Wourgaft, N., Alves, F., Rabi Das, V. N., Topno, R. K., Sharma, B., Balasegaram, M., Bern, C., Hightower, A., Rijal, S., Ellis, S., Sunyoto, T., Burza, S., Lima, N., Das, P., & Alvar, J. (2018). Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India. PLoS Neglected Tropical Diseases, 12(10), e0006830. https://doi.org/10.1371/journal.pntd.0006830
Goyal V, et al. Field Safety and Effectiveness of New Visceral Leishmaniasis Treatment Regimens Within Public Health Facilities in Bihar, India. PLoS Negl Trop Dis. 2018;12(10):e0006830. PubMed PMID: 30346949.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India. AU - Goyal,Vishal, AU - Mahajan,Raman, AU - Pandey,Krishna, AU - Singh,Shambhu Nath, AU - Singh,Ravi Shankar, AU - Strub-Wourgaft,Nathalie, AU - Alves,Fabiana, AU - Rabi Das,Vidya Nand, AU - Topno,Roshan Kamal, AU - Sharma,Bhawna, AU - Balasegaram,Manica, AU - Bern,Caryn, AU - Hightower,Allen, AU - Rijal,Suman, AU - Ellis,Sally, AU - Sunyoto,Temmy, AU - Burza,Sakib, AU - Lima,Nines, AU - Das,Pradeep, AU - Alvar,Jorge, Y1 - 2018/10/22/ PY - 2018/04/02/received PY - 2018/09/10/accepted PY - 2018/10/23/entrez PY - 2018/10/23/pubmed PY - 2019/1/10/medline SP - e0006830 EP - e0006830 JF - PLoS neglected tropical diseases JO - PLoS Negl Trop Dis VL - 12 IS - 10 N2 - 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). SN - 1935-2735 UR - https://www.unboundmedicine.com/medline/citation/30346949/Field_safety_and_effectiveness_of_new_visceral_leishmaniasis_treatment_regimens_within_public_health_facilities_in_Bihar_India_ L2 - https://dx.plos.org/10.1371/journal.pntd.0006830 DB - PRIME DP - Unbound Medicine ER -