A phase III clinical trial study published online in The Lancet shows that three short-course combination treatments for visceral leishmaniasis in India are efficacious and safe.
This Phase III, open-label, non-inferiority, randomised controlled clinical trial on 634 patients has been conducted in Bihar, India, between June 2008 and July 2009 by Professor Shyam Sundar of the Kala-Azar Research Centre in Muzzafarpur, and Prabhat Kumar Sinha of the Patna-based Rajendra Memorial Research Institute of Medical Sciences, part of the Indian Council of Medical Research (ICMR). The trial was sponsored by the Drugs for Neglected Diseases initiative (DNDi) and was conducted in collaboration with the ICMR. The study shows that the three combination therapies — single injection of 5mg/kg liposomal amphotericin B (L-AmB) and 7-day miltefosine, single injection L-AmB and 10-day paromomycin, or miltefosine and paromomycin for 10 days — were highly efficacious, less toxic, and better tolerated than the standard treatment with amphotericin B (infusions on alternate days for 30 days).
“New treatment regimens involving combination therapies of drugs that are already available will offer shorter, safer, and cheaper treatment options than the current standard monotherapy treatment available,” says Manica Balasegaram, Head of the Leishmaniasis Clinical Program at DNDi.
Visceral leishmaniasis (VL), also known as kala-azar or black fever, mainly occurs in poor, remote areas in South Asia, East Africa, and South America. VL, caused by the Leishmania parasite and transmitted by sandflies, is characterized by prolonged fever, enlarged spleen and liver, substantial weight loss, and progressive anemia. Left untreated, the disease is fatal.
Existing treatments have serious limitations, including risk of resistance, low tolerability, long treatment duration, and difficulty in administration. Furthermore, they can be expensive and often do not have high cure rates.
The objective of this study was to identify a safe and efficacious short-course combination therapy using the three drugs registered in India: L-AmB, paromomycin, and miltefosine. While results of a previous study show that a single dose of L-AmB has a high efficacy, with a 95% cure rate, all three combination treatments (L-AmB and paromomycin; L-AmB and miltefosine; paromomoycin and miltefosine) produced a cure rate of 97.5%.
“In addition to their efficacy and safety, results of this study show that these combinations will decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites,” notes Professor Farrokh Modabber, Project Manager of the trial, DNDi.
“The challenge now is to move from research to practice to reach the patients in need at the community level,” adds Dr Bernard Pécoul, Executive Director, DNDi. To facilitate the introduction of these new treatments in India and South Asia, DNDi will actively collaborate with health authorities at national and regional levels.
DNDi intends to implement effectiveness studies in India to demonstrate that such treatments can be feasibly and safely implemented in primary healthcare settings.
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DNDi (Drugs for Neglected Diseases initiative) is a patient-needs driven, not-for-profit drug R&D organization that is currently developing new treatments against the most neglected diseases such as sleeping sickness (or human African trypanosomiasis, HAT), leishmaniasis, Chagas disease and malaria. The initiative’s primary objective is to deliver six to eight new treatments by 2014 and to establish a strong R&D portfolio for these diseases. In doing so, DNDi is also working to use and strengthen existing capacities in disease-endemic countries, and advocate for increased public responsibility. DNDi was established in 2003 by the Indian Council for Medical Research (ICMR), Brazil’s Oswaldo Cruz Foundation (Fiocruz), the Kenya Medical Research Institute (KEMRI), the Ministry of Health of Malaysia, the Pasteur Institute in France, and Médecins Sans Frontières/Doctors Without Borders (MSF), with the World Health Organization/TDR as a permanent observer. Since 2007, DNDi has delivered four treatments including two fixed-dose anti-malarials, ASAQ and ASMQ, the combination treatment NECT (nifurtimox-eflornithine combination therapy) for the advanced stage of sleeping sickness and now a combination treatment in Africa to treat visceral leishmaniasis.