Efficacy and safety of a combination of azithromycin and chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in two multi-country randomised clinical trials in African adults

Sagara et al. Malaria Journal 2014, 13:458 http://www.malariajournal.com/content/13/1/458 RESEARCH Open Access Efficacy and safety of a combination of azithromycin and chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in two multi-country randomised clinical trials in African adults Issaka Sagara1, Abraham R Oduro2, Modest Mulenga3, Yemou Dieng4, Bernhards Ogutu5, Alfred B Tiono6, Peter Mugyenyi7, Ali Sie8, Monique Wasunna9, Kevin C Kain10, Abdoulaye A Djimdé1, Shirsendu Sarkar11, Richa Chandra12, Jeffery Robbins13* and Michael W Dunne14 Abstract Background: Given increasing rates of resistance to existing therapy, new options for treatment and prophylaxis of malaria are needed. Methods: Two randomised, comparative, non-inferiority studies were conducted in Africa, one double-blinded and one open-label. Adults with fever, a positive peripheral blood smear, and a positive rapid diagnostic test for Plasmodium falciparum were randomised in both studies to either azithromycin (AZ) 1,000 mg plus chloroquine (CQ) 600-mg base (AZCQ 1,000 mg) once daily for three days or mefloquine hydrochloride (MQ) 1,250 mg (split dose). In the first study, an additional regimen of AZ 500 mg plus CQ 600-mg base (AZCQ 500 mg) once daily for three days was included. All study participants were hospitalised until three consecutive daily blood smears were negative for asexual P. falciparum parasitaemia. Study participants were evaluated weekly for 42 days, with Day 28 polymerase chain reaction (PCR)-corrected parasitological clearance rate as primary endpoint. Results: A total of 467 subjects were randomised in the two studies. At 28 days’ follow-up, PCR-corrected parasitological clearance rates in the per protocol population in the first study were 101/103 (98%) with AZCQ 1,000 mg compared with 102/103 (99%) with MQ (95% confidence interval [CI]: −5.2, 3.3). The AZCQ 500-mg regimen was stopped during an interim study review (six [86%] clearance of seven evaluable; two lost to follow-up). In the second study, clearance rates were similar: AZCQ 1,000 mg 107/107 (100%) vs MQ 111/112 (99%; 95% CI: −1.8, 3.6). Among the participating countries, in vitro CQ resistance based on pfcrt mutation frequency in the baseline isolates across both studies ranged from 20.8% (Zambia) to 96.1% (Uganda). Serious adverse events (AEs; all causality) were observed more frequently with MQ compared with AZCQ (four vs one, respectively), though discontinuations for AEs were similar (four vs three, respectively). Common AEs in the AZ-containing arms included pruritus, vomiting, dizziness, and headache. (Continued on next page) * Correspondence: 13 Global Research and Development, Pfizer Inc, 445 Eastern Point Road, Groton, CT 06340, USA Full list of author information is available at the end of the article © 2014 Sagara et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sagara et al. Malaria Journal 2014, 13:458 http://www.malariajournal.com/content/13/1/458 Page 2 of 10 (Continued from previous page) Conclusions: Among adults with symptomatic uncomplicated falciparum malaria in Africa, the combination of AZ 1,000 mg and CQ 600-mg base once daily for three days resulted in Day 28 PCR-corrected parasitological clearance rates of ≥98% and was non-inferior to treatment with MQ. AZCQ was well tolerated. Trial registration: ClinicalTrials.gov identifiers NCT00082576 and NCT00367653 Keywords: Azithromycin, Chloroquine, Falciparum malaria, Combination treatment Background Malaria remains one of the most common causes of morbidity and mortality in Africa. In 2011, >80% of the population in most countries in Africa were at high risk for malaria [1]. The use of pesticides and the broad availability of chloroquine (CQ) effectively contained malaria on the African continent through the 1970s, until subsequent development of resistance by the Plasmodium species led to increased morbidity and mortality [2]. Management of malaria in Africa requires a variety of preventive and treatment initiatives, each of which targets different patient subpopulations. As a consequence, these initiatives demand medical therapy that, individually, vary in the requirements for safety, efficacy, and tolerability and, collectively, must integrate within a larger public health strategy. Increasing degrees of parasite resistance to mainstream drug interventions have further limited the choice of therapy available for malaria [3]. For example, there is currently no generally acceptable alternative for sulphadoxine/pyrimethamine in the intermittent preventive therapy in pregnancy programme. New therapy is needed and alternative options must be explored for their potential utility. The anti-malarial properties of azithromycin (AZ) have been documented in vitro and in animal experiments, as well as in treatment and prevention clinical trials of both Plasmodium falciparum and Plasmodium vivax [4-8]. Given as monotherapy, AZ did not meet clinical standards of efficacy for treatment of falciparum malaria. However, further in vitro work suggested the possibility of synergy between AZ and CQ [4], which was subsequently supported by a small clinical trial in India [6]. Given the need for a new anti-malarial therapy and the scarcity of new potential agents, and the promising early results of a pilot clinical study [6], as well as the well-established safety profiles of both agents, there was a need to conduct a study to compare combined AZ and CQ with mefloquine hydrochloride (MQ). MQ was used as the comparator based on the recommendation of the US Food and Drug Administration (FDA). The results of two trials of the combination of AZ and CQ in the treatment of symptomatic uncomplicated P. falciparum malaria in adults in Africa are reported here. Methods Study design The two phase II/III multi-centre, parallel, randomised, controlled, comparative, non-inferiority studies reported here were performed sequentially. Study number A0661134 (referred to hereafter as study 1134; ClinicalTrials.gov identifier NCT00082576; double-blind phase II/III) was conducted between June 2004 and May 2006, and study number A0661155 (referred to hereafter as study 1155; ClinicalTrials.gov identifier NCT00367653; open-label phase III) was conducted between November 2006 and September 2007. Both studies were conducted in African countries; study 1134 in Ghana, Mali, Zambia, Kenya, and Uganda and study 1155 in Ghana, Mali, Zambia, Kenya, Burkina Faso, and Senegal. In both trials, the comparator agent was MQ and both stu (...truncated)