Artesunate-amodiaquine fixed dose combination for the treatment of Plasmodium falciparum malaria in India

Malaria Journal, Mar 2012

Background Artemisinin-based combination therapy (ACT) has been recommended for the treatment of falciparum malaria by the World Health Organization. Though India has already switched to ACT for treating falciparum malaria, there is need to have multiple options of alternative forms of ACT. A randomized trial was conducted to assess the safety and efficacy of the fixed dose combination of artesunate-amodiaquine (ASAQ) and amodiaquine (AQ) for the treatment of uncomplicated falciparum malaria for the first time in India. The study sites are located in malaria-endemic, chloroquine-resistant areas. Methods This was an open label, randomized trial conducted at two sites in India from January 2007 to January 2008. Patients between six months and 60 years of age having Plasmodium falciparum mono-infection were randomly allocated to ASAQ and AQ arms. The primary endpoint was 28-day PCR-corrected parasitological cure rate. Results Three hundred patients were enrolled at two participating centres, Ranchi, Jharkhand and Rourkela, Odisha. Two patients in AQ arm had early treatment failure while there was no early treatment failure in ASAQ arm. Late treatment failures were seen in 13 and 12 patients in ASAQ and AQ arms, respectively. The PCR-corrected cure rates in intent-to-treat population were 97.51% (94.6-99.1%) in ASAQ and 88.65% (81.3-93.9%) in AQ arms. In per-protocol population, they were 97.47% (94.2-99.2%) and 88.30% (80-94%) in ASAQ and AQ arms respectively. Seven serious adverse events (SAEs) were reported in five patients, of which two were reported as related to the treatment. All SAEs resolved without sequel. Conclusion The fixed dose combination of ASAQ was found to be efficacious and safe treatment for P. falciparum malaria. Amodiaquine also showed acceptable efficacy, making it a suitable partner of artesunate. The combination could prove to be a viable option in case India opts for fixed dose combination ACT. Clinical trial registry ISRCTN84408319

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Artesunate-amodiaquine fixed dose combination for the treatment of Plasmodium falciparum malaria in India

Malaria Journal Artesunate-amodiaquine fixed dose combination for the treatment of Plasmodium falciparum malaria in India Anupkumar R Anvikar 0 Bhawna Sharma 2 Bhartendu H Shahi 0 Prajesh K Tyagi 1 Tarit K Bose 4 Surya K Sharma 0 Prakriti Srivastava 0 Bina Srivastava 0 Jean R Kiechel 3 Aditya P Dash 0 Neena Valecha 0 0 National Institute of Malaria Research , Sector 8, Dwarka, New Delhi 110077 , India 1 National Institute of Malaria Research, IDVC Field Unit , Sector 5, Rourkela, Odisha , India 2 Drugs for Neglected Diseases initiative (DNDi), Tuberculosis Association of India Building , 1st Floor, 3 Red Cross Road, Near Parliament House, New Delhi , India 3 Drugs for Neglected Diseases initiative (DNDi) , 15 Chemin Louis-Dunant, 1202 Geneva , Switzerland 4 Community Welfare Society Hospital Jagda , Rourkela, Odisha , India Background: Artemisinin-based combination therapy (ACT) has been recommended for the treatment of falciparum malaria by the World Health Organization. Though India has already switched to ACT for treating falciparum malaria, there is need to have multiple options of alternative forms of ACT. A randomized trial was conducted to assess the safety and efficacy of the fixed dose combination of artesunate-amodiaquine (ASAQ) and amodiaquine (AQ) for the treatment of uncomplicated falciparum malaria for the first time in India. The study sites are located in malaria-endemic, chloroquine-resistant areas. Methods: This was an open label, randomized trial conducted at two sites in India from January 2007 to January 2008. Patients between six months and 60 years of age having Plasmodium falciparum mono-infection were randomly allocated to ASAQ and AQ arms. The primary endpoint was 28-day PCR-corrected parasitological cure rate. Results: Three hundred patients were enrolled at two participating centres, Ranchi, Jharkhand and Rourkela, Odisha. Two patients in AQ arm had early treatment failure while there was no early treatment failure in ASAQ arm. Late treatment failures were seen in 13 and 12 patients in ASAQ and AQ arms, respectively. The PCR-corrected cure rates in intent-to-treat population were 97.51% (94.6-99.1%) in ASAQ and 88.65% (81.3-93.9%) in AQ arms. In per-protocol population, they were 97.47% (94.2-99.2%) and 88.30% (80-94%) in ASAQ and AQ arms respectively. Seven serious adverse events (SAEs) were reported in five patients, of which two were reported as related to the treatment. All SAEs resolved without sequel. Conclusion: The fixed dose combination of ASAQ was found to be efficacious and safe treatment for P. falciparum malaria. Amodiaquine also showed acceptable efficacy, making it a suitable partner of artesunate. The combination could prove to be a viable option in case India opts for fixed dose combination ACT. Clinical trial registry: ISRCTN84408319 Artesunate; Amodiaquine; falciparum malaria; India Background The World Health Organization (WHO) has recommended artemisinin-based combination therapy (ACT) as the treatment for Plasmodium falciparum and many malaria endemic countries are using it. The combination of amodiaquine and artesunate, along with four more combinations, is recommended by WHO for malaria control programmes [ 1 ]. India has switched over to ACT and the National Vector Borne Disease Control Programme recommends the use of artesunate + sulphadoxine-pyrimethamine (AS + SP) for the treatment for falciparum malaria [ 2 ]. There is not much data available on the efficacy of the partner drug SP, but there is evidence of dhfr and dhps mutations [ 3 ] and treatment failure has been reported in north-eastern states [ 4 ]. Further, since the combination is available as blister pack, compliance may be poor and this provides opportunity for consuming monotherapy. There is also the issue of dosage in paediatric age group. This forms the basis of evaluation of different forms of ACT, which may form an alternative to AS + SP combination. The combination artesunate-amodiaquine (ASAQ) has been extensively studied and good efficacy and tolerability has been reported. A systematic review of relevant studies [ 5-8 ] on the treatment of uncomplicated P. falciparum malaria conducted over the past 10 years in Africa showed that amodiaquine (AQ) proved significantly more effective than chloroquine in clearing parasites, with a tendency for faster clinical recovery. This difference was also observed in areas with considerable chloroquine resistance. Further, serious adverse events have not been reported with curative short-term regimen of AQ [9]. A randomized trial was conducted to assess the safety and efficacy of the fixed dose combination of ASAQ and AQ alone for treatment of uncomplicated falciparum malaria for the first time in India. The study sites were located in malaria-endemic, chloroquine-resistant areas. Methods This was an open label, randomized study carried out at Mahadevi Birla Hospital, Ranchi, Jharkhand and Community Welfare Society Hospital, Ro (...truncated)


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Anupkumar R Anvikar, Bhawna Sharma, Bhartendu H Shahi, Prajesh K Tyagi, Tarit K Bose, Surya K Sharma, Prakriti Srivastava, Bina Srivastava, Jean R Kiechel, Aditya P Dash, Neena Valecha. Artesunate-amodiaquine fixed dose combination for the treatment of Plasmodium falciparum malaria in India, Malaria Journal, 2012, pp. 97, 11, DOI: 10.1186/1475-2875-11-97