The preclinical discovery and development of rectal artesunate for the treatment of malaria in young children: a review of the evidence

Carvalho, Laís Pessanha de; Kreidenweiss, Andrea; Held, Jana

doi:10.1080/17460441.2020.1804357

Cited by 13 publications

(14 citation statements)

References 51 publications

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“…As early as 1995 [17] it was shown that a single dose of artesunate, given rectally to adolescents and adults over 15 years, can achieve parasiticidal blood concentrations within 10-20 min, and can halve parasite density within 6-12 h [18][19][20][21]. Artesunate suppositories are easy to administer, safe, well accepted and allow rapid initiation of effective malaria treatment in remote locations [21].…”

Section: Rectal Artesunate (Ras)mentioning

confidence: 99%

“…None of these earlier formulations were ever approved by regulatory authorities. Despite these shortcomings, the 50 mg and 200 mg capsules were added to the WHO Essential Medicine List in 2007 [21] and procured by countries, donors and non-governmental organisation (NGOs) until 2014, when a multi-donoragency taskforce restricted donors from sourcing any anti-malarial products that were not approved by a stringent regulatory authority. Following a concerted action led by the Medicines for Malaria Venture (MMV) product development partnership, two RAS products (made by Cipla Ltd. and Strides Pharma Science Ltd.) became WHO-prequalified in 2018.…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

“…To-date, 14 randomized controlled clinical trials have documented the safety, tolerability, efficacy and the pharmacological characteristics of RAS [21]. But only one large-scale Phase 3 field trial conducted in 2000-2009 assessed the public health impact of introducing RAS as pre-referral treatment in two African settings (Ghana and Tanzania, children between 6-72 months) and in Bangladesh (all ages) [12].…”

Section: Public Health Impact Of Rasmentioning

confidence: 99%

See 2 more Smart Citations

Community access to rectal artesunate for malaria (CARAMAL): a large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda

Lengeler

Burri

Awor

et al. 2021

Preprint

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The key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s. RAS allows the rapid initiation of life-saving antimalarial treatment, before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed to-date: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact.From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in Nigeria, Uganda and the Democratic Republic of the Congo (DRC). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. In order to achieve this, a number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed to track cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS.Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and cost-effectiveness of the RAS intervention.

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Section: Rectal Artesunate (Ras)mentioning

confidence: 99%

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

Section: Public Health Impact Of Rasmentioning

confidence: 99%

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Community access to rectal artesunate for malaria (CARAMAL): a large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda

Lengeler

Burri

Awor

et al. 2021

Preprint

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“…The World Health Organization (WHO) recommends a single dose of intramuscular (IM) artesunate, or, if injections are not available and the patient is <6 years of age, a single rectal dose of artesunate, followed by immediate referral to a higher-level health facility. 2 Rectal artesunate (RAS) rapidly reduces the malaria parasite load 6 and in a placebo-controlled randomized trial conducted in Bangladesh, Ghana and Tanzania, the use of pre-referral RAS was found to reduce case fatality of an episode of broadly defined severe malaria by 26% (risk ratio [RR] 0.74, 95% CI 0.59-0.93) in children below 6 years of age. 7,8 In children who took more than 6 hours to reach a higherlevel facility, RAS reduced death and permanent disability by about 50% (RR 0.49, 95% CI 0.32-0.77).…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children <5 years of age

Hetzel

Okitawutshu

Tshefu

et al. 2021

Preprint

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Background To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, higher-level facilities offering parenteral antimalarials are often difficult to access. A randomised controlled trial found pre-referral rectal artesunate (RAS) to reduce death and disability in children who delay arriving at a referral facility. This study examined the effectiveness of pre-referral RAS treatment in established community-based health care systems. Methods An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo, Nigeria and Uganda. Children < 5 years presenting to a community-based health provider with a positive malaria test and signs of severe malaria were followed-up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment. Findings Post-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 865/6286 patients were sick at follow-up. In all countries, the CFR was higher after RAS-roll-out (6.7 vs. 6.6% in DRC, 16.1 vs. 4.2% in Nigeria, 0.7 vs. 0.3% in Uganda). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR = 3.31, 95% CI 1.43-7.65 and aOR = 2.42, 95% CI 1.25-4.70, respectively). In Uganda, RAS users were less likely to be dead or sick at follow-up (aOR = 0.61, 95% CI 0.46-0.80). Post-referral parenteral antimalarials were protective in all countries; however, the effect of ACT administration was inconsistent. Interpretation RAS pre-referral treatment had no beneficial effect on child survival in three highly malaria endemic settings. RAS is unlikely to reduce malaria deaths unless health system shortfalls such as referral and post-referral treatment are addressed.

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“…RAS is also recommended as a pre-referral treatment in the integrated community case management (iCCM) guidelines (11, 12) or in primary health facilities (PHC) where injectable antimalarials are often not available (2, 13, 14). In many clinical settings, RAS was shown to be an excellent antimalarial, safe and well accepted (15, 16). It was also shown to be a saving-life intervention in a large three-countries randomized controlled trial (17).…”

Section: Introductionmentioning

confidence: 99%

Danger signs and management of suspected severe malaria cases at community level and in referral health facilities: an operational study in the Democratic Republic of the Congo

Okitawutshu

Signorell

Kalenga

et al. 2021

Preprint

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BackgroundEvidence from one trial in Africa suggests that pre-referral Rectal Artesunate (RAS) can be a life-saving intervention for severe malaria in remote settings, where parenteral treatment is not available. Recognition of danger signs indicative of severe malaria is critical for prompt and appropriate case management.MethodsAn observational study was conducted in the Democratic Republic of the Congo (DRC) in the frame of the multi-country CARAMAL project, to assess the effectiveness of RAS under real-world conditions. Severely ill feverish children <5 years seeking care from a community-based healthcare provider were recruited in three rural health zones into a patient surveillance system. They were subsequently followed within the healthcare system and at home after 28 days to determine care seeking, antimalarial treatment provision and health outcomes.ResultsOverall, 66.4% of patients had iCCM general danger signs, as well as more specific danger signs. Children aged 2-5 years (aOR=1.58, 95% CI 1.20–2.08) and those presenting iCCM general danger signs were more likely to receive RAS (aOR = 2.77, 95% CI 2.04–3.77). Injectable treatment was less likely with RAS pre-referral treatment (aOR=0.21, 95% 0.13– 0.33). In the post-RAS phase, the case fatality ratio was 7.1%. Children not receiving RAS had a higher risk of dying, but this was not statistically significant (aOR = 1.50, 95% CI 0.86– 2.60). The odds of dying were reduced in patients without iCCM general danger signs, but just not statistically so (aOR = 0.64, 95% CI 0.38–1.06). Full oral therapy at a RHF was highly protective (aOR = 0.13, 95% CI 0.07-0.26), while a full treatment of severe malaria (injectable + oral) was shown to also decrease massively the odds of dying (aOR = 0.26, 95% CI 0.09– 0.79) compared to injectable treatment alone.ConclusionsBetter understanding the determinants of successful case management, and targeted improvements of the health system (especially the provision of a full course of an oral antimalarial) are crucial for improving health oucomes of children with suspected severe malaria.

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The preclinical discovery and development of rectal artesunate for the treatment of malaria in young children: a review of the evidence

Cited by 13 publications

References 51 publications

Community access to rectal artesunate for malaria (CARAMAL): a large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda

Community access to rectal artesunate for malaria (CARAMAL): a large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda

Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children <5 years of age

Danger signs and management of suspected severe malaria cases at community level and in referral health facilities: an operational study in the Democratic Republic of the Congo

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