Malaria Therapeutic Efficacy Study, Rwanda
Condition: Uncomplicated Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 4

Summary: 
      WHO recommends that Therapeutic Efficacy Studies (TES) for 1st and 2nd line antimalarial
      medicines should be routinely carried out and data made available for decision-making due to
      the threat of emergence and spread of artemisinin resistance in malaria-endemic countries,
      especially in Africa. In line with this WHO recommendation, Rwanda Ministry of Health (MOH)
      is conducting the TES to determine the efficacy of artemether-lumefantrine (ALN), which has
      been used in Rwanda for the last 14 years) and dihydroartemisinin-piperaquine (DHA-PPQ),
      another WHO-approved drug for the treatment of uncomplicated malaria which, though, has not
      been used in Rwanda, is being considered for adoption as a second line or alternative first
      line treatment. The objective of this study is to inform the decisions or actions made by a
      public health authority (Rwanda Rwanda Ministry of Health) to inform decision on revision of
      the antimalarial guidelines and policy in Rwanda. Jhpiego's Impact Malaria project in Rwanda,
      with funding and technical oversight from US President's Malaria Initiative (PMI) through
      USAID and CDC, will support the Rwanda MOH in its effort to evaluate the efficacy of ALN and
      DHA-PPQ in the treatment of children with uncomplicated malaria. The study is being conducted
      by Rwanda MOH, with technical support and funding by PMI-USAID through Jhpiego in Rwanda.
    

Detailed description: 
      WHO recommends that Therapeutic Efficacy Studies (TES) for 1st and 2nd line antimalarial
      medicines should be routinely carried out and data made available for decision-making due to
      the threat of emergence and spread of artemisinin resistance in malaria-endemic countries,
      especially in Africa. The Rwandan Ministry of Health (MOH) in 2006 adopted WHO-approved
      artemether-lumefantrine (ALN) as the first-line drug for the treatment of uncomplicated
      Plasmodium falciparum malaria. A clinical trial carried out in 2004-2005 in Rwanda showed
      that ALN was very efficacious in children although efficacy varied in different parts of the
      country. ALN efficacy was shown to remain high in TES conducted in 2012-2015 and in 2018.
      However, both studies found a molecular marker of parasite resistance to artemisinin
      (included delayed parasite clearance associated with artemisinin resistance in one site in
      2018) and both studies also found high prevalence of markers associated with tolerance to
      lumefantrine. The clinical efficacy of ALN therefore needs to be regularly monitored in
      Rwanda to ensure this first line treatment is still efficacious. Given the detection of
      antimalarial resistance markers in recent TES, it is also important for Rwanda MOH to
      determine the efficacy an additional ACT that could be considered for adoption as a second
      line or alternative first line treatment. This study will monitor the efficacy of ALN (which
      has been used in Rwanda for the last 14 years) and dihydroartemisinin-piperaquine (DHA-PPQ),
      another WHO-approved ACT for the treatment of uncomplicated malaria which has not been used
      in Rwanda.

      In line with the WHO recommendation, Jhpiego Impact Malaria project in Rwanda, with funding
      and technical oversight from US President's Malaria Initiative (PMI) through USAID and CDC,
      will be supporting the Rwanda MOH Malaria and Other Parasitic Diseases Unit (MOPDD) of the
      Rwanda Biomedical Center (RBC) to conduct a TES to monitor the efficacy of ALN and DHA-PPQ in
      children with uncomplicated clinical malaria in rural Rwanda. The study is being conducted by
      Rwanda MOH MOPDD, with technical support and funding by PMI-USAID through the Jhpiego Impact
      Malaria project in Rwanda.

      Objective: To evaluate the efficacy of artemether-lumefantrine (ALN) and
      dihydroartemisinin-piperaquine (DHA-PPQ) in children with uncomplicated clinical malaria in
      rural Rwanda

      Study Sites: The study will be conducted in three sentinel sites - Rukara, Bugarama and
      Masaka rural health centers- where antimalaria efficacy studies are always carried out in
      Rwanda because of the intensity of malaria transmission. Different levels of artemisinin
      resistance have been identified in two of these three (Rukara and Bugarama) in previous
      studies. At each site, there will be two arms: one for ALN and one for DHA-PPQ.

      Study Design: The study will be a two-arm, open-label trial in which patients (children aged
      6 months to 59 months) with uncomplicated P. falciparum malaria will be treated with
      supervised doses of ALN or DHA-PPQ. Children will be followed for 28 days after treatment for
      ALN and 42 days after DHA-PPQ. Data on molecular markers of artemisinin resistance will be
      collected at all sites. The study will be conducted at three sites in Rwanda with
      historically different efficacy profiles to antimalarials, including ACTs.

      The primary endpoint is the clinical and parasitological cure by day 28 (ALN) and day 42
      (DHA-PPQ) post-treatment.

      Study Period: March 2021 to October 2022

      Sample Size: At each site, 88 patients per treatment arm (allowing for 20% loss to follow-up)
      would be enrolled. In total, we will enrol 528 patients in our study.

      Treatment(s) and follow-up: All children enrolled in the study will be admitted to a health
      centre for three days to ensure adherence to treatment regimen, and detect possible adverse
      events. Clinical and parasitological parameters will be monitored over a 28-day follow-up
      period to evaluate ALN efficacy, and over a 42-day follow-up period to evaluate DHA-PPQ
      efficacy.

      Exploratory endpoints: to characterize molecular markers of artemisinin and partner drug
      resistance in all three sites and the clinical (parasite clearance) and in vitro phenotypes
      of resistance in two of the three study sites: Rukara and Masaka.
    

Intervention name(s): artemether-lumefantrine (ALN); dihydroartemisinin-piperaquine (DHA-PPQ)
Intervention type(s): Drug; Drug
Intervention description(s): Assessing the efficacy on current 1st line antimalarial, and an alternative 1st line or 2nd line medicine; dihydroartemisinin-piperaquine (DHA-PPQ)
Intervention MeSH terms: Lumefantrine; Artemether; Piperaquine; Artemether, Lumefantrine Drug Combination; Artenimol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment