Efficacy, Safety, and Tolerability of Dihydroartemisinin-piperaquine + Mefloquine Compared to Dihydroartemisinin-piperaquine or Artesunate-mefloquine in Patients With Uncomplicated Falciparum Malaria in Cambodia
Condition: Acute Falciparum Malaria
MeSH terms: Malaria; Malaria, Falciparum
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      Malaria is an illness caused by a parasite that enters people s bodies when a mosquito bites
      them. It can cause fevers, headaches, body aches, and weakness. If not treated, it can make
      some people very ill. Malaria can be cured. A mix of 2 drugs that has worked well in the past
      is not working as well in some parts of Cambodia. Researchers want to see if a mix of 3 drugs
      works better and is safe.

      Objectives:

      To see if a 3-drug mix can be used to treat malaria in areas where a 2-drug mix is less
      effective.

      Eligibility:

      People aged 2 65 years with mild malaria in Pursat, Preah Vihear, and Ratanakiri Provinces in
      Cambodia.

      Design:

      Participants will be screened with medical history, physical exam, urine and blood tests, and
      an electrocardiogram (ECG). For this, electrodes will be placed on their skin to check their
      heartbeat.

      Participants will spend about 5 nights in the hospital. They will have physical exams and
      will complete symptom questionnaires daily. They will give blood periodically throughout
      their stay. For this, a thin plastic tube is placed in an arm vein for the first day, and
      blood draws using a needle are done after that.

      Participants will get either a 2-drug mix or a 3-drug mix for 3 days. They will have 2 ECGs
      each day of receiving the drugs.

      Participants will have follow-up visits once a week over 5 weeks. At these visits, they will
      have a physical exam and have blood taken. If they have any signs of malaria, they will be
      re-treated.

      The study will last up to 42 days.
    

Detailed description: 
      Dihydroartemisinin-piperaquine (DHA-PPQ) Cambodia s frontline artemisinin (ART) combination
      therapy (ACT) for Plasmodium falciparum malaria is failing to cure nearly half of patients in
      its western provinces. These treatment failures are caused by parasite strains that are
      resistant to both ART and PPQ, yet sensitive to mefloquine (MQ) in vitro and in vivo. These
      findings, and previous studies showing that PPQ treats MQ-resistant infections in patients,
      led us to hypothesize that parasites have not developed cross-resistance to both PPQ and MQ.
      Given that DHA-PPQ and AS+MQ have both failed rapidly to resistance when used alone, we
      propose to treat patients with triple ACT (TACT) containing DHA-PPQ + MQ. We believe that
      this TACT will more effectively cure patients than either ACT alone, and will continue to
      achieve acceptably high cure rates and help to eliminate malaria in Cambodia until new drugs
      are developed and deployed. This protocol thus aims to measure the efficacy, safety, and
      tolerability of DHA-PPQ + MQ versus DHA-PPQ or AS-MQ alone in a multi-site, open-label,
      randomized clinical trial. In each of three Cambodian provinces (Pursat, Preah Vihear, and
      Ratanakiri) where DHA-PPQ is failing, we will recruit subjects aged 2 to 65 years with
      uncomplicated falciparum malaria (randomized 1:1), In Pursat and Preah Vihear we will treat
      them with either DHA-PPQ + MQ or AS-MQ alone and in Ratanakiri we will treat them with either
      DHA-PPQ + MQ or DHA-PPQ alone for three days, and follow them for 42 days to assess for
      recrudescent parasitemia an indicator of treatment failure. The main safety concern of this
      study is that DHA-PPQ + MQ may cause electrocardiographic (ECG) changes that could predispose
      a patient to develop clinically significant arrhythmias. This is because PPQ is known to
      cause prolongation of the ECG corrected QT (QTc) interval, and MQ may further increase PPQ
      levels (and thus the risk of further QTc prolongation) through pharmacokinetic interactions
      involving CYP3A4, a liver enzyme that metabolizes both drugs. To monitor for such an event,
      we will obtain ECG recordings before and after each drug dose. The safety and tolerability of
      TACT versus ACT will also be assessed through periodic tests of hematopoietic, hepatic, and
      renal function, and frequent symptom questionnaires. We will also administer a single low
      dose of primaquine, which kills P. falciparum gametocytes, on Day 2 to interrupt the
      transmission of parasites to mosquitoes and promote the elimination of malaria in Cambodia.
      During hospitalization and followup, we will obtain a series of research blood samples to
      estimate the prevalence of genetic markers for ART, PPQ, and MQ resistance; to develop a
      genotyping platform for rapidly surveying known drug resistance-associated mutations;
      investigate the genomic and transcriptomic basis of drug-resistance mechanisms; confirm the
      elimination of parasites and gametocytes from the bloodstream using sensitive molecular
      methods; measure the ex-vivo susceptibility of parasites to antimalarial drugs, and
      cryopreserve parasites for future studies to elucidate the molecular mechanisms of drug
      resistance.
    

Intervention name(s): Dihydroartemisinin-piperaquine (DHA-PPQ); Mefloquine (MQ)
Intervention type(s): Drug; Drug
Intervention description(s): Co-formulated anti-malarial drug used as standard of care treatment for uncomplicated malaria in Cambodia; ACT partner drug
Intervention MeSH terms: Piperaquine; Artenimol; Mefloquine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Plasmodium Falciparum; Artemisinin Combination Therapy; Triple Artemisinin Combination Therapy; Piperaquine; Mefloquine