FocaL Mass Drug Administration for Vivax Malaria Elimination (FLAME)

University of California San Francisco (UCSF)

Status and phase: Enrolling; Phase 3

Conditions: Plasmodium Vivax Malaria; Malaria

Treatments: Drug: Focal Mass Drug Administration (fMDA)

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05690841

1U01AI157962 (U.S. NIH Grant/Contract)

22-36417

23-0008 (Other Identifier)

Details and patient eligibility

About

FLAME is an open-label cluster-randomized controlled trial that aims to determine the effectiveness of focal mass drug administration (fMDA) to reduce the incidence of Plasmodium vivax malaria in the Loreto Department in Peru. Standard interventions, including symptomatic and asymptomatic screening for malaria infections, provision of insecticide-treated bednets, and environmental transmission monitoring, will be compared to clusters of villages randomized to receive anti-malarial drugs.

Full description

This trial is an open-label cluster-randomized controlled trial in Loreto Region, Peru, a low transmission setting (i.e. anual incidence <250/1000), where the unit of randomization is a village, or cluster. There will be two study arms: Control and fMDA. Villages will receive fMDA or control based on a restricted randomization that includes baseline factors such as incidence, distance to a health post, and population.

The interventions for both control and fMDA clusters will include standard interventions (high coverage of vector control, passive and active symptomatic case management, and RACD of asymptomatic cases). The intervention will take place in 2 rounds for three cycles, each cycle separated by regular intervals. fMDA will target high-risk villagers (individuals residing in households that are within 200 meters of a Pv index case households from the prior 2 years). High-risk status will be determined in each survey before the administration of Round "a" of fMDA. Pv index cases refers to confirmed Pv cases reported by the health system.

In each cycle of fMDA, the 1st round will include 3 days of chloroquine (CQ) for treatment of Pv asexual blood stages, with TQ for Pv liver stages. With a prolonged half-life up to 15 days and post-treatment effect observed up to 77 days. TQ will also have a prophylactic and likely gametocytocidal effect for Pv and Pf. For continued anti-relapse, prophylactic, and transmission-blocking effects, a follow-up round will include TQ with single-dose CQ (sdCQ). If TQ, but not PQ, is contraindicated, a standard 7-day PQ course will be used. CQ, including in a single dose, will potentiate the anti-relapse effect of PQ, and likely TQ. Preliminary data from the study area shows that 32% of the study population is <16 years old and will receive PQ. However, the investigators do not anticipate this to influence the impact of the fMDA due to our use of directly observed therapy (DOT). If pediatric TQ is approved for use in Peru during the study, an addendum to the protocol will be presented for approval by the IRB and INS and incorporated into the study.

An endline survey will be carried out at the end of the 3-year trial intervention period. An interim survey will also be conducted in a subset of the population both arms. In each of these surveys, a dried blood spot will be collected from all participants. Anyone with fever in the prior 48 hours and a positive blood smear from a local health post will receive treatment per national policy. Anyone with fever in the prior 48 hours without a positive blood smear will be encouraged to go to a health post. To maximize public health relevance, the trial will be pragmatic and implemented through the existing health system.

The primary research objectives are:

1. To determine the effectiveness of three rounds of fMDA to reduce Pv transmission in the Loreto Department, Peru compared to standard interventions.
2. To evaluate the safety and tolerability of fMDA by measuring incidence of severe adverse events or severe malaria in the treatment arm.
3. To measure the cost-effectiveness and acceptability of fMDA by calculating the cost per malaria case averted for intervention and control arms.

Enrollment: 7,530 estimated patients

Sex: All

Ages: 6+ months old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

1. Cluster eligibility

   • Within 8 hours transport of Iquitos
   • Incidence <250/1000 and >2 cases year prior to trial
   • Population size (<650)

2. Chloroquine (CQ) eligibility

   • Resides in neighboring household but within 200 m of Pv index case in the past 2 years
   • Age ≥6 months old
   • Present for intervention
   • Adult ≥18 years old that provides informed consent
   • A child ≥8 years and <18 years old that provides informed assent and has informed consent from their parents
   • A child ≥6 months old and <8 years old that has informed consent from their parents

3. Tafenoquine (TQ) eligibility

   • Eligible to receive CQ
   • Age ≥16 years old
   • Adult ≥18 years old that provides informed consent
   • A child ≥16 years and <18 years old that provides informed assent and has informed consent from their parents

4. Primaquine eligibility

   • Eligible to receive CQ and ineligible to receive TQ
   • Age ≥6 months old
   • Adult ≥18 years old that provides informed consent
   • A child ≥8 years and <18 years old that provides informed assent and has informed consent from their parents
   • A child ≥6 months old and <8 years old that has informed consent from their parents

5. Baseline evaluation and informed consent

   -Villagers will be eligible to participate in surveys if they slept in a household in cluster randomized to control or focal mass drug administration (fMDA) for at least one night in the past four weeks

6. Eligibility for fMDA

   • High-risk villagers are defined as individuals residing in households that are within 200 meters of a Plasmodium vivax index case households from the prior 2 years (including individuals in the index case household) will be eligible to receive fMDA that cycle
   • Villagers that were eligible but missed in the 1st round in a cycle, or become eligible in the next two months, will not be eligible to receive fMDA in the 2nd round in a cycle.

Exclusion criteria

1. Chloroquine eligibility

   • History of retinal or visual field changes
   • Known hypersensitivity or adverse reaction to CQ
   • Currently taking CQ or have taken CQ in the past four weeks
   • Ineligible for TQ or PQ (see criteria below)
   • Hemoglobin <9 g/dL

2. Tafenoquine eligibility

   • G6PD deficiency or intermediate status (defined as activity ≤6.0 UI/gHb per SD biosensor)
   • G6PD status unknown or refusal of G6PD status test
   • Acute or severe malaria
   • Pregnancy (known or identified by pregnancy test)
   • Refusal of pregnancy test if new amenorrhea in the past 4 weeks
   • Woman breastfeeding a child that is G6PD deficient or with unknown G6PD status
   • Known hypersensitivity or adverse reaction to TQ or PQ
   • Have taken mefloquine (i.e. artesunate- mefloquine), TQ or PQ, or other antimalarial in the past four weeks
   • Hemoglobin < 9 g/dL

3. Primaquine eligibility

   • G6PD deficiency (defined as activity ≤4.0 UI/gHb per SD biosensor)
   • G6PD status unknown or refusal of G6PD status test
   • Acute or severe malaria
   • Pregnancy (known or identified by pregnancy test)
   • Refusal of pregnancy test if new amenorrhea in the past 4 weeks
   • Breastfeeding child with documented or unknown G6PD deficiency status
   • Known hypersensitivity or adverse reaction to TQ or PQ
   • Have taken mefloquine (i.e. artesunate- mefloquine), TQ or PQ, or other antimalarial in the past four weeks
   • Hemoglobin < 9 g/dL

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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7,530 participants in 2 patient groups

Control: Standard Interventions

No Intervention group

Description:

Standard interventions for the control cluster will include providing participants with long-lasting insecticide-treated bednets, management of known and possible mosquito breeding sites, passive case detection through detection and diagnosis of symptomatic cases of malaria in health facilities and through community health workers (conducted in villagers with fever), microscopy testing in households of recent index cases to detect asymptomatic malaria cases, and treatment of active cases of malaria (artesunate-mefloquine (AS-MQ) for Plasmodium falciparum and Chloroquine (CQ) (10 mg/kg on days 1 and 2, followed by 5 mg/kg on day 3) + PQ (0.5mg/kg x 7 days).

Focal Mass Drug Administration (fMDA)

Experimental group

Description:

Standard interventions in addition to focal mass drug administration. Focal mass drug administration will include using primaquine, chloroquine, and tafenoquine, for high-risk individuals residing in households that are within 200 meters of a Plasmodium vivax (Pv) index case households from the prior 2 years (including individuals in the index case household). Pv index cases include symptomatic cases detected at health facilities or in fever screenings, and asymptomatic cases identified during routine active case detection by health facilities. Households will then be notified regarding their potential to receive two rounds fMDA that cycle. Eligibility to receive medications as part of fMDA will be assessed prior to each administration and include glucose 6 phosphate dehydrogenase (G6PD) testing and counseling if not previously conducted or result is not available on the participant's identification card.

Treatment:

Drug: Focal Mass Drug Administration (fMDA)