Clinical trial NCT05690841: FocaL Mass Drug Administration for Vivax Malaria Elimination
Official title: FocaL Mass Drug Administration for Vivax Malaria Elimination (FLAME): a Pragmatic Cluster Randomized Controlled Trial in Peru
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Malaria, Vivax
Malaria
Keywords: Antimalarial drugs
Primaquine
Chloroquine
Tafenoquine
Parasitic disease
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Universidad Peruana Cayetano Heredia- subcontractor to UCSF as local Sponsor
name: PATH
name: Stanford University
name: Eijkman Oxford Clinical Research Unit, Indonesia
name: Menzies School of Health Research
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2023-01-19
Enrollment: 7530
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: This trial 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, distance to Iquitos, and population size.

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 two months apart 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 (2 months after each 1st 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 end-line 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cumulative Incidence of Plasmodium vivax infections
timeFrame: From enrollment through study completion, over 36-month follow-up study period
Secondary outcomes:
measure: Prevalence of Plasmodium vivax infection
timeFrame: At endline survey in trial year 4, 3 years after enrollment in study in trial year 1
measure: Plasmodium vivax seroprevalence
timeFrame: At endline survey in trial year 4, 3 years after enrollment in study in trial year 1
measure: Genetic diversity of Plasmodium vivax
timeFrame: From enrollment through study completion, over 4 trial years
measure: Tolerability of study drugs
timeFrame: Over drug administration period, unique for each study drug (7 days for CQ/PQ regimens and 3 days for CQ/TQ regimens)
measure: Adherence to study drugs
timeFrame: Unique for each patient based on drug regimen (7 days for CQ/PQ regimens and 3 days for CQ/TQ regimens)
measure: Refusal rates
timeFrame: During each fMDA round, twice per year for 3 consecutive years
measure: Program costs per unit fMDA round
timeFrame: From enrollment through study completion, over 4 years
measure: Program costs per unit
timeFrame: From enrollment through study completion, over 4 years
measure: Cost per incident case averted
timeFrame: From enrollment through study completion, over 4 years
measure: Cost per disability life year (DALY)
timeFrame: From enrollment through study completion, over 4 years
measure: Cost per economic dollar due to malaria saved
timeFrame: From enrollment through study completion, over 4 years
Other outcomes:
Locations:
city: Iquitos
country: Peru
facility: Asociación Civil Selva Amazónica
Study officials:
affiliation: University of California, San Francisco
name: Michelle Hsiang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universidad Peruana Cayetano Heredia
name: Alejandro Llanos-Cuentas, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: PAHO. Fourth Meeting of the Malaria Technical Advisory Group (TAG) to the Pan American Health Organization (PAHO). Washington D.C.: Pan American Health Organization, World Health Organization, Americas. https://www.paho.org/hq/index.php?option=com_docman&view=download&alias=50391-fourthmalaria-technical-advisory-group-meeting-report-may-washington-dc&category_slug=malariatechnical-advisory-group&Itemid=270&lang=en; 2019.
citation: Hsiang MS, Ntuku H, Roberts KW, Dufour MK, Whittemore B, Tambo M, McCreesh P, Medzihradsky OF, Prach LM, Siloka G, Siame N, Gueye CS, Schrubbe L, Wu L, Scott V, Tessema S, Greenhouse B, Erlank E, Koekemoer LL, Sturrock HJW, Mwilima A, Katokele S, Uusiku P, Bennett A, Smith JL, Kleinschmidt I, Mumbengegwi D, Gosling R. Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial. Lancet. 2020 Apr 25;395(10233):1361-1373. doi: 10.1016/S0140-6736(20)30470-0.
citation: Ntuku H, Smith-Gueye C, Scott V, Njau J, Whittemore B, Zelman B, Tambo M, Prach LM, Wu L, Schrubbe L, Kang Dufour MS, Mwilima A, Uusiku P, Sturrock H, Bennett A, Smith J, Kleinschmidt I, Mumbengegwi D, Gosling R, Hsiang M. Cost and cost effectiveness of reactive case detection (RACD), reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) to reduce malaria in the low endemic setting of Namibia: an analysis alongside a 2x2 factorial design cluster randomised controlled trial. BMJ Open. 2022 Jun 23;12(6):e049050. doi: 10.1136/bmjopen-2021-049050.
citation: Hsiang MS, Hwang J, Tao AR, Liu Y, Bennett A, Shanks GD, Cao J, Kachur SP, Feachem RG, Gosling RD, Gao Q. Mass drug administration for the control and elimination of Plasmodium vivax malaria: an ecological study from Jiangsu province, China. Malar J. 2013 Nov 1;12:383. doi: 10.1186/1475-2875-12-383.
citation: Llanos-Cuentas A, Lacerda MVG, Hien TT, Velez ID, Namaik-Larp C, Chu CS, Villegas MF, Val F, Monteiro WM, Brito MAM, Costa MRF, Chuquiyauri R, Casapia M, Nguyen CH, Aruachan S, Papwijitsil R, Nosten FH, Bancone G, Angus B, Duparc S, Craig G, Rousell VM, Jones SW, Hardaker E, Clover DD, Kendall L, Mohamed K, Koh GCKW, Wilches VM, Breton JJ, Green JA. Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria. N Engl J Med. 2019 Jan 17;380(3):229-241. doi: 10.1056/NEJMoa1802537.
citation: World Health Organization (WHO). WHO Guidelines for malaria. 3 June 2022. https://reliefweb.int/report/world/who-guidelines-malaria-3-june-2022#:~:text=The%20WHO%20global%20malaria%20strategy,residual%20foci%20of%20malaria%20transmission.