Clinical trial NCT02653898: Malaria Elimination Pilot Study in Military Forces in Cambodia
Official title: Defining Effective, Appropriate, Implementable Strategies for Malaria Elimination in Military Forces in Cambodia as a Model for Mobile Populations
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Malaria
Parasitic Diseases
Keywords: Malaria
Antimalarials
Malaria Elimination
Mass Drug Administration
Malaria Prophylaxis
Mobile population
Drug resistance
Focused screening and treatment
Monthly Malaria Prophylaxis
Mass screening and treatment
Primaquine
Malaria transmission
Permethrin insecticide
Thai-Cambodian border
Cambodia
AFRIMS
Lead sponsor: Armed Forces Research Institute of Medical Sciences, Thailand
Sponsor class: OTHER_GOV
Collaborators: name: National Center for Parasitology, Entomology, and Malaria Control (CNM)
name: Ministry of National Defense, Royal Cambodian Armed Forces Department of Health
First posted: 2016-01-13
Enrollment: 1050
Sex: ALL
Minimum age (years): 2
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Antimalarial drug resistance has reached critical levels on the Thai-Cambodian border. Many have begun advocating for concerted malaria elimination efforts in Cambodia. However, there is currently no consensus on how malaria elimination is to be achieved with the tools available.

In this study, the investigators will conduct operational research with the Royal Cambodian Armed Forces (RCAF) and National Malaria Center (CNM) to quantify the relative effectiveness of the two major interventional approaches - monthly malaria prophylaxis (MMP) or focused screening and treatment (FSAT) - in a head to-head comparison. In addition, the investigators will quantify the relative contribution of a recently advocated vector intervention for military personnel - the insecticide treated uniform (ITU) - in addition to other vector control measures currently employed by the RCAF. The investigators will employ the same permethrin insecticide self-application kits currently used by the US military. The investigators will estimate the cost effectiveness of each approach and attempt to define the best way forward for malaria elimination efforts in a critically important malaria reservoir in military population (and their dependents) who reside on the Thai-Cambodian border. The aim of the study is not only to conduct research to better define the best way forward in malaria elimination efforts in the high risk military populations, but to also build capacity within the RCAF to support and lead future elimination efforts in the most difficult-to-reach mobile populations.

Detailed description: This is a cluster-randomized, open label interventional study to determine the feasibility of achieving significant reduction in malaria cases in military encampments on the Thai-Cambodian border. The study will compare the effectiveness, safety, and tolerability of monthly malaria prophylaxis (MMP) to monthly focused screening and treatment (FSAT). This study will thus investigate the effectiveness of two potential interventions for malaria elimination. Subjects in the monthly malaria prophylaxis (MMP) arm will receive a standard 3-day treatment course of dihydroartemisinin-piperaquine on months 1, 2 and 3 and weekly low-dose primaquine (22.5mg for 12 weeks). Volunteers in the focused screening and treatment (FSAT) arm will be screened monthly and then treated for malaria following national treatment guidelines. For G6PD-deficient volunteers in the FSAT arm, primaquine will be administered weekly (45mg for 8 weeks) as radical curative and/or presumptive anti-relapse therapy. For G6PD normal volunteers with vivax infection, primaquine will be administered daily (15mg for 14 days). All FSAT volunteers with confirmed P. falciparum infection will receive a single, low dose (15mg) Primaquine as a P. falciparum transmission-blocking agent. The incremental benefit of an insecticide treated uniform (ITU) will also be assessed as a single-blind sham-controlled intervention in addition to personal protective measures currently employed by the RCAF. Volunteers will be followed monthly for a total of 6 months, to determine the proportion remaining malaria-free on day 180 following enrollment.

Eligibility criteria: Inclusion Criteria:

1. Military volunteers aged 18-65 years of age plus their dependents \> 2 years of age, eligible for care at an RCAF facility, or otherwise eligible Cambodian civilians at risk for contracting malaria who live within the designated geographical areas
2. Able to give informed consent/assent
3. Resides in the selected study areas, and available for monthly follow-up for 6 month study duration
4. Agrees not to seek outside medical care for febrile illness unless referred by study team
5. Authorized by local commander to participate in the study if on active duty

Exclusion Criteria:

1. Allergic reaction or contraindication to dihydroartemisinin-piperaquine or primaquine or artesunate+mefloquine
2. Pregnant or lactating female, or female of childbearing age, up to 50 years of age or otherwise individually assessed for childbearing potential, who does not agree to use an acceptable form of contraception during the study
3. Judged by the investigator to be otherwise unsuitable for study participation

Primary outcomes:
measure: The absolute risk reduction based on the proportion of subjects remaining malaria-free at the end of 6 months between the study arms as diagnosed by PCR-corrected malaria microscopy
timeFrame: 6 months
Secondary outcomes:
measure: Overall rate of sexual stage infections at Months 1 through 6 in each arm based on a combined endpoint of light microscopy and PCR analysis for detection of gametocyte maturity.
timeFrame: 6 months
measure: Number of participants with abnormal lab values and/or Adverse Events that are related to the treatments in each arm
timeFrame: 6 months
measure: Kaplan-Meier survival analysis of asexual and sexual blood stage at 28-day intervals after treatment or prophylaxis up to 180 days
timeFrame: 6 months
measure: Comparison of all-species and species-specific malaria incidence density in each arm over 180-day period
timeFrame: 6 months
measure: Comparative incidence of malaria detected by RDT versus RT-PCR versus microscopy
timeFrame: 6 months
measure: Comparative incidence of G6PD deficiency in the study population as determined by RDT, quantitative, and qualitative tests
timeFrame: At the time of enrollment
measure: Estimate of apparent rates of preexisting immunity to malaria based on medical history, days of fever prior to presentation, and preexisting parasitological parameters (gametocytemia, low asexual stage parasitemias)
timeFrame: 6 months
measure: Sensitivity and specificity assessment of the currently recommended rapid diagnostic test in Cambodia to detect moderate to severe G6PD deficiency using quantitative G6PD testing as the reference standard
timeFrame: At the time of enrollment
measure: Odds ratio for P.v recurrence for each CYP2D6 phenotype
timeFrame: 6 months
measure: Rate of cytochrome P450 2D6 genotypes/phenotypes in the population at risk
timeFrame: 6 months
measure: Percent reduction in hemoglobin and HTC for each 2D6 haplotype in subjects with available CBC following PQ dosing
timeFrame: Day 3 (and day 7 in those volunteers with Hgb or HCT drop of at least 10% from baseline on Day 3)
measure: Percentage of subjects with malaria recurrence for each CYP2D6 phenotype
timeFrame: 6 months
Other outcomes:
Locations:
city: Anlong Veng
country: Cambodia
facility: RCAF treatment facilities
state: Oddar Meancheay
Study officials:
affiliation: Armed Forces Research Institute of Medical Sciences, Thailand
name: Chanthap Lon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Armed Forces Research Institute of Medical Sciences, Thailand
name: Mariusz Wojnarski, MD
role: STUDY_CHAIR
References:
citation: Manning J, Lon C, Spring M, Wojnarski M, Somethy S, Chann S, Gosi P, Soveasna K, Sriwichai S, Kuntawunginn W, Fukuda MM, Smith PL, Rekol H, Sinoun M, So M, Lin J, Satharath P, Saunders D. Cluster-randomized trial of monthly malaria prophylaxis versus focused screening and treatment: a study protocol to define malaria elimination strategies in Cambodia. Trials. 2018 Oct 16;19(1):558. doi: 10.1186/s13063-018-2931-x.