Clinical trial NCT04009343: Pharmacokinetics and Pharmacodynamics of the Gametocytocidal and Post-treatment Chemoprotective Effects of Antimalarials
Official title: Field Study of the Pharmacokinetics and Pharmacodynamics of Artemisinin-based Combination Therapy for Gametocyte Clearance and Post-treatment Chemoprotection in Zambian Children With Uncomplicated Falciparum Malaria
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Uncomplicated Falciparum Malaria
Lead sponsor: Johns Hopkins Bloomberg School of Public Health
Sponsor class: OTHER
Collaborators: name: Tropical Diseases Research Centre
First posted: 2019-07-05
Enrollment: 182
Sex: ALL
Minimum age (years): 6
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Single-center phase II/III clinical investigation of the pharmacokinetics and pharmacodynamics of artemether-lumefantrine and dihydroartemisinin-piperaquine for gametocyte clearance and post-treatment chemoprotection in Zambian children with uncomplicated falciparum malaria.

Detailed description: Artemisinin-based combination therapies (ACTs) are the first-line agents for uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted ACT in sub-Saharan Africa for case management. Dihydroartemisinin-piperaquine (DP) is increasingly used for mass drug administration in malaria eliminating regions, and is being explored as a candidate for intermittent preventive therapy. AL and DP possess similar clinical efficacy against uncomplicated falciparum malaria in areas of drug susceptible parasites. However, AL appears to clear gametocytes (the transmissible stage of the malaria parasite) more rapidly than DP, while DP confers a longer duration of post-treatment protection against reinfection. It is not known whether the observed difference in gametocyte clearance between AL and DP is due to pharmacokinetic (PK) and/or pharmacodynamic (PD) differences of the artemisinin derivatives, PK/PD features of the non-artemisinin companions, or contributions from both. The longer duration of protection against reinfection provided by DP is due to the long elimination half-life of the partner drug, but further characterization of its relative benefit in high-transmission settings compared to AL is needed to inform malaria drug policy. The investigators are conducting a single-center randomized controlled clinical trial comparing the efficacies of AL and DP for gametocyte clearance and post-treatment chemoprotection among 6- to 59-month-old children with uncomplicated falciparum malaria in a high malaria transmission area of northern Zambia. Children with microscopy-confirmed Plasmodium falciparum monoinfection will be admitted for 72 hours for directly observed therapy with either AL or DP and serial sampling for parasite clearance and multi-dose PK measurements. Twenty children from each arm will be recruited to an intensive PK subgroup. Participants will be followed for 9 weeks for outcome assessment according to World Health Organization-defined clinical endpoints and to measure clearance of the long-acting partner drugs. Parasite genotyping will be done to distinguish recrudescence from reinfection and query genetic markers of drug resistance. Participants will contribute fecal specimens to help investigate bidirectional associations between the intestinal microbiota and antimalarial drug pharmacokinetics, as well as enterotype association with risk of reinfection.

Eligibility criteria: Inclusion Criteria:

* Weight ≥10 kg
* Any indication for malaria diagnostic testing as determined by a treating provider (e.g., fever or history of fever)
* P. falciparum parasitemia (by microscopy) of any density not meeting criteria for severe malaria
* Ability to swallow oral medication
* Ability and willingness of parents or guardians to comply with study protocol for the duration of the study and to comply with the study follow-up visit schedule
* Residence within hospital catchment area
* Signed informed consent obtained from a legal representative of the participant

Exclusion Criteria:

* Complicated or severe falciparum malaria as defined by WHO criteria
* Hemoglobin concentration \< 7 g/dL
* Use of any drug with antimalarial activity within the prior 4 weeks
* History of hypersensitivity reaction or intolerance to AL or DP
* Co-infection with Plasmodium spp. other than P. falciparum as determined by microscopy
* Confirmed or suspected concurrent acute infection other than malaria (e.g. measles, acute lower respiratory tract infection)
* Current therapy with QT interval-prolonging agents
* Family history of sudden cardiac death or personal history of cardiac disease
* Residence outside the study area, or plan to leave the study area
* Residence in foster care or otherwise under government supervision
* Previous enrollment in the study, or enrollment in any other investigational drug trial during the previous 30 days
* Presence of any other condition or abnormality that in the opinion of the investigator would compromise the safety of the participant or the quality of the data

Primary outcomes:
measure: Treatment outcome
timeFrame: 9 weeks
measure: Area-under-the-curve (AUC) of the gametocyte concentration-time curve
timeFrame: 72 hours
measure: Incidence of reinfection during the 9-week follow-up period
timeFrame: 9 weeks
Secondary outcomes:
measure: Elimination half-life of the gametocyte concentration-time curve
timeFrame: 72 hours up to 9 weeks for those with persistent gametocytemia
measure: Change over time of the gametocyte sex ratio (female:male)
timeFrame: 72 hours up to 9 weeks for those with persistent, emergent, or recurrent gametocytes
measure: Elimination half-life of the asexual parasite concentration-time curve
timeFrame: 72 hours
measure: Allele frequency of genetic markers of parasite drug resistance in initial vs. recurrent parasites and fast vs. slow clearing parasites
timeFrame: 9 weeks
measure: Incidence of treatment-emergent adverse events (safety and tolerability)
timeFrame: 9 weeks
Other outcomes:
measure: AUC of the plasma concentration-time curve
timeFrame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
measure: Peak plasma concentration (Cmax) of study drugs and metabolites
timeFrame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
measure: Oral clearance (Cl/F) for all drug analytes
timeFrame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
measure: Nutrition status-related associations with drug PK
timeFrame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
measure: Body surface area-related associations with drug PK
timeFrame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
measure: Gut microbiota enterotype
timeFrame: 9 weeks
Locations:
city: Ndola
country: Zambia
facility: Tropical Diseases Research Centre
state: Copperbelt
Study officials:
affiliation: Johns Hopkins Bloomberg School of Public Health
name: William J Moss, MD MPH
role: PRINCIPAL_INVESTIGATOR
References: