Pharmacokinetics and Pharmacodynamics of the Gametocytocidal and Post-treatment Chemoprotective Effects of Antimalarials

December 9, 2025 updated by: Johns Hopkins Bloomberg School of Public Health

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
182

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Zambia
    • Copperbelt
      • Ndola, Copperbelt, Zambia
        • Tropical Diseases Research Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

6 months to 4 years (Child)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Artemether-lumefantrine
Standard 6-dose regimen
Drug: Artemether-lumefantrine
Children will receive artemether-lumefantrine (20/120 mg) dosed according to weight (5 to <15 kg: 1 tablet, 15 to <25 kg: 2 tablets) at 0, 8, 24, 36, 48 and 60 hours. Medications will be administered according to the manufacturer's instructions.
Other Names:
  • Coartem®
Experimental: Dihydroartemisinin-piperaquine
Standard 3-dose regimen
Drug: Dihydroartemisinin-piperaquine
Children will receive dihydroartemisinin-piperaquine (40/320 mg) dosed according to weight (5 to <8 kg: 1/2 tablet, 8 to <11 kg: 3/4 tablet, 11 to <17 kg: 1 tablet, 17 to <25 kg: 1 1/2 tablets) at 0, 24, and 48 hours. Medications will be administered according to the manufacturer's instructions.
Other Names:
  • D-Artepp®

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Treatment outcome
Time Frame: 9 weeks
Defined according to World Health Organization (WHO) classification as adequate clinical and parasitological response, early treatment failure, late clinical failure, or late parasitological failure corrected by genotyping to distinguish reinfection from recrudescent infection.
9 weeks
Area-under-the-curve (AUC) of the gametocyte concentration-time curve
Time Frame: 72 hours
Primary gametocyte-related pharmacodynamic (PD) endpoint of the study
72 hours
Incidence of reinfection during the 9-week follow-up period
Time Frame: 9 weeks
Primary measure of the post-treatment chemoprotective effect of the drugs
9 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Elimination half-life of the gametocyte concentration-time curve
Time Frame: 72 hours up to 9 weeks for those with persistent gametocytemia
Alternative PD outcome of gametocyte dynamics
72 hours up to 9 weeks for those with persistent gametocytemia
Change over time of the gametocyte sex ratio (female:male)
Time Frame: 72 hours up to 9 weeks for those with persistent, emergent, or recurrent gametocytes
The ratio of female and male gametocytes over time during treatment is a hypothesized marker of transmissibility
72 hours up to 9 weeks for those with persistent, emergent, or recurrent gametocytes
Elimination half-life of the asexual parasite concentration-time curve
Time Frame: 72 hours
In addition to gametocyte dynamics, asexual parasite dynamics and how they relate to PK parameters and other covariates with also be examined
72 hours
Allele frequency of genetic markers of parasite drug resistance in initial vs. recurrent parasites and fast vs. slow clearing parasites
Time Frame: 9 weeks
Relative barriers to drug resistance of AL and DP will be tested using known and newly described parasite genetic markers of resistance and association with phenotypic susceptibility
9 weeks
Incidence of treatment-emergent adverse events (safety and tolerability)
Time Frame: 9 weeks
We will assess adverse events and serious adverse events associated with the study drugs in accordance with the WHO Toxicity Grading Scale for Determining the Severity of Adverse Events
9 weeks

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
AUC of the plasma concentration-time curve
Time Frame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
Pharmacokinetic (PK) endpoint of the study, determined for each drug and drug metabolite
72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
Peak plasma concentration (Cmax) of study drugs and metabolites
Time Frame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
PK endpoint of the study, determined for each drug and drug metabolite
72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
Oral clearance (Cl/F) for all drug analytes
Time Frame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
PK endpoint of the study, determined for each drug and drug metabolite
72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
Nutrition status-related associations with drug PK
Time Frame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
In nonlinear mixed effects PK models, we will test associations between nutrition status (weight-for-age Z score) and drug PK parameters
72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
Body surface area-related associations with drug PK
Time Frame: 72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
We will test, in nonlinear mixed effects PK models, associations between body surface area and drug PK
72 hours (artemisinin derivatives) and 9 weeks (long-acting companions)
Gut microbiota enterotype
Time Frame: 9 weeks
We will characterize the gut microbiota of study participants and examine bidirectional associations between enterotype and drug PK, and enterotype and incidence of reinfection
9 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Johns Hopkins Bloomberg School of Public Health

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Tropical Diseases Research Centre

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: William J Moss, MD MPH, Johns Hopkins Bloomberg School of Public Health

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 19, 2019

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 24, 2020

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 7, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 3, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 5, 2019

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 17, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 9, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IRB00007663 (JHSPH IRB)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data will be made available to other researchers upon reasonable request. Parasite clearance and drug resistance data will be contributed to the Worldwide Antimalarial Resistance Network database.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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