NCT03454048

Controlled Human Malaria Infection Model for Evaluation of Transmission-blocking Interventions - Study 2

Controlled Human Malaria Infection Study to Assess Gametocytemia and Mosquito Transmissibility in Participants Challenged With Plasmodium Falciparum by Sporozoite or Blood Stage Challenge to Establish a Model for the Evaluation of Transmission-blocking Interventions

• Status: Completed
• Phase: N/A
• Study type: Interventional
• Enrollment: 24 (actual)
• Sponsor: Radboud University Medical Center · Academic / Other
• Sex: All
• Age: 18 Years – 35 Years
• Healthy volunteers: Accepted

Summary

This is a single-center, open label study. The primary aim of this project is to develop a controlled human malaria infection transmission model ("CHMI-trans") or "challenge model" to evaluate the capacity of vaccines, biologics (monoclonal antibodies, or mAbs), and drugs to block malaria parasite transmission by assessing infectiousness of Plasmodium falciparum (Pf) gametocyte carriers for Anopheles mosquitoes.

Detailed description

A total of 24 volunteers, in two cohorts (n=12), will be randomly assigned to two groups per cohort (n=6). Cohort A will be subjected to a standard controlled human malaria infection (CHMI) delivered by five Pf-infected mosquitoes (groups 1 and 2). Cohort B will be subjected to a standard blood stage challenge with \~2,800 Pf-infected erythrocytes by intravenous injection (groups 3 and 4). Treatment is subsequently initiated to induce gametocytemia (treatment 1, T1) and to clear pathogenic asexual parasites whilst leaving gametocytes unaffected (treatment 2 and 3, T2 and T3). At the end of the study, treatment of all parasite stages is provided following national treatment guidelines (end treatment, ET). Once malaria infections are detected by 18S qPCR positive (sporozoite challenge) or on day 8 (blood stage challenge), all volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Using blood samples taken twice daily, the initial clearance of parasitemia will be carefully monitored. After T1, volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. On day 21 or when a recrudescence occurs after T2, volunteers in group 1 and 3 (LD-PIP/LD-PIP2/PIP) will be curatively treated with piperaquine (960mg) and group 2 and 4 (LD-PIP/LD-PIP2/SP) with sulfadoxine-pyrimethamine (1000mg/50mg). These treatment regimens cure asexual parasitemia while leaving immature and mature gametocytes unaffected. To ensure the radical clearance of all parasite stages, all volunteers will receive a final treatment (ET) according to national guidelines with atovaquone/proguanil (Malarone®) on day 36. Daily blood samples will allow detailed quantification of gametocytes, gametocyte sex ratio and ex vivo assessments of gametocyte fitness. Additionally, blood samples will be obtained for Direct Membrane Feeding Assay (DMFA) and volunteers will be subjected to Direct Skin Feeding Assays (DFA). These assays will provide evidence on the infectivity of volunteers.

Conditions

• Malaria,Falciparum
• Gametocytes
• Controlled Human Malaria Infection
• Transmission

Interventions

Type	Name	Description
DRUG	Piperaquine (low dose)	subcurative regimen (480 mg)
DRUG	Piperaquine (high dose)	Curative regimen (960mg)
DRUG	Sulfadoxine pyrimethamine	Curative regimen (1000mg/50mg)
DRUG	Atovaquone Proguanil	Curative regimen (1000/400 mg, for 3 days)
OTHER	malaria challenge infection, P. falciparum 3D7	malaria challenge infection by P. falciparum 3D7-infected mosquito bites
OTHER	Blood stage malaria challenge infection, P. falciparum 3D7	P. falciparum 3D7-infected human erythrocytes administered intravenously for the purpose controlled human malaria infection.

Timeline

• Start date: 2018-05-07
• Primary completion: 2018-11-01
• Completion: 2018-11-20
• First posted: 2018-03-05
• Last updated: 2020-07-07
• Results posted: 2020-03-31

Locations

1 site across 1 country: Netherlands