Controlled Human Malaria Infection Model for Evaluation of Transmission-blocking Interventions - Study 2
Condition: Malaria,Falciparum; Gametocytes; Controlled Human Malaria Infection; Transmission
MeSH terms: Infections; Communicable Diseases; Malaria; Malaria, Falciparum
Study type: Interventional

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.
    

Intervention name(s): Piperaquine (low dose); Piperaquine (high dose); Sulfadoxine pyrimethamine; Atovaquone Proguanil; malaria challenge infection, P. falciparum 3D7; Blood stage malaria challenge infection, P. falciparum 3D7
Intervention type(s): Drug; Drug; Drug; Drug; Other; Other
Intervention description(s): subcurative regimen (480 mg); Curative regimen (960mg); Curative regimen (1000mg/50mg); Curative regimen (1000/400 mg, for 3 days); malaria challenge infection by P. falciparum 3D7-infected mosquito bites; P. falciparum 3D7-infected human erythrocytes administered intravenously for the purpose controlled human malaria infection.
Other intervention name(s): piperaquine phosphate; piperaquine phosphate; Fansidar; Malarone; 3D7 Plasmodium falciparum; P. falciparum 3D7-infected human erythrocytes
Intervention MeSH terms: Pyrimethamine; Piperaquine; Sulfadoxine; Fanasil, pyrimethamine drug combination; Atovaquone; Proguanil; Atovaquone, proguanil drug combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other