Safety, Tolerability and Chemoprotective Activity of P218 in PfSPZ Challenge Model
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      This was a single centre, randomised, double-blind, placebo-controlled Phase Ib study, to
      evaluate the safety, tolerability and chemoprotective activity of P218 in a controlled P.
      falciparum sporozoite infection model.

      Healthy men and women, aged 18 to 45 years were to be enrolled in 3 study cohorts and to be
      administered either P218 or placebo twice, 48 hours apart. Subjects in cohorts 2 and 3 were
      to be inoculated with P. falciparum sporozoites. Enrolment in cohorts was to proceed
      sequentially, to facilitate review of data by a Safety Review Team (SRT) before proceeding
      with a subsequent cohort.

      In cohort 1, safety and tolerability of P218 was assessed. In cohorts 2 and 3,
      chemoprotective activity of P218 against malaria infection was assessed, as well as the
      Influence of time of initiation of the P218 treatment on the protective effect.
    

Detailed description: 
      This was a single centre, randomised, double-blind, placebo-controlled Phase Ib study, to
      evaluate the safety, tolerability and chemoprotective activity of P218 in a controlled P.
      falciparum sporozoite infection model.

      32 healthy men and women, aged 18 to 45 years were to be enrolled in 3 cohorts of
      respectively 8, 12 and 12 subjects. A subject could be enrolled in one cohort only and was to
      be randomised in a 3:1 ratio, to receive two consecutive administrations, 48 hours apart, of
      either P218 or placebo. Enrolment in cohorts proceeded sequentially, to facilitate review of
      data by a Safety Review Team (SRT) before populating a subsequent cohort.

      Cohort 1 consisted of 2 subgroups of subjects, to be enrolled sequentially: subgroup 1 was to
      be composed of 2 subjects: one to receive two 1000 mg doses of P218 and one to receive
      placebo twice. Subgroup 2 was to be composed of 6 subjects: five to receive two 1000 mg doses
      of P218 and one to receive placebo twice. Subjects in subgroup 2 would not be treated until
      24 hours after second IMP administration in the last subject of subgroup 1 and only after
      review of the safety data from subgroup 1 by the PI. Duration of each subject treatment and
      follow-up in Cohort 1 was 9 days. Progression to Cohort 2 was subject to review of the safety
      and tolerability data by a SRT.

      Cohort 2 consisted of three subgroups of subjects, to be enrolled sequentially. Subgroup 1
      was to be composed of 2 subjects: one to receive two 1000 mg doses of P218 and one to receive
      placebo twice. Subgroups 2 and 3 were to be composed of 5 subjects each: four to receive two
      1000 mg doses of P218 and one to receive placebo twice. Subjects in subgroup 2 would not be
      treated until 24 hours after second IMP administration in the last subject of subgroup 1. On
      Day 1, each subject in Cohort 2 would be administered 3200 P. falciparum sporozoites (PfSPZ
      Challenge) by direct venous inoculation (DVI). First administration of 1000 mg of P218 or
      placebo will take place 2 hours after PfSPZ Challenge DVI; second administration of 1000 mg
      of P218 or placebo would take place 48 hours later. As of Day 7, parasitemia in every subject
      was to be assessed daily until the installation of malarial infection or until Day 28.
      Overall duration of each subject observation in Cohort 2 was 35 days. Progression to Cohort 3
      was subject to assessment of safety and parasitemia data, as well as malaria signs and
      symptoms by a SRT.

      Cohort 3 was to consist of two subgroups each with 6 subjects, to be enrolled sequentially.
      Treatment was to be allocated in a ratio of 3 active: 1 placebo. In each subgroup, at least 1
      subject was to receive placebo and the remaining subjects would receive two 100 mg doses of
      P218 48 hours apart. Subjects in subgroup 2 would not be inoculated until 24 hours after
      second IMP administration in the last subject of subgroup 1. On Day 1, subjects were to be
      administered 3200 P. falciparum sporozoites by DVI. As of Day 7, parasitemia in every subject
      was to be assessed daily until the installation of malarial infection or until Day 28.
      Overall duration of each subject observation in Cohort 3 is 35 days.

      All subjects in Cohorts 2 and 3 would receive antimalarial rescue therapy, either upon
      installation of malarial infection or on Day 28 or if leaving the study prematurely.

      In Cohort 1, safety and tolerability of two 1000 mg doses of P218 administered 48 hours apart
      was to be assessed over 9 days of observation. Pharmacokinetic assessments of P218 and its
      main metabolites were to take place over 9 days of observation.

      In Cohorts 2 and 3, chemoprotective activity of two doses P218 (1000 mg or 100 mg
      respectively) administered 48 hours apart, were to be assessed over 28 days. Safety and
      tolerability of two doses of P218 (1000 mg or 100 mg respectively) administered 48 hours
      apart were to be assessed over 35 days of observation. Pharmacokinetic assessments of P218
      would take place over 9 days of observation.
    

Intervention name(s): P218 (1000 mg) Oral Capsules; Placebo Oral Capsules; P218 (100 mg) Oral Capsules; PfSPZ Challenge
Intervention type(s): Drug; Drug; Drug; Biological
Intervention description(s): 1000 mg P218 (4 x 250 mg capsules); Placebo capsules matched to the P218 capsules with regard to appearance and taste; 100 mg P218 (2 x 50 mg capsules); 3200 P. falciparum Sporozoites by direct venous inoculation (DVI)
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In each of the three treatment cohorts, subjects will be randomly allocated to receive either P218 or placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: malaria; PfSPZ Challenge; chemoprotection