Safety, Tolerability and Chemoprotective Activity of P218 in PfSPZ Challenge Model

Phase 1

Completed

Conditions: Malaria

Interventions: Drug: P218 (1000 mg) Oral Capsules
Drug: P218 (100 mg) Oral Capsules
Drug: Placebo Oral Capsules
Biological: PfSPZ Challenge

Registration Number: NCT03707041

Lead Sponsor: Medicines for Malaria Venture

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
P218 100 mg (Oral Capsules) - Cohort 3	PfSPZ Challenge	One administration of 100 mg P218 (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of 100 mg P218 (capsules p.o.), 48 hours after first administration.
P218 1000 mg (Oral Capsules) - Cohort 1	P218 (1000 mg) Oral Capsules	Two administrations of 1000 mg P218 (capsules p.o.), 48 hours apart
P218 Placebo Oral Capsules - Cohort 2	PfSPZ Challenge	One administration of P218 placebo (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of P218 placebo (capsules p.o.,) 48 hours after first administration.
P218 100 mg (Oral Capsules) - Cohort 3	P218 (100 mg) Oral Capsules	One administration of 100 mg P218 (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of 100 mg P218 (capsules p.o.), 48 hours after first administration.
P218 Placebo Oral Capsule - Cohort 3	PfSPZ Challenge	One administration of P218 placebo (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of P218 placebo (capsules p.o.), 48 hours after first administration.
P218 Placebo Oral Capsules - Cohort 1	Placebo Oral Capsules	Two administrations of P218 placebo (capsules p.o.), 48 hours apart
P218 1000 mg (Oral Capsules) - Cohort 2	P218 (1000 mg) Oral Capsules	One administration of 1000 mg P218 (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of 1000 mg P218 (capsules p.o.), 48 hours after first administration.
P218 1000 mg (Oral Capsules) - Cohort 2	PfSPZ Challenge	One administration of 1000 mg P218 (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of 1000 mg P218 (capsules p.o.), 48 hours after first administration.
P218 Placebo Oral Capsules - Cohort 2	Placebo Oral Capsules	One administration of P218 placebo (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of P218 placebo (capsules p.o.,) 48 hours after first administration.
P218 Placebo Oral Capsule - Cohort 3	Placebo Oral Capsules	One administration of P218 placebo (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of P218 placebo (capsules p.o.), 48 hours after first administration.

Primary Outcome Measures

Name	Time	Method
Cohorts 2 and 3: Geometric Mean Time From PfSPZ Challenge to First Quantitative Polymerase Chain Reaction (qPCR) Outcome Equal or Greater Than 250 Asexual Parasites Per mL of Blood	Number of days from PfSPZ Challenge DVI to positive parasitaemia, or 28 days	Chemoprotective activity of two single doses of 1000 mg P218 administered 2 hours after PfSPZ Challenge and 48 hours later in healthy adult volunteers
Cohort 1: Number of TEAEs	9 days	Incidence, severity and relationship to the treatment of observed or self-reported treatment emergent adverse events (TEAEs) after two single doses of 1000 mg P218 administered 48 hours apart in healthy adult volunteers.

Secondary Outcome Measures

Name	Time	Method
Cohorts 2 and 3: Number of PfSPZ Challenge TEAEs	35 days	Incidence, severity and relationship to the PfSPZ Challenge of observed or self-reported treatment emergent adverse events in non-immune healthy adult volunteers before and after P218 administration
Cohorts 2 and 3: Number of P218 TEAEs	35 days	Incidence, severity and relationship to the P218 treatment of observed or self-reported treatment emergent adverse events in non-immune healthy adult volunteers after two single doses of 1000 mg P218 administered 48 hours apart in a controlled human malaria infection (PfSPZ Challenge)
Cohorts 2 and 3: Malaria Clinical Score at the Time of Introduction of Rescue Therapy	On the day of positive parasitaemia or on Day 28	The malaria clinical score consists of 14 signs/symptoms frequently associated with malaria and graded using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3) and summed to generate a total malaria clinical score (maximum score possible is 42): headache, myalgia (muscle ache), arthralgia (joint ache), fatigue/lethargy, malaise (general discomfort/uneasiness), chills/shivering/rigors, sweating/hot spells, anorexia, nausea, vomiting, abdominal discomfort, fever, tachycardia and hypotension. To determine severity of the 14 signs/symptoms the CTCAE grading scale grade 1 - 5 was used. Mild (1) equates to CTCAE grade 1, Moderate (2) equates to CTCAE grade 2 and Severe (3) equates to CTCAE grade 3 or above. Individual scores for each symptom as well as the total score were recorded.
Cohorts 1, 2 and 3: P218 AUC[0-48h] - Day 1	9 days	Area under the P218 plasma concentration-time curve from first administration to 48 hours after first administration
Cohorts 1, 2 and 3: P218 Tmax - Day 1	9 days	Time to P218 Cmax after each P218 administration
Cohort 1: P218-beta-acyl-glucuronide-OH AUC[48-96h]	9 days	Area under the P218-beta-acyl-glucuronide-OH plasma concentration-time curve from 48 hours after first P218 administration to 96 hours after first P218 administration
Cohorts 1, 2 and 3: P218 Cmax - Day 1	9 days	Maximum observed P218 plasma concentration after each P218 administration