Chemoprotective Activity of MMV390048 in PfSPZ Challenge Model

Malaria,Falciparum Clinical Trial

Official title: A Single Site, Randomized, Double-blind, Placebo-controlled Phase Ib Study, to Evaluate the Chemoprotective Activity of a Single Dose of MMV390048 in a Controlled P. Falciparum Sporozoite Infection Model in Non-immune Healthy Volunteers

Status Withdrawn

Clinical Trial Summary

This study follows a First-In-Human dose-escalation study of MMV390048 (5 to 120 mg MMV390048 powder-in-bottle formulation), a formulation bioavailability study to establish suitable tablet formulation, and a two-part dose-escalation (40 to 120 mg of MMV390048) / induced blood stage malaria (ISBM) challenge study with the new tablet formulation. After identification of the predicted efficacious MMV390048 plasma concentrations in the IBSM model, the current study will evaluate the chemoprotective efficacy of MMV390048 in a standardised and validated controlled human malaria infection (CHMI) model using direct venous inoculation (DVI) of aseptic, purified, cryopreserved, vialed P. falciparum sporozoites (PfSPZ Challenge).

Three sequential cohorts of healthy men and women of non-childbearing potential (WONCBP) will be administered the investigational medicinal product (IMP, i.e. MMV390048) under different conditions. This may identify preventative regimens, to be further investigated in a Phase II program. In the first two cohorts, protective administration of the IMP will occur 1 and 7 days before DVI of PfSPZ challenge. The timing of IMP administration and dosage in the last cohort will be determined on the basis of emerging data from the preceding cohorts, but will not exceed 28 days prior to the challenge nor 120 mg MMV390048.

Clinical Trial Description

Subjects are enrolled into one of three cohorts of 12 subjects each. Cohorts are recruited sequentially, to facilitate on-going review of data.

Investigational medicinal product (IMP) administration takes place between 28 and 1 days before the P. falciparum sporozoites (PfSPZ) challenge. Subjects are randomised to receive either MMV390048 120 mg or placebo in a 3:1 ratio.

After IMP administration, each subject is inoculated with 3200 PfSPZ. The dose of IMP to be administered and the interval between IMP administration and the PfSPZ challenge are as follows:

• Cohort 1: Subjects receive a single oral dose of MMV390048 (9 subjects) or placebo (3 subjects) on Day -1, prior to PfSPZ challenge on Day 0.

• Cohort 2: Subjects receive a single oral dose of MMV390048 (9 subjects) or placebo (3 subjects) on Day -7, prior to PfSPZ Challenge on Day 0.

• Cohort 3: Subjects receive a single oral dose of MMV390048 (9 subjects; dose to be determined) or placebo (3 subjects) on a day (to be determined) prior to PfSPZ challenge on Day 0. IMP dosage and day of administration will be determined on the basis of data emerging from the first two cohorts, but will not exceed 120 mg nor 28 days prior to PfSPZ challenge.

Parasitaemia and malaria symptoms and signs are monitored daily from Day 6 and as long as subjects exhibit parasitaemia (defined as either a positive thick blood smear microscopy or three positive quantitative polymerase chain reactions at least 12 hours apart with one measurement greater 100 parasites per mL), or until Day 28 if no parasitemia is not detected. All subjects receive antimalarial rescue therapy upon positive parasitaemia or at the end of the treatment period if parasites are not detected during follow-up. A final safety follow-up visit takes place on Day 60.

After treating cohorts 1 and 2 (up to, and including Day 28 assessments), a safety review team (SRT) meeting takes place, to consider enrolment of the subsequent cohort. At the first meeting, the SRT reviews safety and parasitaemia data to Day 28 and determines whether progression to treatment of cohort 2 is indicated. If no safety concerns are identified by the SRT and the geometric mean time to parasitaemia is less than 12 days for Cohort 1, progression to Cohort 2 takes place. Should Cohort 2 be enrolled, safety and parasitaemia data to Day 28 and PK data to at least Day 14 from this cohort are reviewed by the SRT prior to enrolling Cohort 3.

Recruitment of cohort 3 will be put on hold if:

• Any inoculum- or MMV390048-related SAEs are reported, or

• Two or more MMV390048-related severe (Grade 3 or higher) adverse events are reported in the same organ class, or

• Any significant inoculum-related adverse event is reported which may place subjects in a subsequent cohort at risk, or

• Any other critical findings are identified which may place subjects in a subsequent cohort at risk.

Dosing of a subsequent cohort at the same or lower dose with the same or increased interval between dosing and inoculation, will not be performed if:

• The cohort-specific geometric mean time to parasitaemia is less than 12 days.

If progression of the study to recruiting cohort 3 is approved the by SRT, the optimal dose of MMV390048, as well as the time point of its administration will be estimated based on PK modelling, using data from all trials and assuming that asexual liver and blood stage have similar MMV390048 sensitivities. ;

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum
• Malaria,Falciparum

• NCT number: NCT03195387
• Study type: Interventional
• Source: Medicines for Malaria Venture
• Status: Withdrawn
• Phase: Phase 1
• Start date: January 2018
• Completion date: December 2018