Analysis of the efficacy, safety and tolerability of a new combination of ganaplacide and lumefantrine in adults and children with uncomplicated malaria

Trial Design:

This will be a multicenter, open-label, randomized, parallel-group, non-inferiority study in adults and children with uncomplicated P. falciparum malaria (P. falciparum with or without other Plasmodium spp. co-infection). After completion of the Core phase of the study, patients may enter in the Extension phase (single-group).

Purpose:

This study aims to confirm the efficacy, safety and tolerability of KLU156, a fixed dose combination of ganaplacide (KAF156) and a solid dispersion formulation of lumefantrine (lumefantrine-SDF), when administered once daily for three days in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection).

In the Extension phase, the safety, tolerability and efficacy of repeated treatment with KLU156 will be assessed for a maximum of two years in patients who did not experience early treatment failure (ETF), who did not experience any study treatment-related SAE (Serious Adverse Event) previously and who gave informed consent to participate in the Extension phase

Study Rationale:

This Phase 3 study includes a Core phase and an Extension phase.

The Core phase of this study aims to confirm the efficacy, safety and tolerability of KLU156, a fixed dose combination of ganaplacide (KAF156) and a solid dispersion formulation of lumefantrine (lumefantrine-SDF), when administered once daily for 3 days in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection) in order to support marketing authorization application for KLU156. There is an unmet medical need for anti-malarial combination treatment including a partner drug with a new mechanism of action to counter the emergence of resistance to artemisinin.

The Extension phase is designed to assess the safety, tolerability and efficacy of repeated treatment with KLU156 for a maximum of two years in patients who have completed the Core phase without experiencing early treatment failure (ETF) nor any study treatment-related SAE and who consent to participate in the Extension phase.

Primary objective(s)

● Core phase:

• To confirm the efficacy of KLU156 in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated malaria caused by P.falciparum (with or without other Plasmodium spp. coinfection) by demonstrating that KLU156 is noninferior to Coartem (non‑inferiority margin = 5%) based on the PCR-corrected ACPR at Day 29.

Secondary objective(s)

● Core phase:

• Key secondary objective: To further confirm the efficacy of KLU156 by demonstrating non-inferiority of KLU156 to Coartem (NI margin 7.5%) based on the uncorrected ACPR at Day 29

● Extension phase:

• To assess the safety and tolerability over repeated treatment with KLU156 in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) for a maximum of 2 years.

• To evaluate efficacy over repeated treatment with KLU156 in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) for a maximum of 2 years.

Exploratory objective(s)

● Core phase:

• To explore the transmission-blocking activity of KLU156 (direct membrane feeding assay (DMFA)) at selected sites

• To quantify parasites that are below the detection level of microscopy using quantitative PCR (qPCR) as a diagnostic tool.

• To explore the impact of PCR methods on efficacy estimates.

• To assess in vitro susceptibility profile of tested parasites at selected sites (if feasible).

• To assess the effect of the main ADME gene factors on ganaplacide PK at selected sites (if feasible).

• To assess the pharmacokinetics of ganaplacide and lumefantrine in malaria patients.

• To explore the acceptability, palatability and ease of administration of KLU156.

Ø  To explore the emergence of drug resistance markers and the relationship between parasite genotypes of interest and parasite clearance kinetics/efficacy.

● Extension phase:

Ø  To assess the efficacy over repeated treatment with KLU156.

To explore the emergence and/or selection of drug resistance markers and the relationship between parasite genotypes of interest and parasite clearance kinetics/efficacy, upon repetitive treatment.

Study Population:

The study population will consist of male and female patients ≥ 5 kg of body weight and ≥ 2 months of age with confirmed uncomplicated P. falciparum malaria. Only patients with malaria symptoms and a P. falciparum count ≥ 1,000 parasites/μL and ≤ 200,000 parasites/μL (with or without other Plasmodium spp. co-infection) will be included in the study. Approximately 1,500 patients will be enrolled in the study (see Section 9.9 of the Protocol v00 for more details on sample size determination).