To evaluate efficacy, safety, tolerability and PK of intravenous cipargamin in participants with severe Plasmodium falciparum

Purpose and rationale:

The purpose of this study is to identify the safe and effective dose of intravenous cipargamin in participants with moderately severe and severe malaria.

The study also intends to evaluate clinical treatment success using a novel clinical endpoint for drug development in severe malaria.

Severe malaria is a medical emergency and is affecting primarily young children in Africa. Injectable artesunate is the standard of care for the treatment of severe malaria and is highly efficacious. However, the spread of artemisinin-resistance in Plasmodium falciparum in Asian countries poses a threat for future treatment of patients with this life-threatening disease. To

mitigate this risk, there is a need of another drug in malaria endemic countries. Cipargamin treatment results in rapid clearance of parasites including artemisinin resistant parasites.

Primary Objective(s):

The primary objective is to assess the efficacy of different doses of intravenous cipargamin vs artesunate by evaluating the proportion of participants with ≥ 90% reduction of parasitemia at 12 hours post administration of the first dose.

Secondary Objective(s)

The key secondary objective is to assess the clinical outcome as measured by the proportion of participants with clinical success at 48 hours.

The other secondary objectives are:

1. To assess the presence/absence of severe malaria related individual signs over time
2. To evaluate parasite clearance dynamics and proportion of participants with recrudescence and reinfection
3. To assess recovery of participants as measured by time (days and hours) to discharge from hospital or recovery from prostration
4. To evaluate the safety and tolerability of IV cipargamin
5. To assess the risk of long term neurological sequelae for participants at Day 29
6. The assess the risk of hemolysis (early and delayed) during the study duration
7. To characterize the plasma pharmacokinetics of IV cipargamin

Study design

This will be an adaptive, multicenter, randomized, open label, sequential cohort study in participants aged ≥ 12 years (Cohorts 1-2) and ≥ 6 months to < 12 years (Cohorts 3-5) with a diagnosis of moderately severe and severe P. falciparum malaria. This study is investigating the efficacy (parasite reduction and clinical outcome), safety, tolerability and pharmacokinetics of

different injectable dose regimens of cipargamin in comparison to injectable artesunate. The first cohort (Cohort 1) will be small, and will include participants aged 12 years or over, diagnosed with moderately severe malaria and high parasitemia. This cohort will be used for initial evaluation of safety and parasite clearance rates before continuing into Cohorts 2-5, which

will include only severe malaria patients according to WHO criteria. Progressively younger participants will be included with each new cohort from Cohort 2 onwards. This design aims at minimizing risks for pediatric participants < 12 years.

Study Population

The study population will consist of male and female participants, including pediatric participants aged ≥ 6 months or older. Approximately 252 participants (60 participants of ≥ 12 years and 192 participants < 12 years) will be randomized.

Study Treatment

Study treatments:

• Cipargamin 10 mg/ml and/or 15mg/ml vial (investigational drug) for intravenous administration
• Artesunate 60 mg vials (control drug) for intravenous administration Study treatment will be followed by a full course of oral standard of care antimalarial.

Additional treatments:

• Oral standard of care: artemether/lumefantrine
• Rescue medication: IV artesunate