NCT04675931

To Evaluate Efficacy, Safety, Tolerability and PK of Intravenous Cipargamin in Participants With Severe Plasmodium Falciparum Malaria

An Adaptive, Randomized, Active-controlled, Open-label, Sequential Cohort, Multicenter Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of Intravenous Cipargamin (KAE609) in Adult and Pediatric Participants With Severe Plasmodium Falciparum Malaria (KARISMA - KAE609's Role In Severe Malaria)

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 254 (actual)
• Sponsor: Novartis Pharmaceuticals · Industry
• Sex: All
• Age: 6 Months – 100 Years
• Healthy volunteers: Not accepted

Summary

The purpose of this study was to identify the safe and effective dose of intravenous cipargamin in participants with moderately severe and severe malaria. The study also intended 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 for another drug in malaria-endemic countries. Cipargamin treatment results in rapid clearance of parasites, including artemisinin-resistant parasites.

Detailed description

This study was an adaptive, multicenter, randomized, open label, sequential cohort study in participants aged ≥12 years old in Cohorts 1-2 and \<12 years old to ≥6 months in Cohorts 3-5 with a diagnosis of moderately severe (Cohort 1) and severe P. falciparum malaria (Cohorts 2-5). This study investigated the efficacy (parasite reduction and clinical outcome), safety, tolerability, and pharmacokinetics (PK) of different intravenous (IV) dose regimens of cipargamin in comparison to IV artesunate. Cohorts 1 and 2: Participants were randomized to one of three treatment arms in a 1:1:1 ratio: two cipargamin-based treatment arms with dose levels of 20 mg and 40 mg, and the control arm with IV artesunate, a standard of care. The analysis of results from Cohorts 1 and 2 was planned to be used to determine the safe and efficacious exposure range and the corresponding dose (in a weight-adjusted manner) for the participants in Cohorts 3 to 5. Cohorts 3 to 5: Participants were randomized to 40 mg of cipargamin administered in a dose-adjusted manner and standard dose of IV artesunate in 1:1 ratio. In all cohorts, participants in IV cipargamin arms were treated once daily for at least 24 hours (2 doses at 0 and 24 hour timepoints) and a maximum of 48 hours (3 doses at 0, 24, and 48 hour timepoints) and with IV artesunate as rescue medication. Participants in the IV artesunate arm received IV artesunate for at least 24 hours (3 doses at 0, 12, and 24 hours timepoints) and for a maximum of 8 doses (7 days), if necessary. Participants in all arms received Coartem twice daily (b.i.d.) for 3 days following IV therapy. The study was conducted in a hospital setting, and participants were followed up until Day 29.

Conditions

• Severe Malaria

Interventions

Type	Name	Description
DRUG	Cipargamin	Cipargamin, 20 mg or 40 mg, by intravenous administration of solution for injection
DRUG	IV Artesunate	Artesunate, 2.4 mg/kg or 3 mg/kg, by intravenous administration of reconstituted solution
DRUG	Coartem	Oral standard of care (Coartem tablets, dosed per weight, as per label)

Timeline

• Start date: 2022-03-07
• Primary completion: 2025-07-24
• Completion: 2025-08-20
• First posted: 2020-12-19
• Last updated: 2026-04-09
• Results posted: 2026-04-09

Locations

9 sites across 7 countries: Burkina Faso, Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Mozambique, Rwanda, Uganda