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)

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.

Study Overview

• Status: Completed
• Conditions: Severe Malaria
• Intervention / Treatment: Drug: Cipargamin; Drug: Coartem; Drug: IV Artesunate

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.

• Study Type: Interventional
• Enrollment (Actual): 254
• Phase: Phase 2

Contacts and Locations

Study Locations

• Burkina Faso
  • Burkina Faso, Burkina Faso, 2208
    • Novartis Investigative Site
  • Ouagadougou, Burkina Faso
    • Novartis Investigative Site
• Côte d’Ivoire
  • Abidjan, Côte d’Ivoire, 13BP972
    • Novartis Investigative Site
  • Agboville, Côte d’Ivoire, BP 154
    • Novartis Investigative Site
• Democratic Republic of the Congo
  • Democratic Republic of Congo
    • Kinsasha, Democratic Republic of Congo, Democratic Republic of the Congo, BP 7948
      • Novartis Investigative Site
• Kenya
  • Siaya, Kenya, 2300
    • Novartis Investigative Site
• Mozambique
  • Maputo Province
    • Manhiça, Maputo Province, Mozambique, 1929
      • Novartis Investigative Site
• Rwanda
  • Kigali, Rwanda, BP 4560
    • Novartis Investigative Site
• Uganda
  • Tororo, Uganda, 10102
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Cohort 1: Participants aged ≥ 12 years with moderately severe malaria as defined in (prostration and/or repeated vomiting) without presence of other signs of severe malaria (and with high P. falciparum parasitemia (60,000-250,000 parasites per µl)

  • Subsequent Cohorts 2 to 5: Participants diagnosed with severe malaria as defined in modified version of WHO criteria and P. falciparum parasite count of ≥ 5000 per µl
  • Cohort 2: Participants aged ≥ 12 years
  • Cohort 3: Participants aged 6 - < 12 years
  • Cohort 4: Participants aged 2 - < 6 years
  • Cohort 5: Participants aged ≥ 6 months - < 2 years

Exclusion Criteria:

Exclusion criteria applying to all Cohorts 1 to 5:

• Mixed Plasmodium infections
• Treatment with quinine or artemisinin derivative or any other antimalarial drug or any antibiotic with known antimalarial activity within 12 hours of screening.

• Signs/symptoms of severe malnutrition in general accordance with WHO guidelines:

  1. Under 18 years: <-3 Z-scores of WHO growth standard for weight-for-height/length (in children < 5 years) or BMI for age (5-18 years), or very low mid-upper arm circumference (MUAC < 115 mm in children < 12 years, < 160mm 12-18 years), or bilateral pitting edema
  2. Over 18 years: BMI < 16 kg/m2 or MUAC < 160mm or bilateral pitting edema

• Known underlying illness, surgical or medical condition, which is not related to ongoing event of severe malaria and which might jeopardize the participant's health in case of participation in the study or which might alter the distribution, metabolism or excretion of study treatment. For example:

  1. neurological or neurodegenerative disorders,
  2. cardiac, renal, or hepatic disease, diabetes,
  3. epilepsy, cerebral palsy,
  4. known or suspected to be HIV-1 positive and/or receiving antiretroviral treatment
  5. malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
  6. known or suspected cases of active infections or concurrent febrile illness such as TB, Typhoid, COVID-19 etc.

Additional exclusion criteria are as follows:

Exclusion criteria for Cohort 1:

• ALT > 5 x the upper limit of normal range (ULN), regardless the level of total bilirubin
• Total bilirubin is > 3 mg/dL
• Body weight of < 35 kg or >75 kg

Exclusion criteria for Cohort 2:

• Body weight of < 35 kg or >75 kg
• Participants diagnosed as moderately severe malaria due to repeated vomiting without presence of any of the symptoms of severe malaria

Exclusion criteria for Cohorts 3 to 5:

• Body weight of < 5 kg
• Participants diagnosed as moderately severe malaria due to repeated vomiting without presence of any of the symptoms of severe malaria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IV Cipargamin 20 mg; Participants received intravenous cipargamin 20 mg, as a minimum of two doses every 24 hours, not exceeding 3 doses followed by oral medication (Coartem®, twice daily [b.i.d.] for 3 days).	Drug: Cipargamin; Cipargamin, 20 mg or 40 mg, by intravenous administration of solution for injection; Other Names: KAE609; Drug: Coartem; Oral standard of care (Coartem tablets, dosed per weight, as per label); Other Names: Artemether; Lumefantrine
Experimental: IV Cipargamin 40 mg; Participants received intravenous cipargamin 40 mg, as a minimum of two doses every 24 hours, not exceeding 3 doses followed by oral medication (Coartem®, twice daily [b.i.d.] for 3 days).	Drug: Cipargamin; Cipargamin, 20 mg or 40 mg, by intravenous administration of solution for injection; Other Names: KAE609; Drug: Coartem; Oral standard of care (Coartem tablets, dosed per weight, as per label); Other Names: Artemether; Lumefantrine
Active Comparator: IV Artesunate; Participants received IV artesunate according to label and followed by oral medication (Coartem® b.i.d. for 3 days).	Drug: Coartem; Oral standard of care (Coartem tablets, dosed per weight, as per label); Other Names: Artemether; Lumefantrine; Drug: IV Artesunate; Artesunate, 2.4 mg/kg or 3 mg/kg, by intravenous administration of reconstituted solution; Other Names: Artesunate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum) at 12 Hours	A blood draw was performed at each collection time point for parasitemia assessment.	12 Hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Clinical Success at 48 Hours	Clinical success was a composite endpoint based on following criteria: Was participant dead or alive; Presence of asexual parasites (yes/no); Presence of any of the key signs of severe malaria (yes/no)	48 Hours
Percentage of Participants With Individual Signs of Severe Malaria Over Time	Individual signs of severe malaria over time were monitored for the presence of the following signs of severe malaria during the entire study duration: Altered consciousness - Prostration or GCS < 11 for participants > 5 years / BCS < 3 for participants =< 5 years of age; Renal Impairment - Serum creatinine > 3xULN or > 3 mg/dL or need for renal replacement therapy; Acidosis - Serum lactate > 4 mmol/L; Respiratory distress - present or absent; Severe anemia - Hb < 5 g/dl or Hb < 7g/dl in pediatric and adults respectively or need of blood transfusion; Jaundice - Serum bilirubin > 3 g/dl; Hypoglycemia- plasma glucose < 40 mg/dL	Baseline to Day 29
Percentage of Participants Developing Hemolysis (Early and Delayed) After Treatment	Development (early and delayed) of hemolysis after treatments was defined as follows: Early Hemolytic anemia was defined as 10% or greater decrease in hemoglobin levels and an increase of lactate dehydrogenase (LDH) levels to >390 U/L, or an increase of >= 10% above baseline occurring up to Day 8 of the study. Delayed hemolytic anemia occurred > 7 days after initiation of parenteral study drug (IV artesunate or IV cipargamin) during the study period. The event was characterized by a 10% or greater decrease in hemoglobin levels accompanied by increase of LDH levels to >390 U/L, or an increase of >= 10% compared to the values measured at Day 8 of the study.	Day 8 and Day 29
Percentage of Participants With Neurological Sequelae at Day 29	Detailed neurological examination was conducted and relevant medical history collected to assess the extent of neurological signs and symptoms at baseline and to monitor the extent of neurological sequelae in follow-up visits.	Day 29
Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum)	A blood draw was performed at each collection time point for parasitemia assessment.	24 hours and 48 hours
Time to Parasite Clearance (PCT)	Parasite clearance time (PCT) was defined as the time from the first dose until the first total and continued disappearance of asexual parasite forms which remained at least a further 24 hours.	Up to 72 hours
Parasite Clearance Estimator (PCE) Slope Half-life	Slope half-life (hours) for parasite clearance was calculated for each patient using the WWARN (World Wide Antimalarial Resistance Network) Parasite Clearance Estimator.	Up to 72 hours
Time to Fever Clearance (FCT)	Fever clearance time (FCT) was defined as the time from the first dose until the first time the axillary body temperature decreased below and remained below 37.5°C axillary or 38.0°C oral/tympanic/rectal for at least a further 24 hours.	Up to 72 hours
P. Falciparum Parasite Reduction Ratios (PRR) at 12, 24 and 48 Hours	PRR was defined as the ratio of asexual parasite at baseline divided by asexual parasite at post-baseline. If the asexual parasite count at post-baseline was 0, the half value of detection limit was used to calculate the ratio.	12 hours, 24 hours, and 48 hours
Percentage of Participants With Recrudescence and Reinfection	Recrudescence was defined as appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at baseline. Reinfection was defined as appearance of asexual parasites after clearance of initial infection with a genotype different from those parasites present at baseline. Reinfection and Recrudescence were confirmed by polymerase chain reaction (PCR) analysis.	Day 29
Time to Switch to Oral Therapy	Time to switch participants from IV therapy to Coartem (standard of drug for oral therapy) was analyzed.	Day 3 to Day 29
Time to Discharge From Hospital		Day 3 to Day 29
Time to Recover From Prostration	To assess recovery of participants as measured by time to recovery from prostration compared to baseline.	Day 1 to Day 29
Number of Participants With Adverse Events or Serious Adverse Events, or Who Died	Adverse events (AEs) and serious adverse events (SAEs) were collected from first dosing. Death routine laboratory assessments were assessed up to last follow-up visit or until the event had resolved to baseline grade or better, or the event was assessed stable by the investigator, or the participant was lost to follow-up or withdrew consent.	Day 1 to Day 29
Observed Maximum Plasma Concentration (Cmax) of IV Cipargamin	Blood samples were collected for pharmacokinetics characterization. Cmax is the maximum (peak) observed plasma concentration of cipargamin after dose administration. Cmax was listed and summarized using descriptive statistics.	Day 1 - Day 8
Time of Maximum Observed Drug Concentration Occurrence (Tmax) of IV Cipargamin	Blood samples were collected for pharmacokinetics characterization. Tmax was listed and summarized using descriptive statistics. Time to reach maximum observed plasma concentration of cipargamin after dose administration.	Day 1 - Day 8
Area Under the Serum Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of IV Cipargamin	Blood samples were collected for pharmacokinetics characterization. AUClast was listed and summarized using descriptive statistics.	Day 1 - Day 8
Area Under the Concentration Time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUCinf) of IV Cipargamin	Blood samples were collected for pharmacokinetics characterization. AUC(0-inf) post last dose was listed and summarized using descriptive statistics.	Day 1 - Day 8
Area Under the Plasma Concentration-time Curve From the Time 0 to 24 Hours (AUC0-24hours) of IV Cipargamin	Blood samples were collected for pharmacokinetics characterization. AUC(0-24h) was listed and summarized using descriptive statistics.	Day 1 - Day 8
Terminal Elimination Half Life (T1/2) of IV Cipargamin	Blood samples were collected for pharmacokinetics characterization. The half-life post last dose was summarized using descriptive statistics.	Day 1 - Day 8
Total Systemic Clearance for Intravenous Administration (CL) of IV Cipargamin	Blood samples were collected for pharmacokinetics characterization. CL post last dose was summarized using descriptive statistics.	Day 1 - Day 8
Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) of IV Cipargamin	Blood samples were collected for pharmacokinetics characterization. Vz post last dose was listed and summarized using descriptive statistics.	Day 1 - Day 8

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Wellcome Trust; European and Developing Countries Clinical Trials Partnership (EDCTP)
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2022
• Primary Completion (Actual): July 24, 2025
• Study Completion (Actual): August 20, 2025

Study Registration Dates

• First Submitted: December 1, 2020
• First Submitted That Met QC Criteria: December 17, 2020
• First Posted (Actual): December 19, 2020

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: March 20, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: tolerability; safety; pediatric; pharmacokinetics; intravenous; dose-finding; KAE609; artesunate; cipargamin; i.v.
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; Protozoan Infections; Parasitic Diseases; Malaria; Organic Chemicals; Pharmaceutical Preparations; Hydrocarbons; Hydrocarbons, Cyclic; Terpenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Inorganic Chemicals; Drug Combinations; Reactive Oxygen Species; Free Radicals; Artemisinins; Fluorenes; Sesquiterpenes; Lumefantrine; Artemether; Artesunate; Artemether, Lumefantrine Drug Combination; NITD 609
• Other Study ID Numbers: CKAE609B12201; 217692/Z/19/Z (Other Grant/Funding Number: Wellcome Trust and EDCTP within the PAMAFRICA Grant); 2020-005035-70 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of participants who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No