Severe MalariaPhase 2NCT04675931
To Evaluate Efficacy, Safety, Tolerability and PK of Intravenous Cipargamin in Participants With Severe Plasmodium Falciparum Malaria
A Phase 2 study testing Cipargamin, IV Artesunate and Coartem in people with Severe Malaria, run by Novartis Pharmaceuticals at 9 sites in 7 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 months to 100 years
- Conditions the study is for
- Severe Malaria
- What is being tested?
- Cipargamin, IV Artesunate and Coartem
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 254 participants
- Where
- 9 sitesin 7 countries
- Study dates
- 7 Mar 2022to 20 Aug 2025
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months to 100 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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:
- 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
- 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:
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- neurological or neurodegenerative disorders,
- cardiac, renal, or hepatic disease, diabetes,
- epilepsy, cerebral palsy,
- known or suspected to be HIV-1 positive and/or receiving antiretroviral treatment
- 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
- known or suspected cases of active infections or concurrent febrile illness such as TB, Typhoid, COVID-19 etc.
- Additional exclusion criteria are as follows:
- 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
- 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
- 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
Trial locations and contacts
9 sites in 7 countries.
9 sites in 7 countries
Burkina Faso2 sites
Novartis Investigative Site
Burkina Faso, 2208
Novartis Investigative Site
Ouagadougou
Côte d’Ivoire2 sites
Novartis Investigative Site
Abidjan, 13BP972
Novartis Investigative Site
Agboville, BP 154
Democratic Republic of the Congo1 site
Novartis Investigative Site
Kinsasha, Democratic Republic of Congo, BP 7948
Mozambique1 site
Novartis Investigative Site
Manhiça, Maputo Province, 1929
About this study
Official title: 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.
Read the 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
- Being tested
- Cipargamin, IV Artesunate, Coartem
- Keywords
- KAE609, cipargamin, artesunate, intravenous, i.v., pediatric, dose-finding, safety, tolerability, pharmacokinetics
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CipargaminDrug
Also called KAE609
Cipargamin, 20 mg or 40 mg, by intravenous administration of solution for injection
IV ArtesunateDrug
Also called Artesunate
Artesunate, 2.4 mg/kg or 3 mg/kg, by intravenous administration of reconstituted solution
CoartemDrug
Also called Artemether, Lumefantrine
Oral standard of care (Coartem tablets, dosed per weight, as per label)
| Study group | Role | What they receive |
|---|---|---|
| IV Cipargamin 20 mg | Experimental | 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). Receives: Drug: Cipargamin; Drug: Coartem |
| IV Cipargamin 40 mg | Experimental | 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). Receives: Drug: Cipargamin; Drug: Coartem |
| IV Artesunate | Active comparator | Participants received IV artesunate according to label and followed by oral medication (Coartem® b.i.d. for 3 days). Receives: Drug: IV Artesunate; Drug: Coartem |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 Hours
Secondary outcomes (22)
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)
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 3 to Day 29
Time to Discharge From Hospital
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 1 - Day 8
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Dec 2020
- Study start7 Mar 2022
- Primary completion24 Jul 2025
- Study completion20 Aug 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Severe MalariaStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- This 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 and severe P. falciparum malaria. In Cohorts 1-2, participants were randomized to one of the three treatment arms (2 dose of intravenous cipargamin or intravenous artesunate - comparator). After Cohort 2, interim analysis was performed to take one best dose of intravenous cipargamin forward for Cohorts 3-5. Participants in Cohorts 3-5 were randomized to one of two treatments arms (intravenous cipargamin or intravenous artesunate - comparator).
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 254 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Wellcome Trust, European and Developing Countries Clinical Trials Partnership (EDCTP)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04675931
- Sponsor's protocol ID
- CKAE609B12201
- Other IDs
- 217692/Z/19/Z, 2020-005035-70
- Status last verified
- Mar 2026
- First submitted
- 1 Dec 2020
- Last updated
- 9 Apr 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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