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

NCT04675931 | Completed Phase 2 Results DMC

• 3 other identifiers: CKAE609B12201217692/Z/19/Z2020-005035-70
• Study Type: interventional
• Target: 254
• Locations: 7 countries
• Sites: 9

Brief 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.

Conditions

Severe Malaria

Keywords

KAE609; cipargamin; artesunate; intravenous; i.v.; pediatric; dose-finding; safety; tolerability; pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (22)

• Percentage of Participants Achieving Clinical Success at 48 Hours

  48 Hours

• Percentage of Participants With Individual Signs of Severe Malaria Over Time

  Baseline to Day 29

• Percentage of Participants Developing Hemolysis (Early and Delayed) After Treatment

  Day 8 and Day 29

• Percentage of Participants With Neurological Sequelae at Day 29

  Day 29

• Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum)

  24 hours and 48 hours

Study Arms (3)

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).

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).

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).

Drug: IV Artesunate; Drug: Coartem

Interventions

IV Artesunate DRUG

Artesunate, 2.4 mg/kg or 3 mg/kg, by intravenous administration of reconstituted solution

Also known as: Artesunate

IV Artesunate

Coartem DRUG

Oral standard of care (Coartem tablets, dosed per weight, as per label)

Also known as: Artemether, Lumefantrine

IV Artesunate; IV Cipargamin 20 mg; IV Cipargamin 40 mg

Cipargamin DRUG

Cipargamin, 20 mg or 40 mg, by intravenous administration of solution for injection

Also known as: KAE609

IV Cipargamin 20 mg; IV Cipargamin 40 mg

Eligibility Criteria

• Age: 6 Months - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:
• 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.
• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• Wellcome Trust: collaborator
• European and Developing Countries Clinical Trials Partnership (EDCTP): collaborator

Study Sites (9)

Novartis Investigative Site

Burkina Faso, 2208, Burkina Faso

Location

Novartis Investigative Site

Ouagadougou, Burkina Faso

Location

Novartis Investigative Site

Abidjan, 13BP972, Côte d’Ivoire

Location

Novartis Investigative Site

Agboville, BP 154, Côte d’Ivoire

Location

Novartis Investigative Site

Kinsasha, Democratic Republic of Congo, BP 7948, Democratic Republic of the Congo

Location

Novartis Investigative Site

Siaya, 2300, Kenya

Location

Novartis Investigative Site

Manhiça, Maputo Province, 1929, Mozambique

Location

Novartis Investigative Site

Kigali, BP 4560, Rwanda

Location

Novartis Investigative Site

Tororo, 10102, Uganda

Location

MeSH Terms

Conditions

Malaria

Interventions

NITD 609; Artesunate; Artemether, Lumefantrine Drug Combination; Artemether; Lumefantrine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Sesquiterpenes; Terpenes; Hydrocarbons; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Although the study was open label, in order to minimize the potential impact of treatment knowledge, treatment allocation, dose information, PK/AAG assessment schedule and concentration data, as well as other data that could result in systematic unblinding, were not available to the Clinical Trial Team (CTT) (particularly clinicians, trial statisticians, trial programmers) until the database was locked after IA of Cohorts 1-2. After interim database lock, the CTT would be unblinded with the results, however, the blinding would then be continued for Cohorts 3-5 until the final database was locked.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: December 1, 2020
• First Posted: December 19, 2020
• Study Start: March 7, 2022
• Primary Completion: July 24, 2025
• Study Completion: August 20, 2025
• Last Updated: April 9, 2026
• Results First Posted: April 9, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

RW (1); UG (1); CÔ (2); KE (1); DE (1); BU (2); MO (1)