Evaluating intravenous cipargamin for severe malaria treatment

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)

This study is testing if a new intravenous treatment called cipargamin can safely help people with severe malaria feel better and recover.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 252 (estimated)
• Ages: 6 Months to 100 Years
• Sex: All
• Sponsor: Novartis (Industry-sponsored)
• Locations: 14 sites (Burkina Faso and 13 other locations)
• Trial ID: NCT04675931 on ClinicalTrials.gov

What this trial studies

This study aims to determine the efficacy, safety, and tolerability of intravenous cipargamin in patients suffering from severe Plasmodium falciparum malaria. It will assess the appropriate dosage and evaluate clinical treatment success using a novel endpoint specifically designed for severe malaria cases. The study is particularly relevant due to the emergence of artemisinin-resistant malaria strains, highlighting the need for alternative treatment options. Participants will be categorized into cohorts based on age and severity of malaria symptoms.

Who should consider this trial

Good fit: Ideal candidates include individuals aged 6 months and older diagnosed with moderately severe to severe malaria.

Not a fit: Patients with mixed Plasmodium infections or those who have recently received other antimalarial treatments may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with severe malaria, especially in regions facing drug resistance.

How similar studies have performed: Other studies have shown promising results with alternative treatments for malaria, but the specific use of cipargamin in this context is novel.

Eligibility criteria

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

Where this trial is running

Burkina Faso and 13 other locations

• Novartis Investigative Site — Burkina Faso, Burkina Faso (Recruiting)
• Novartis Investigative Site — Ouagadougou, Burkina Faso (Recruiting)
• Novartis Investigative Site — Kinsasha, Democratic Republic Of Congo, Congo, The Democratic Republic of the (Recruiting)
• Novartis Investigative Site — Abidjan, Côte D'Ivoire (Recruiting)
• Novartis Investigative Site — Agboville, Côte D'Ivoire (Recruiting)
• Novartis Investigative Site — Lambarene, Gabon (Recruiting)
• Novartis Investigative Site — Raipur, Chhattisgarh, India (Withdrawn)
• Novartis Investigative Site — Surat, Gujrat, India (Withdrawn)
• Novartis Investigative Site — Jaipur, Rajasthan, India (Withdrawn)
• Novartis Investigative Site — Siaya, Kenya (Recruiting)
• Novartis Investigative Site — Manhica, Maputo Province, Mozambique (Recruiting)
• Novartis Investigative Site — Ilorin, Nigeria (Recruiting)
• Novartis Investigative Site — Kigali, Rwanda (Recruiting)
• Novartis Investigative Site — Tororo, Uganda (Recruiting)

Study contacts

• Study coordinator: Novartis Pharmaceuticals

Conditions Severe Malaria; KAE609; cipargamin; artesunate; intravenous; i.v.; pediatric; dose-finding