An adaptive randomized active-controlled open-label sequentialcohort multicenter study to evaluate the efficacy safetytolerability and pharmacokinetics of intravenous cipargamin(KAE609) in adult and pediatric participants with severePlasmodium falciparum malaria

Phase 2

Conditions: Health Condition 1: B508- Other severe and complicated Plasmodium falciparum malaria

Registration Number: CTRI/2022/03/041310

Lead Sponsor: ovartis Healthcare Pvt Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Open to Recruitment

Sex: Not specified

Target Recruitment: 0

Inclusion Criteria

1. Cohort 1: Participants aged = 12 years with moderately severe malaria as defined in

Barnes et al 2004 (prostration and/or repeated vomiting) without presence of other signs of

severe malaria (Section 16.4) 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

Section 16.4 (modified version of severe malaria criteria in WHO 2014) 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

2. Written informed consent form must be obtained prior to any study related procedure. If

the participant is unable to read and write or otherwise incapable of signing an informed

consent, then a witnessed consent according to local ethical standards is permitted

(formally documented and witnessed, ideally via an independent trusted witness).

Participants aged < 18 years, who are capable of providing assent, must provide assent

with parental/legal guardian consent or as per local ethical guidelines. The participant or

parent/legal guardian (in case of pediatric participants) is able to understand and comply

with protocol requirements, instructions and protocol-stated restrictions for their child and

is likely to complete the study as planned.

Exclusion Criteria

1 Mixed plasmodium infections

2 Treatment with any antimalarial drug (including quinine or artemisinin derivative) or any antibiotic with known antimalarial activity within 12 hours of screening

3 Known underlying illness, surgical or medical condition not related to ongoing episode of malaria which might jeopardize the patient’s health

4 Known or suspected case of active infections or concurrent febrile illness such as HIV, TB, Typhoid, COVID-19 etc.

5 Known h/o ECG abnormalities indicating significant risk to safety of participants-Clinically significant cardiac arrhythmias-H/o familial long QT syndrome or Torsades de Pointes-QTcF > 450 ms in males and QTcF > 460 ms in females

aged = 12 years old and QTcF > 450 ms in females aged < 12 years

6 Severe malnutrition – In accordance with WHO guidelines

7 Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer

8 Participants taking prohibited medications as per protocol

9 Pregnant or nursing (lactating) women

10 Female of child bearing potential and sexually active males unless they are using one of the highly effective contraception methods (refer protocol section 5.2) during dosing and one week after last IV dose

Exclusion criteria for Cohort 1:

1. ALT > 5 x the upper limit of normal range (ULN), regardless the level of total

bilirubin

2. ALT > 3 x ULN and total bilirubin is > 3 mg/dL

3. Body weight of < 35 kg or > 75 kg

Exclusion criteria for Cohort 2:

1. Body weight of < 35 kg or >75 kg

2. 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:

1. Body weight of < 5 kg

2. Participants diagnosed as moderately severe malaria due to repeated vomiting without

presence of any of the symptoms of severe malaria.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To assess the efficacy of IV cipargaminTimepoint: Variable: A binary outcome indicating = 90% reduction in P. falciparum parasite at 12 hours (H12) after first IV dose as compared to baseline.

Secondary Outcome Measures

Name	Time	Method
To assess clinical outcomeTimepoint: Proportion of participants with clinical success over time. Clinical success at 48 hours is considered as the key secondary endpoint,for the secondary estimand.;To assess the presence/absence of individual signs of severe malariaTimepoint: Proportion of participants with individual signs of severe malaria over time;To assess the risk of hemolysisTimepoint: Proportion of participants developing hemolysis (early and delayed) after treatment;To assess the risk of long term neurological sequelaeTimepoint: Proportion of participants with neurological sequelae at Day 29;To evaluate parasite clearance dynamicsTimepoint: Proportions of participants with = 90% parasite reduction at 24 and 48 hours <br/ ><br>PCE slope half-life <br/ ><br>Time to P. falciparum parasite clearance (PCT) <br/ ><br>P. falciparum parasite reduction ratios (PRR) at 12, 24 and 48 hours <br/ ><br>Proportion of participants with recrudescence and reinfection by Day 29 <br/ ><br>