Clinical trial NCT04675931: To Evaluate Efficacy, Safety, Tolerability and PK of Intravenous Cipargamin in Participants With Severe Plasmodium Falciparum Malaria
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Severe Malaria
Keywords: KAE609
cipargamin
artesunate
intravenous
i.v.
pediatric
dose-finding
safety
tolerability
pharmacokinetics
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Wellcome Trust
name: European and Developing Countries Clinical Trials Partnership (EDCTP)
First posted: 2020-12-19
Enrollment: 252
Sex: ALL
Minimum age (years): 6
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This will be 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 will get randomized to one of the three treatment arms (2 dose of intravenous cipargamin or intravenous artesunate - comparator ). After Cohort 2, interim analysis will be performed to take one best dose of intravenous cipargamin forward for Cohorts 3-5. Participants in Cohorts 3-5 with be randomized to one of two treatments arms ( intravenous cipargamin or intravenous artesunate - comparator).
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to identify the safe and effective dose of intravenous cipargamin in participants with moderately severe and severe malaria.

The study also intends 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 of another drug in malaria endemic countries. Cipargamin treatment results in rapid clearance of parasites including artemisinin resistant parasites.


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

Primary outcomes:
measure: Percentage of participants achieving at least 90% reduction in Plasmodium falciparum (P. falciparum) at 12 hours
timeFrame: Day 1 (12 Hours)
Secondary outcomes:
measure: Percentage of participants achieving clinical success over time
timeFrame: Day 3 (48 Hours), Day 4 to Day 29
measure: Percentage of participants with individual signs of severe malaria over time
timeFrame: Day 1 to Day 29
measure: Percentage of participants developing hemolysis (early and delayed) after treatment
timeFrame: Day 8 and Day 29
measure: Percentage of participants with neurological sequelae at Day 29
timeFrame: Day 29
measure: Percentage of participants achieving at least 90% reduction in Plasmodium falciparum (P. falciparum)
timeFrame: Day 2 (24 hours), Day 3 (48 hours)
measure: Time to parasite clearance (PCT)
timeFrame: Day 1 (12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)
measure: Time to fever clearance (FCT)
timeFrame: Day 1 (12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)
measure: Percentage of participants achieving P. falciparum parasite reduction ratios (PRR) at 12, 24 and 48 hours
timeFrame: Day 1 (12 hours), Day 2 (24 hours) and Day 3 (48 hours)
measure: Percentage of participants with recrudescence and reinfection
timeFrame: Day 29
measure: Time to recover from prostration
timeFrame: Day 1 to Day 29
measure: Time to switch to oral therapy
timeFrame: Day 3 to Day 29
measure: Time to discharge from hospital
timeFrame: Day 3 to Day 29
measure: Number of Participants impacted on safety and tolerability assessments
timeFrame: Day 1 to Day 29
measure: Observed maximum plasma concentration (Cmax) of IV Cipargamin
timeFrame: Day 1 - Day 8
measure: Time of maximum observed drug concentration occurrence (Tmax) of IV Cipargamin
timeFrame: Day 1 - Day 8
measure: Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of IV Cipargamin
timeFrame: Day 1 - Day 8
measure: Area under the concentration time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of IV Cipargamin
timeFrame: Day 1 - Day 8
measure: Area Under the plasma concentration-time Curve from the time 0 to the last observed quantifiable concentration (AUC(0-t)) of IV Cipargamin
timeFrame: Day 1 - Day 8
measure: AUC(0-t) divided by the dose administered (AUC(0- t)/D) of IV Cipargamin
timeFrame: Day 1 - Day 8
measure: Terminal elimination half life (T^1/2) of IV Cipargamin
timeFrame: Day 1 - Day 8
measure: Total systemic clearance for intravenous administration (CL) of IV Cipargamin
timeFrame: Day 1 - Day 8
measure: volume of distribution during the terminal phase following intravenous elimination (Vz) of IV Cipargamin
timeFrame: Day 1 - Day 8
Other outcomes:
Locations:
city: Burkina Faso
country: Burkina Faso
facility: Novartis Investigative Site
city: Ouagadougou
country: Burkina Faso
facility: Novartis Investigative Site
city: Kinsasha
country: Congo, The Democratic Republic of the
facility: Novartis Investigative Site
state: Democratic Republic Of Congo
city: Abidjan
country: Côte D'Ivoire
facility: Novartis Investigative Site
city: Agboville
country: Côte D'Ivoire
facility: Novartis Investigative Site
city: Lambarene
country: Gabon
facility: Novartis Investigative Site
city: Raipur
country: India
facility: Novartis Investigative Site
state: Chhattisgarh
city: Surat
country: India
facility: Novartis Investigative Site
state: Gujrat
city: Jaipur
country: India
facility: Novartis Investigative Site
state: Rajasthan
city: Siaya
country: Kenya
facility: Novartis Investigative Site
city: Manhica
country: Mozambique
facility: Novartis Investigative Site
state: Maputo Province
city: Ilorin
country: Nigeria
facility: Novartis Investigative Site
city: Kigali
country: Rwanda
facility: Novartis Investigative Site
city: Tororo
country: Uganda
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: