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

NCT04675931
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Phase
Phase 2
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Recruitment status
Completed
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Participants
254
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Lead sponsor
Novartis Pharmaceuticals
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Start date
2022-03-07
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Number of sites
9
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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.
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Short title
To Evaluate Efficacy, Safety, Tolerability and PK of Intravenous Cipargamin in Participants With Severe Plasmodium Falciparum Malaria
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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)
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Control arm
Active comparator
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Registry reports results
Yes
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Listing at source
Listed
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Recruitment status
Completed
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Phase
Phase 2
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Study type
Interventional
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Completion date
2025-08-20
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First posted
2020-12-19
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Registry last updated
2026-04-09
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Primary completion date
2025-07-24
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Start date
2022-03-07
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Actual participants
254
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Participants
254
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Participant count basis
Actual
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Protocol amendments
4
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Randomisation ratio
1:1:1
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Number of sites
9
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Data monitoring committee
Yes
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Registry sponsor category
Industry
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Lead sponsor
Novartis Pharmaceuticals
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Source registry
ClinicalTrials.gov
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Registry ID
NCT04675931
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ClinicalTrials.gov ID
NCT04675931
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Registry record
Open registry record
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Allocation
Randomised
Model
Sequential
Purpose
Treatment
Masking
Single masking
Masking description
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.
Masked roles
Outcome assessors
Sources for study design
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  1. Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum) at 12 Hours

    Timeframe: 12 Hours

    A blood draw was performed at each collection time point for parasitemia assessment.

  1. Percentage of Participants Achieving Clinical Success at 48 Hours

    Timeframe: 48 Hours

    Clinical success was a composite endpoint based on following criteria: 1. Was participant dead or alive 2. Presence of asexual parasites (yes/no) 3. Presence of any of the key signs of severe malaria (yes/no)

  2. Percentage of Participants With Individual Signs of Severe Malaria Over Time

    Timeframe: Baseline to Day 29

    Individual signs of severe malaria over time were monitored for the presence of the following signs of severe malaria during the entire study duration: 1. Altered consciousness - Prostration or GCS \< 11 for participants \> 5 years / BCS \< 3 for participants =\< 5 years of age 2. Renal Impairment - Serum creatinine \> 3xULN or \> 3 mg/dL or need for renal replacement therapy 3. Acidosis - Serum lactate \> 4 mmol/L 4. Respiratory distress - present or absent 5. Severe anemia - Hb \< 5 g/dl or Hb \< 7g/dl in pediatric and adults respectively or need of blood transfusion 6. Jaundice - Serum bilirubin \> 3 g/dl 7. Hypoglycemia- plasma glucose \< 40 mg/dL

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

    Timeframe: Day 8 and Day 29

    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.

  4. Percentage of Participants With Neurological Sequelae at Day 29

    Timeframe: 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.

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

    Timeframe: 24 hours and 48 hours

    A blood draw was performed at each collection time point for parasitemia assessment.

  6. Time to Parasite Clearance (PCT)

    Timeframe: Up to 72 hours

    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.

  7. Parasite Clearance Estimator (PCE) Slope Half-life

    Timeframe: Up to 72 hours

    Slope half-life (hours) for parasite clearance was calculated for each patient using the WWARN (World Wide Antimalarial Resistance Network) Parasite Clearance Estimator.

  8. Time to Fever Clearance (FCT)

    Timeframe: Up to 72 hours

    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.

  9. P. Falciparum Parasite Reduction Ratios (PRR) at 12, 24 and 48 Hours

    Timeframe: 12 hours, 24 hours, 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.

  10. Percentage of Participants With Recrudescence and Reinfection

    Timeframe: Day 29

    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.

  11. Time to Switch to Oral Therapy

    Timeframe: Day 3 to Day 29

    Time to switch participants from IV therapy to Coartem (standard of drug for oral therapy) was analyzed.

  12. Time to Discharge From Hospital

    Timeframe: Day 3 to Day 29

  13. Time to Recover From Prostration

    Timeframe: Day 1 to Day 29

    To assess recovery of participants as measured by time to recovery from prostration compared to baseline.

  14. Number of Participants With Adverse Events or Serious Adverse Events, or Who Died

    Timeframe: Day 1 to Day 29

    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.

  15. Observed Maximum Plasma Concentration (Cmax) of IV Cipargamin

    Timeframe: Day 1 - Day 8

    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.

  16. Time of Maximum Observed Drug Concentration Occurrence (Tmax) of IV Cipargamin

    Timeframe: Day 1 - Day 8

    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.

  17. 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

    Blood samples were collected for pharmacokinetics characterization. AUClast was listed and summarized using descriptive statistics.

  18. Area Under the Concentration Time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUCinf) of IV Cipargamin

    Timeframe: Day 1 - Day 8

    Blood samples were collected for pharmacokinetics characterization. AUC(0-inf) post last dose was listed and summarized using descriptive statistics.

  19. Area Under the Plasma Concentration-time Curve From the Time 0 to 24 Hours (AUC0-24hours) of IV Cipargamin

    Timeframe: Day 1 - Day 8

    Blood samples were collected for pharmacokinetics characterization. AUC(0-24h) was listed and summarized using descriptive statistics.

  20. Terminal Elimination Half Life (T1/2) of IV Cipargamin

    Timeframe: Day 1 - Day 8

    Blood samples were collected for pharmacokinetics characterization. The half-life post last dose was summarized using descriptive statistics.

  21. Total Systemic Clearance for Intravenous Administration (CL) of IV Cipargamin

    Timeframe: Day 1 - Day 8

    Blood samples were collected for pharmacokinetics characterization. CL post last dose was summarized using descriptive statistics.

  22. Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) of IV Cipargamin

    Timeframe: Day 1 - Day 8

    Blood samples were collected for pharmacokinetics characterization. Vz post last dose was listed and summarized using descriptive statistics.

Sources for outcomes
clinicaltrials.gov

Sex
All
Age groups
Children, Adults, Older adults
Minimum age
6 Months
Maximum age
100 Years
Healthy volunteers
No

  • 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 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
Sources for eligibility
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  • Novartis Investigative SiteBurkina Faso, Burkina Faso
  • Novartis Investigative SiteOuagadougou, Burkina Faso
  • Novartis Investigative SiteAbidjan, Côte d’Ivoire
  • Novartis Investigative SiteAgboville, Côte d’Ivoire
  • Novartis Investigative SiteKinsasha, Democratic Republic of the Congo
  • Novartis Investigative SiteSiaya, Kenya
  • Novartis Investigative SiteManhiça, Mozambique
  • Novartis Investigative SiteKigali, Rwanda
  • Novartis Investigative SiteTororo, Uganda
Sources for sites
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  • 2020-005035-70
  • 217692/Z/19/Z
Sources for references
clinicaltrials.gov

Related records

Drugs (3)

Collaborators (2)

Lead sponsors (1)

Conditions (1)