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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04675931
Recruitment Status : Recruiting
First Posted : December 19, 2020
Last Update Posted : April 20, 2023
Sponsor:
Collaborators:
Wellcome Trust
European and Developing Countries Clinical Trials Partnership (EDCTP)
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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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.


Condition or disease Intervention/treatment Phase
Severe Malaria Drug: KAE609 Drug: IV Artesunate Drug: Coartem Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 252 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
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).
Masking: Single (Outcomes Assessor)
Masking Description: Although the study is open label however 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 may result in systematic unblinding will not be available to the Clinical Trial Team (CTT) (particularly clinicians, trial statisticians, trial programmers) until the database is locked after IA of Cohorts 1-2. After interim database lock, the CTT would be unblinded with the results, however, the blinding will then be continued for Cohorts 3-5 until the final database is locked.
Primary Purpose: Treatment
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)
Actual Study Start Date : March 7, 2022
Estimated Primary Completion Date : May 20, 2025
Estimated Study Completion Date : May 20, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arms and Interventions
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Arm Intervention/treatment
Experimental: IV KAE609 Dose regimen 1
Intravenous KAE609 (cipargamin) 20 mg
 Drug: KAE609

Two doses of Intravenous Cipargamin will be evaluated in the initial phase of the study (Cohorts 1-2).

These doses will cover a wider exposure range and facilitate the selection of an appropriate dose for later Cohorts 3-5.

Other Name: Cipargamin
Experimental: IV KAE609 Dose regimen 2
Intravenous KAE609 (cipargamin) 40 mg
 Drug: KAE609

Two doses of Intravenous Cipargamin will be evaluated in the initial phase of the study (Cohorts 1-2).

These doses will cover a wider exposure range and facilitate the selection of an appropriate dose for later Cohorts 3-5.

Other Name: Cipargamin
Experimental: IV KAE609 Dose regimen 3
Intravenous KAE609 (cipargamin) Dose regimen 3 (dose will be evaluated post Interim analysis from Cohort 1 and Cohort 2.
 Drug: KAE609

Two doses of Intravenous Cipargamin will be evaluated in the initial phase of the study (Cohorts 1-2).

These doses will cover a wider exposure range and facilitate the selection of an appropriate dose for later Cohorts 3-5.

Other Name: Cipargamin
Active Comparator: IV Artesunate
IV Artesunate 2.4 mg/kg (for participants weighing at least 20 kg) IV Artesunate 3 mg/kg (for participants weighing less than 20 kg)
 Drug: IV Artesunate
Parenteral artesunate is the WHO recommended first line treatment for severe malaria. Hence IV artesunate is used as comparator. Also, this will be used as rescue medication for participants where IV KAE609 is not working.
Other Name: Artesunate
Coartem
Standard of care (Coartem) will be given to all participants for 3 days as part of treatment.
 Drug: Coartem
Oral Standard of Care
Other Names:
  • Artemether
  • Lumefantrine


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of participants achieving at least 90% reduction in Plasmodium falciparum (P. falciparum) at 12 hours [ Time Frame: Day 1 (12 Hours) ]
    A blood draw will be performed at each collection time point for parasitemia assessment.


Secondary Outcome Measures :
  1. Percentage of participants achieving clinical success over time [ Time Frame: Day 3 (48 Hours), Day 4 to Day 29 ]

    Clinical success is a composite endpoint based on following criterias:

    1. Is 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 [ Time Frame: Day 1 to Day 29 ]

    Individual signs of severe malaria over time will be 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 [ Time Frame: Day 8 and Day 29 ]

    Development (early and delayed) of hemolysis after treatment are defined as follows:

    Early Hemolytic anemia is defined as 10% or greater decrease in hemoglobin levels and an increase of LDH levels to >390 U/L, or an increase of >= 10% above baseline occurring up to Day 8 of the study.

    Delayed hemolytic anemia might occur > 7 days after initiation of parenteral study drug (IV artesunate or IV cipargamin) during the study period. The event is 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 [ Time Frame: Day 29 ]

    Detailed neurological examination will be conducted and relevant medical history collected under the following categories to assess the extent of neurological signs and symptoms at baseline and to monitor the extent of neurological sequelae in follow-up visits:

    1. Consciousness
    2. Cranial Nerve Palsy
    3. Motor system
    4. Convulsions
    5. Sense organs (Examination more useful at time of hospital discharge and in follow-up visits)

  5. Percentage of participants achieving at least 90% reduction in Plasmodium falciparum (P. falciparum) [ Time Frame: Day 2 (24 hours), Day 3 (48 hours) ]
    A blood draw will be performed at each collection time point for parasitemia assessment

  6. Time to parasite clearance (PCT) [ Time Frame: Day 1 (12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]
    Parasite Clearance Time (PCT) is 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. Time to fever clearance (FCT) [ Time Frame: Day 1 (12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]
    Fever Clearance Time (FCT) is 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.

  8. Percentage of participants achieving P. falciparum parasite reduction ratios (PRR) at 12, 24 and 48 hours [ Time Frame: Day 1 (12 hours), Day 2 (24 hours) and Day 3 (48 hours) ]
    PRR is defined as the ratio of asexual parasite at baseline divided by asexual parasite at post-baseline. If the asexual parasite count at post-baseline is 0, the half value of detection limit will be used to calculate the ratio.

  9. Percentage of participants with recrudescence and reinfection [ Time Frame: Day 29 ]

    Time to event (recrudescence or reinfection) will be calculated from the time of first study medication to the date of first event if a patient experiences the event and be censored at the time of last parasite assessment if a patient does not experience the event due to whatever reason.

    Reinfection is defined as appearance of asexual parasites after clearance of initial infection with a genotype different from those parasites present at baseline.

    Recrudescence is defined as appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at baseline.

    Reinfection and Recrudescence must be confirmed by PCR analysis.


  10. Time to recover from prostration [ Time Frame: Day 1 to Day 29 ]
    To assess recovery of participants as measured by time (days and hours) to discharge from hospital or recovery from prostration compared to baseline.

  11. Time to switch to oral therapy [ Time Frame: Day 3 to Day 29 ]
    Time to switch participants from IV therapy to Coartem (standard of drug for oral therapy) will be analyzed.

  12. Time to discharge from hospital [ Time Frame: Day 3 to Day 29 ]
    All participants will be hospitalized. Time (Days and Hours) to discharge from hospital will be analyzed.

  13. Number of Participants impacted on safety and tolerability assessments [ Time Frame: Day 1 to Day 29 ]
    Adverse events (AE), Serious Adverse events (SAEs) will be collected from first dosing, Death including whether in-hospital death and routine laboratory assessments will be done up to last follow-up visit or until the event has 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.

  14. Observed maximum plasma concentration (Cmax) of IV Cipargamin [ Time Frame: Day 1 - Day 8 ]
    Blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

  15. Time of maximum observed drug concentration occurrence (Tmax) of IV Cipargamin [ Time Frame: Day 1 - Day 8 ]
    Blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.

  16. Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of IV Cipargamin [ Time Frame: Day 1 - Day 8 ]
    Blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.

  17. Area under the concentration time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of IV Cipargamin [ Time Frame: Day 1 - Day 8 ]
    Blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-inf) will be listed and summarized using descriptive statistics.

  18. Area Under the plasma concentration-time Curve from the time 0 to the last observed quantifiable concentration (AUC(0-t)) of IV Cipargamin [ Time Frame: Day 1 - Day 8 ]
    Blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-t) will be listed and summarized using descriptive statistics.

  19. AUC(0-t) divided by the dose administered (AUC(0- t)/D) of IV Cipargamin [ Time Frame: Day 1 - Day 8 ]
    Blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-t)/D will be listed and summarized using descriptive statistics.

  20. Terminal elimination half life (T^1/2) of IV Cipargamin [ Time Frame: Day 1 - Day 8 ]
    Blood samples will be collected for activity-based pharmacokinetics characterization. The half-live will be listed and summarized using descriptive statistics.

  21. Total systemic clearance for intravenous administration (CL) of IV Cipargamin [ Time Frame: Day 1 - Day 8 ]
    Blood samples will be collected for activity-based pharmacokinetics characterization. CL will be listed and summarized using descriptive statistics.

  22. volume of distribution during the terminal phase following intravenous elimination (Vz) of IV Cipargamin [ Time Frame: Day 1 - Day 8 ]
    Blood samples will be collected for activity-based pharmacokinetics characterization. Vz will be listed and summarized using descriptive statistics.


Eligibility Criteria
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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04675931


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals

Locations
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Congo, The Democratic Republic of the
Novartis Investigative Site Recruiting
Kinsasha, Democratic Republic Of Congo, Congo, The Democratic Republic of the, BP 7948
Côte D'Ivoire
Novartis Investigative Site Recruiting
Abidjan, Cote D Ivoire, Côte D'Ivoire, 13BP972
Novartis Investigative Site Recruiting
Agboville, Cote D Ivoire, Côte D'Ivoire, BP 154
Gabon
Novartis Investigative Site Recruiting
Lambarene, Gabon, BP 242
India
Novartis Investigative Site Recruiting
Raipur, Chhattisgarh, India, 492099
Novartis Investigative Site Recruiting
Surat, Gujrat, India, 395002
Nigeria
Novartis Investigative Site Recruiting
Ilorin, Nigeria, 240003
Rwanda
Novartis Investigative Site Recruiting
Kigali, Rwanda, BP 4560
Sponsors and Collaborators
Novartis Pharmaceuticals
Wellcome Trust
European and Developing Countries Clinical Trials Partnership (EDCTP)
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04675931    
Other Study ID Numbers: CKAE609B12201
217692/Z/19/Z ( Other Grant/Funding Number: Wellcome Trust and EDCTP within the PAMAFRICA Grant )
First Posted: December 19, 2020    Key Record Dates
Last Update Posted: April 20, 2023
Last Verified: April 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of participants who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
KAE609
cipargamin
artesunate
intravenous
i.v.
 pediatric
dose-finding
safety
tolerability
pharmacokinetics
Additional relevant MeSH terms:
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Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Infections
Vector Borne Diseases
Artesunate
Lumefantrine
Artemether
Artemether, Lumefantrine Drug Combination
 Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics