Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202102626263606 Date of Approval: 04/02/2021
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title To Evaluate Efficacy, Safety, Tolerability and PK of Intravenous Cipargamin in Participants With Severe Plasmodium Falciparum Malaria - KAE609B12201(KARISMA)
Official scientific 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)
Brief summary describing the background and objectives of the trial 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.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) KARISMA
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Malaria
Purpose of the trial Treatment: Drugs
Anticipated trial start date 28/06/2021
Actual trial start date
Anticipated date of last follow up 28/12/2023
Actual Last follow-up date
Anticipated target sample size (number of participants) 252
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
CKAE609B12201 Not Applicable
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Central randomisation by phone/fax Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group IV KAE609 IV KAE609 Dose regimen 1 - Intravenous KAE609 (cipargamin) 20 mg IV KAE609 Dose regimen 2 - Intravenous KAE609 (cipargamin) 40 mg IV KAE609 Dose regimen 3 - Intravenous KAE609 (cipargamin) Dose regimen 3 (dose will be evaluated post Interim analysis from Cohort 1 and Cohort 2. IV KAE609 20 mg - dose regimen 1 - Minimum of two doses; q24h (to be administered at 0 hour and 24 hours) and not exceeding three doses (Dose 3 at 48 hours) IV KAE609 40 mg - dose regimen 2 - Minimum of two doses; q24h (to be administered at 0 hour and 24 hours) and not exceeding three doses (Dose 3 at 48 hours) IV KAE609 - dose regimen 3 - Minimum of two doses; q24h (to be administered at 0 hour and 24 hours) and not exceeding three doses (Dose 3 at 48 hours) 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. 136
Control Group 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) IV Artesunate - 0, 12, and 24 h and q24h for maximum 8 doses (7 days) according to label Injectable artesunate is the standard of care for the treatment of severe malaria 116 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
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 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 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. 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 for Cohort 2: - Body weight of < 35 kg or >75 kg - moderately severe malaria due to repeated vomiting without presence of any of the symptoms of severe malaria for Cohorts 3 to 5: - Body weight of < 5 kg - moderately severe malaria due to repeated vomiting without presence of any of the symptoms of severe malaria 80 and over: 80+ Year,Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Child: 6 Year-12 Year,Middle Aged: 45 Year(s)-64 Year(s),Preschool Child: 2 Year-5 Year 6 Month(s) 110 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 11/11/2020 Comite National Ethique pour la Recherche CNER
Ethics Committee Address
Street address City Postal code Country
Libreville, Gabon Gabon B.P 2217 Gabon
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 07/12/2020 Comite Consultatif National de Bioethique de la Republique de Cote DIvoire
Ethics Committee Address
Street address City Postal code Country
Abidjan, Cote DIvoire Cote Divoire BP V 297 Cote Divoire
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 05/01/2021 UITH ERC
Ethics Committee Address
Street address City Postal code Country
Studiopedia, Off Ministry of Health, Fate Tanke Rd Ilorin 4228 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 28/01/2021 Universite de Kinshasa
Ethics Committee Address
Street address City Postal code Country
Ecole de Sante Publique Kinshasa 11850 Democratic Republic of the Congo
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 07/12/2020 Comite National Dethiquedes Sciences de la vie et de la sante
Ethics Committee Address
Street address City Postal code Country
Agboville Agboville 154 Cote Divoire
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 26/02/2021 National Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Ministry of Health, Kigali, Rwanda Kigali 84 Rwanda
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome 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. Day 1 at 12 Hours
Secondary Outcome 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: a.Is participant dead or alive b.Presence of asexual parasites (yes/no) c.Presence of any of the key signs of severe malaria (yes/no) Day 3 at 48 Hours, Day 4 to Day 29
Secondary Outcome 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: a.Altered consciousness - Prostration or GCS < 11 for participants > 5 years / BCS < 3 for participants =< 5 years of age b.Renal Impairment - Serum creatinine > 3xULN or > 3 mg/dL or need for renal replacement therapy c.Acidosis - Serum lactate > 4 mmol/L d.Respiratory distress - present or absent e.Severe anemia - Hb < 5 g/dl or Hb < 7g/dl in pediatric and adults respectively or need of blood transfusion f.Jaundice - Serum bilirubin > 3 g/dl g.Hypoglycemia- plasma glucose < 40 mg/dL Day 1 to Day 29
Secondary Outcome 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. Day 8 and Day 29
Secondary Outcome 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: a.Consciousness b.Cranial Nerve Palsy c.Motor system d.Convulsions e.Sense organs (Examination more useful at time of hospital discharge and in follow-up visits) Day 29
Secondary Outcome 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 Day 2 at 24 hours, Day 3 at 48 hours
Secondary Outcome 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 Day 1 at 12 hours, Day 2 at 24 hours, Day 3 at 48 hours and Day 4 at 72 hours
Secondary Outcome 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. Day 1 at 12 hours, Day 2 at 24 hours, Day 3 at 48 hours and Day 4 at 72 hours
Secondary Outcome 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. Day 1 at 12 hours, Day 2 at 24 hours and Day 3 at 48 hours
Secondary Outcome 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. Day 29
Secondary Outcome 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. Day 1 to Day 29
Secondary Outcome 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. Day 3 to Day 29
Secondary Outcome 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. Day 3 to Day 29
Secondary Outcome 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. Day 1 to Day 29
Secondary Outcome 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. Day 1 - Day 8
Secondary Outcome 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. Day 1 - Day 8
Secondary Outcome 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. Day 1 - Day 8
Secondary Outcome 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. Day 1 - Day 8
Secondary Outcome 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. Day 1 - Day 8
Secondary Outcome 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. Day 1 - Day 8
Secondary Outcome 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. Day 1 - Day 8
Secondary Outcome 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. Day 1 - Day 8
Secondary Outcome 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. Day 1 - Day 8
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Centre Hospitalier du Mont Amba Universite de Kinshasa Kinsasha BP 7948 Democratic Republic of the Congo
Centre de Recherches Medicales de Centre de Recherches Medicales de Lambarene BP 242 Gabon
Formation Sanitaire a Base Pasteur Institute of Ivory Coast Abidjan 01 BP 490 Cote Divoire
Hopital Regionale d Agboville Centre Hospitalier Regional d Agboville Institut National de Sante Publique Agboville BP 154 Cote Divoire
Malaria and Other Tropical Diseases University of Ilorin Ilorin 240 Nigeria
Rinda Ubuzima Rwanda Military Hosp CMHS KG 11 Avenue 47 Remera Campus Kigali BP 4560 Rwanda
Nirmal Hospital Pvt Ltd Ring Road Sagrampura Surat 395002 India
Community Welfare Society Hospital Northen Avenue Jagda Rourkela 769042 India
AIIMS Raipur GE Road Tatibandh Raipur 492099 India
Infectious Diseases Research Collaboration Tororo Hospital Station Road Tororo 749 Uganda
KEMRI Siaya Clinical Research Annexe Siaya District Siaya 2300 Kenya
Investigacao em Saiude de Manhica Rua 12 Bairro Cambeve Manhica Mozambique
Centre National de Recherche et de Formation sur le Paludisme Rue 1487, Avenue Kunda Yonre Ouagadougou 01 2208 Burkina Faso
Groupe de Recherche Actions en Sante 06 BP 10248 Ouagadougou 10248 Burkina Faso
FUNDING SOURCES
Name of source Street address City Postal code Country
Welcome Trust Gibbs Building, 215 Euston Road London NW1 2BE United Kingdom
European and Developing Countries Clinical Trials Partnership EDCTP Tygerberg Cape Town 19070 South Africa
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Novartis Pharma AG Lichtstrasse 35 Basel CH-4056 Switzerland Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
Welcome Trust Gibbs Building, 215 Euston Road London NW1 2BE United Kingdom
European and Developing Countries Clinical Trials Partnership EDCTP Tygerberg Capetown 19070 South Africa
Medicines for Malaria Venture 20 Route de Pre-Bois Geneva 15 1215 Switzerland
CONTACT PEOPLE
Role Name Email Phone Street address
Public Enquiries Kanan Jhala kanan.jhala@novartis.com +917032917059 Salarpuria-Sattva Knowledge City, Inorbit Mall Rd, Durgam Cheruvu Rd, HITEC City
City Postal code Country Position/Affiliation
Hyderabad 500081 India Global Trial Director
Role Name Email Phone Street address
Scientific Enquiries Esther Schmitt esther.schmitt@novartis.com +41798230213 Novartis Campus, Novartis Pharma AG
City Postal code Country Position/Affiliation
Basel 4056 Switzerland Clinical Development Director
Role Name Email Phone Street address
Principal Investigator To be decided To be decided xxx.yyyo@zzz.ww +243990024201 To be decided
City Postal code Country Position/Affiliation
To be dicided Democratic Republic of the Congo Principal Investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. Study Protocol This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com 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 patients who have participated in the trial in line with applicable laws and regulations.
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