Back to resultsSafety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria.
Primary Purpose
Malaria
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
KAE609
Coartem
Sponsored by
About this trial
This is an interventional treatment trial for Malaria focused on measuring uncomplicated Plasmodium falciparum Malaria.
Eligibility Criteria
KEY Inclusion Criteria:
- Male and female patients ≥ 18 years with a body weight ≥ 45 kg.
- Microscopic confirmation of acute uncomplicated P. falciparum using by Giemsa-stained thick film.
- P. falciparum parasitaemia of 500 to 50 000 parasites/µL.
- Axillary temperature ≥ 37.5ºC or oral/tympanic/rectal temperature ≥ 38.0ºC; or history of fever during the previous 24 hours.
- Written informed consent must be obtained before any study assessment is performed. If the patient is unable to write, then a witnessed consent according to local ethical standards is permitted.
KEY Exclusion Criteria:
- Mixed Plasmodium infections.
- Signs and symptoms of severe malaria according to World Health Organization (WHO) 2016 criteria (WHO 2016).
- Known liver abnormalities, liver cirrhosis (compensated or decompensated), known active or history of hepatitis B or C (testing not required), known gallbladder or bile duct disease, acute or chronic pancreatitis.
- Clinical or laboratory evidence of any of the following:
- AST/ALT > 1.5 x the upper limit of normal range (ULN), regardless of the level of total bilirubin
- AST/ALT > 1.0 and ≤ 1.5 x ULN and total bilirubin is > ULN
- Total bilirubin > 2 x ULN, regardless of the level of AST/ALT
- History of photodermatitis/increased sensitivity to sun.
- Pregnant or nursing (lactating) women.
- Known disturbances of electrolyte balance, e.g. hypokalemia, hypocalcemia or hypomagnesemia.
- Moderate to severe anemia (Hemoglobin level <8 g/dL).
Other protocol-defined inclusion/exclusion criteria may apply
Sites / Locations
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Active Comparator
Arm Label
Treatment arm 1: KAE609 10 mg Single Dose (SD)
Treatment arm 2:KAE609 25 mg SD
Treatment arm 3:KAE609 10 mg 3 Days
Treatment arm 4:KAE609 50 mg SD
Treatment arm 5:KAE609 25 mg 3 Days
Treatment arm 6:KAE609 75 mg SD
Treatment arm 7:KAE609 50 mg 3 Days
Treatment arm 8: KAE609 150 mg SD
Treatment arm 9: Coartem Control
Arm Description
KAE609 10 mg once daily (QD) for 1 day
KAE609 25 mg once daily (QD) for 1 day
KAE609 10 mg (QD) for 3 days
KAE609 50 mg once daily (QD) for 1 day
KAE609 25 mg once daily (QD) for 3 days
KAE609 75 mg once daily (QD) for 1 day
KAE609 50 mg once daily (QD) for 3 days
KAE609 150 mg once daily (QD) for 1 day
Coartem® control
Outcomes
Primary Outcome Measures
Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)
The occurrence of at least 2 CTCAE grades increase from baseline in ALT or AST during the 4 weeks study period was evaluated to characterize hepatic safety aspects of single and multiple ascending doses of KAE609 in adult malaria subjects for treatment of uncomplicated malaria caused by plasmodium falciparum. If 2 patients in a 10 patient cohort (Cohorts 1 and 2) or 3 patients in a 20 patient cohort (Cohorts 3, 4 and 5) had at least 2 CTCAE grades increase from Baseline in ALT or AST, recruitment was suspended and a review of liver safety (and any other relevant data) by safety review committee was initiated. Any further progression of the study was based on the decision by the safety review committee.
Secondary Outcome Measures
Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29
PCR-corrected and PCR-uncorrected were evaluated at Days 15 and 29 (i.e., 14 and 28 days post-dose). The presence of parasitaemia after 7 days due to reinfection was considered as PCR-corrected ACPR. Missing blood smear data at Day 15 visit and thereafter were not considered as responder for the visit unless there was a later blood smear test indicating no parasitaemia.
Parasite Clearance Time (PCT)
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 48 hours. In case a patient received rescue medication before (parasite) clearance, the time to event was censored at the first use of rescue medication.
Fever Clearance Time (FCT)
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. In case a patient received rescue medication before (fever) clearance, the time to event was censored at the first use of rescue medication.
Time to Recrudescence and Reinfection at Study Day 29
Time to recrudescence is calculated from the date of first study medication to the date of first event. Participants without recrudescence/reinfection after Day 7 are censored at the time of treatment failure or at the time of last parasite assessment if no treatment failure occured.
Maximum Peak Observed Concentration (Cmax)
Maximum Peak Observed Concentration (Cmax)
Tmax
Tmax
AUC0-24
AUC0-24
Half-life (T^1/2)
Half-life (T^1/2)
Full Information
NCT ID
NCT03334747
First Posted
October 27, 2017
Last Updated
October 7, 2021
Sponsor
Novartis Pharmaceuticals
Collaborators
Supported by Wellcome Trust via Grant # Grant Number 207813/Z/17/Z
1. Study Identification
Unique Protocol Identification Number
NCT03334747
Brief Title
Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria.
Official Title
A Phase 2, Multi-center, Randomized, Open-label, Dose-escalation Study to Determine Safety of Single (QD) and Multiple (3 QD) Doses of KAE609, Given to Adults With Uncomplicated Plasmodium Falciparum Malaria.
Study Type
Interventional
2. Study Status
Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
November 16, 2017 (Actual)
Primary Completion Date
November 23, 2019 (Actual)
Study Completion Date
November 23, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
Collaborators
Supported by Wellcome Trust via Grant # Grant Number 207813/Z/17/Z
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
KAE609 will be evaluated primarily for hepatic safety of single and multiple doses in sequential cohorts with increasing doses.This study aims to determine the maximum safe dose of the investigational drug KAE609 in malaria patients.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria
Keywords
uncomplicated Plasmodium falciparum Malaria.
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Patients were randomized to KAE609 and Coartem in parallel treatment arms. Increasing doses of KAE609 (single dose and multiple dose) were evaluated in dose escalated manner in sequential cohorts
Masking
None (Open Label)
Allocation
Randomized
Enrollment
188 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment arm 1: KAE609 10 mg Single Dose (SD)
Arm Type
Experimental
Arm Description
KAE609 10 mg once daily (QD) for 1 day
Arm Title
Treatment arm 2:KAE609 25 mg SD
Arm Type
Experimental
Arm Description
KAE609 25 mg once daily (QD) for 1 day
Arm Title
Treatment arm 3:KAE609 10 mg 3 Days
Arm Type
Experimental
Arm Description
KAE609 10 mg (QD) for 3 days
Arm Title
Treatment arm 4:KAE609 50 mg SD
Arm Type
Experimental
Arm Description
KAE609 50 mg once daily (QD) for 1 day
Arm Title
Treatment arm 5:KAE609 25 mg 3 Days
Arm Type
Experimental
Arm Description
KAE609 25 mg once daily (QD) for 3 days
Arm Title
Treatment arm 6:KAE609 75 mg SD
Arm Type
Experimental
Arm Description
KAE609 75 mg once daily (QD) for 1 day
Arm Title
Treatment arm 7:KAE609 50 mg 3 Days
Arm Type
Experimental
Arm Description
KAE609 50 mg once daily (QD) for 3 days
Arm Title
Treatment arm 8: KAE609 150 mg SD
Arm Type
Experimental
Arm Description
KAE609 150 mg once daily (QD) for 1 day
Arm Title
Treatment arm 9: Coartem Control
Arm Type
Active Comparator
Arm Description
Coartem® control
Intervention Type
Drug
Intervention Name(s)
KAE609
Other Intervention Name(s)
Cipargamin
Intervention Description
Exploration of different doses of KAE609 to establish safety profile.
Intervention Type
Drug
Intervention Name(s)
Coartem
Other Intervention Name(s)
Artemether Lumefantrine
Intervention Description
Control Arm
Primary Outcome Measure Information:
Title
Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)
Description
The occurrence of at least 2 CTCAE grades increase from baseline in ALT or AST during the 4 weeks study period was evaluated to characterize hepatic safety aspects of single and multiple ascending doses of KAE609 in adult malaria subjects for treatment of uncomplicated malaria caused by plasmodium falciparum. If 2 patients in a 10 patient cohort (Cohorts 1 and 2) or 3 patients in a 20 patient cohort (Cohorts 3, 4 and 5) had at least 2 CTCAE grades increase from Baseline in ALT or AST, recruitment was suspended and a review of liver safety (and any other relevant data) by safety review committee was initiated. Any further progression of the study was based on the decision by the safety review committee.
Time Frame
Day 29
Secondary Outcome Measure Information:
Title
Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29
Description
PCR-corrected and PCR-uncorrected were evaluated at Days 15 and 29 (i.e., 14 and 28 days post-dose). The presence of parasitaemia after 7 days due to reinfection was considered as PCR-corrected ACPR. Missing blood smear data at Day 15 visit and thereafter were not considered as responder for the visit unless there was a later blood smear test indicating no parasitaemia.
Time Frame
Day 15, Day 29
Title
Parasite Clearance Time (PCT)
Description
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 48 hours. In case a patient received rescue medication before (parasite) clearance, the time to event was censored at the first use of rescue medication.
Time Frame
Day 29
Title
Fever Clearance Time (FCT)
Description
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. In case a patient received rescue medication before (fever) clearance, the time to event was censored at the first use of rescue medication.
Time Frame
Day 29
Title
Time to Recrudescence and Reinfection at Study Day 29
Description
Time to recrudescence is calculated from the date of first study medication to the date of first event. Participants without recrudescence/reinfection after Day 7 are censored at the time of treatment failure or at the time of last parasite assessment if no treatment failure occured.
Time Frame
Day 29
Title
Maximum Peak Observed Concentration (Cmax)
Description
Maximum Peak Observed Concentration (Cmax)
Time Frame
Day 1, Day 3
Title
Tmax
Description
Tmax
Time Frame
Day 1, Day 3
Title
AUC0-24
Description
AUC0-24
Time Frame
Day 1, Day 3
Title
Half-life (T^1/2)
Description
Half-life (T^1/2)
Time Frame
Upto day 15 post dose
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
KEY Inclusion Criteria:
Male and female patients ≥ 18 years with a body weight ≥ 45 kg.
Microscopic confirmation of acute uncomplicated P. falciparum using by Giemsa-stained thick film.
P. falciparum parasitaemia of 500 to 50 000 parasites/µL.
Axillary temperature ≥ 37.5ºC or oral/tympanic/rectal temperature ≥ 38.0ºC; or history of fever during the previous 24 hours.
Written informed consent must be obtained before any study assessment is performed. If the patient is unable to write, then a witnessed consent according to local ethical standards is permitted.
KEY Exclusion Criteria:
Mixed Plasmodium infections.
Signs and symptoms of severe malaria according to World Health Organization (WHO) 2016 criteria (WHO 2016).
Known liver abnormalities, liver cirrhosis (compensated or decompensated), known active or history of hepatitis B or C (testing not required), known gallbladder or bile duct disease, acute or chronic pancreatitis.
Clinical or laboratory evidence of any of the following:
AST/ALT > 1.5 x the upper limit of normal range (ULN), regardless of the level of total bilirubin
AST/ALT > 1.0 and ≤ 1.5 x ULN and total bilirubin is > ULN
Total bilirubin > 2 x ULN, regardless of the level of AST/ALT
History of photodermatitis/increased sensitivity to sun.
Pregnant or nursing (lactating) women.
Known disturbances of electrolyte balance, e.g. hypokalemia, hypocalcemia or hypomagnesemia.
Moderate to severe anemia (Hemoglobin level <8 g/dL).
Other protocol-defined inclusion/exclusion criteria may apply
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Lambarene
Country
Gabon
Facility Name
Novartis Investigative Site
City
Kintampo
Country
Ghana
Facility Name
Novartis Investigative Site
City
Navrango
Country
Ghana
Facility Name
Novartis Investigative Site
City
Bamako
Country
Mali
Facility Name
Novartis Investigative Site
City
Sotuba
Country
Mali
Facility Name
Novartis Investigative Site
City
Kigali
Country
Rwanda
Facility Name
Novartis Investigative Site
City
Bushenyi
Country
Uganda
Facility Name
Novartis Investigative Site
City
Kampala
Country
Uganda
Facility Name
Novartis Investigative Site
City
Tororo
Country
Uganda
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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 patients 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
Citations:
PubMed Identifier
34930267
Citation
Ndayisaba G, Yeka A, Asante KP, Grobusch MP, Karita E, Mugerwa H, Asiimwe S, Oduro A, Fofana B, Doumbia S, Jain JP, Barsainya S, Kullak-Ublick GA, Su G, Schmitt EK, Csermak K, Gandhi P, Hughes D. Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa. Malar J. 2021 Dec 20;20(1):478. doi: 10.1186/s12936-021-04009-1.
Results Reference
derived
PubMed Identifier
34410358
Citation
Schmitt EK, Ndayisaba G, Yeka A, Asante KP, Grobusch MP, Karita E, Mugerwa H, Asiimwe S, Oduro A, Fofana B, Doumbia S, Su G, Csermak Renner K, Venishetty VK, Sayyed S, Straimer J, Demin I, Barsainya S, Boulton C, Gandhi P. Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria. Clin Infect Dis. 2022 May 30;74(10):1831-1839. doi: 10.1093/cid/ciab716.
Results Reference
derived
Links:
URL
https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=726
Description
A Plain Language Trial Summary is available on novartisclinicaltrials.com
Learn more about this trial
Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria.
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