Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria.

• ClinicalTrials.gov Identifier: NCT03334747
• Recruitment Status: Completed
• First Posted: November 7, 2017
• Results First Posted: September 25, 2020
• Last Update Posted: October 11, 2021
• Sponsor: Novartis Pharmaceuticals
• Collaborator: Supported by Wellcome Trust via Grant # Grant Number 207813/Z/17/Z
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease	Intervention/treatment	Phase
Malaria	Drug: KAE609; Drug: Coartem	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 188 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: November 16, 2017
• Actual Primary Completion Date: November 23, 2019
• Actual Study Completion Date: November 23, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment arm 1: KAE609 10 mg Single Dose (SD); KAE609 10 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Name: Cipargamin
Experimental: Treatment arm 2:KAE609 25 mg SD; KAE609 25 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Name: Cipargamin
Experimental: Treatment arm 3:KAE609 10 mg 3 Days; KAE609 10 mg (QD) for 3 days	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Name: Cipargamin
Experimental: Treatment arm 4:KAE609 50 mg SD; KAE609 50 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Name: Cipargamin
Experimental: Treatment arm 5:KAE609 25 mg 3 Days; KAE609 25 mg once daily (QD) for 3 days	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Name: Cipargamin
Experimental: Treatment arm 6:KAE609 75 mg SD; KAE609 75 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Name: Cipargamin
Experimental: Treatment arm 7:KAE609 50 mg 3 Days; KAE609 50 mg once daily (QD) for 3 days	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Name: Cipargamin
Experimental: Treatment arm 8: KAE609 150 mg SD; KAE609 150 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Name: Cipargamin
Active Comparator: Treatment arm 9: Coartem Control; Coartem® control	Drug: Coartem; Control Arm; Other Name: Artemether Lumefantrine

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) [ Time Frame: Day 29 ]
   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 :

1. Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 [ Time Frame: Day 15, 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.
2. Parasite Clearance Time (PCT) [ Time Frame: Day 29 ]
   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.
3. Fever Clearance Time (FCT) [ Time Frame: Day 29 ]
   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.
4. Time to Recrudescence and Reinfection at Study Day 29 [ Time Frame: 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.
5. Maximum Peak Observed Concentration (Cmax) [ Time Frame: Day 1, Day 3 ]
   Maximum Peak Observed Concentration (Cmax)
6. Tmax [ Time Frame: Day 1, Day 3 ]
   Tmax
7. AUC0-24 [ Time Frame: Day 1, Day 3 ]
   AUC0-24
8. Half-life (T^1/2) [ Time Frame: Upto day 15 post dose ]
   Half-life (T^1/2)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

KEY Inclusion Criteria:

1. Male and female patients ≥ 18 years with a body weight ≥ 45 kg.
2. Microscopic confirmation of acute uncomplicated P. falciparum using by Giemsa-stained thick film.
3. P. falciparum parasitaemia of 500 to 50 000 parasites/µL.
4. Axillary temperature ≥ 37.5ºC or oral/tympanic/rectal temperature ≥ 38.0ºC; or history of fever during the previous 24 hours.
5. 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:

1. Mixed Plasmodium infections.
2. Signs and symptoms of severe malaria according to World Health Organization (WHO) 2016 criteria (WHO 2016).
3. 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.
4. Clinical or laboratory evidence of any of the following:
5. AST/ALT > 1.5 x the upper limit of normal range (ULN), regardless of the level of total bilirubin
6. AST/ALT > 1.0 and ≤ 1.5 x ULN and total bilirubin is > ULN
7. Total bilirubin > 2 x ULN, regardless of the level of AST/ALT
8. History of photodermatitis/increased sensitivity to sun.
9. Pregnant or nursing (lactating) women.
10. Known disturbances of electrolyte balance, e.g. hypokalemia, hypocalcemia or hypomagnesemia.
11. Moderate to severe anemia (Hemoglobin level <8 g/dL).

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

Gabon

Novartis Investigative Site

Lambarene, Gabon

Ghana

Novartis Investigative Site

Kintampo, Ghana

Novartis Investigative Site

Navrango, Ghana

Mali

Novartis Investigative Site

Bamako, Mali

Novartis Investigative Site

Sotuba, Mali

Rwanda

Novartis Investigative Site

Kigali, Rwanda

Uganda

Novartis Investigative Site

Bushenyi, Uganda

Novartis Investigative Site

Kampala, Uganda

Novartis Investigative Site

Tororo, Uganda

Sponsors and Collaborators

Novartis Pharmaceuticals

Supported by Wellcome Trust via Grant # Grant Number 207813/Z/17/Z

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] May 27, 2019

Statistical Analysis Plan  [PDF] April 7, 2020

More Information

Additional Information:

A Plain Language Trial Summary is available on novartisclinicaltrials.com 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03334747
• Other Study ID Numbers: CKAE609A2202; 207813/Z/17/Z ( Other Grant/Funding Number: Wellcome Trust )
• First Posted: November 7, 2017
• Results First Posted: September 25, 2020
• Last Update Posted: October 11, 2021
• Last Verified: October 2021

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 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

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

uncomplicated Plasmodium falciparum Malaria.

Additional relevant MeSH terms:

Malaria; Malaria, Falciparum; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents