Clinical trial NCT03334747: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malaria
Keywords: uncomplicated Plasmodium falciparum Malaria.
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Wellcome Trust
First posted: 2017-11-07
Enrollment: 188
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)
timeFrame: Day 29
Secondary outcomes:
measure: Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29
timeFrame: Day 15, Day 29
measure: Parasite Clearance Time (PCT)
timeFrame: Day 29
measure: Fever Clearance Time (FCT)
timeFrame: Day 29
measure: Time to Recrudescence and Reinfection at Study Day 29
timeFrame: Day 29
measure: Maximum Peak Observed Concentration (Cmax)
timeFrame: Day 1, Day 3
measure: Tmax
timeFrame: Day 1, Day 3
measure: AUC0-24
timeFrame: Day 1, Day 3
measure: Half-life (T^1/2)
timeFrame: Upto day 15 post dose
Other outcomes:
Locations:
city: Lambarene
country: Gabon
facility: Novartis Investigative Site
city: Kintampo
country: Ghana
facility: Novartis Investigative Site
city: Navrango
country: Ghana
facility: Novartis Investigative Site
city: Bamako
country: Mali
facility: Novartis Investigative Site
city: Sotuba
country: Mali
facility: Novartis Investigative Site
city: Kigali
country: Rwanda
facility: Novartis Investigative Site
city: Bushenyi
country: Uganda
facility: Novartis Investigative Site
city: Kampala
country: Uganda
facility: Novartis Investigative Site
city: Tororo
country: Uganda
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
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.
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.