Clinical trial NCT05842954: Efficacy, Safety and Tolerability of KLU156 in Adults and Children ≥ 5 kg Body Weight With Uncomplicated P. Falciparum Malaria
Official title: A Randomized, Open-label, Multicenter Study to Compare Efficacy, Safety and Tolerability of KLU156 With Coartem® in the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Adults and Children ≥ 5 kg Body Weight Followed by an Extension Phase With Repeated KLU156 Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Uncomplicated Plasmodium Falciparum Malaria
Keywords: malaria
Plasmodium falciparum
KLU156
Coartem
artemether
lumefantrine
ganaplacide
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: MMV, EDCTP, WANECAM
First posted: 2023-05-06
Enrollment: 1500
Sex: ALL
Minimum age (years): 2
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to confirm the efficacy, safety and tolerability of KLU156, a fixed dose combination of ganaplacide (KAF156) and a solid dispersion formulation of lumefantrine (lumefantrine-SDF), when administered once daily for three days in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection).

In the Extension phase, the safety, tolerability and efficacy of repeated treatment with KLU156 will be assessed for a maximum of two years in patients who did not experience early treatment failure (ETF), who did not experience any study treatment-related SAE (Serious Adverse Event) previously and who gave informed consent to participate in the Extension phase.

Detailed description: The purpose of this study is to confirm the efficacy, safety and tolerability of KLU156 in patients with uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection) by demonstrating that KLU156 is non-inferior to Coartem.

* The study duration will be 43 days (Core phase) plus 24 months (Extension phase).
* The treatment duration will be 3 days for each malaria episode.
* The visit frequency will be Days 1-3 (hospitalized) and 5 follow-up visits (Days 4, 8, 22, 29 and 43) in the Core phase and Days 1-3 (hospitalized) and 3 follow-up visits (Days 4, 8 and 29) in the Extension phase.

Eligibility criteria: Key Inclusion criteria (Core phase)

1. Male or female patients ≥ 5 kg of body weight and ≥ 2 months of age
2. Microscopically confirmed diagnosis of uncomplicated P. falciparum malaria with an asexual P. falciparum parasitemia ≥ 1,000 and ≤ 200,000 parasites/µL at the time of pre-screening with or without other Plasmodium spp. co-infection.
3. Axillary temperature ≥ 37.5 ºC or oral temperature ≥ 38.0 ºC or tympanic/rectal temperature ≥ 38.5 ºC; or history of fever during the previous 24 hours (at least documented verbally)
4. Negative pregnancy test for patients of childbearing potential
5. Signed informed consent must be obtained before any assessment is performed; for minors, signed informed consent must be obtained from parent/legal guardian. If the parent/legal guardian is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients who are capable of providing assent, must provide it along with parent/legal guardian consent or as per local ethical standards
6. The patient and/or their parent/legal guardian is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned.

Key Exclusion criteria (Core phase)

1. Signs and symptoms of severe malaria according to WHO 2015 (World Health Organization)
2. Concurrent febrile illnesses (e.g., typhoid fever, known or suspected dengue fever, known COVID19)
3. Severe malnutrition. For patients ≥ 12 years: body mass index (BMI) \< 16.0. For children \< 12 years: less than 70% of median normalized WHO reference weight or very low mid-upper arm circumference (MUAC \< 115 mm)
4. Repeated vomiting (defined as \> 3 times in the 24 hours prior to start of screening) or severe diarrhea (defined as \> 3 watery stools in the 24 hours prior to start of screening)
5. Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia
6. Anemia (hemoglobin level \<7 g/dL)
7. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (e.g., Human immunodeficiency virus (HIV) patients on antiretroviral therapy (ART) or tuberculosis (TB) patients on treatment), or which may jeopardize the patient in case of participation in the study.
8. Any of the following:

   * Aspartate Aminotransferase/ Alanine Aminotransferase (AST/ALT) \> 3 x the upper limit of normal (ULN), regardless of the level of total bilirubin
   * Total bilirubin \> 3 x ULN
   * Resting QT interval corrected by Fridericia's formula (QTcF) \> 450 ms at screening
9. Prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five plasma half-lives (or within 4 weeks of screening if half-life is unknown)
10. History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease
11. Pregnant or nursing (lactating) patients.

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: PCR-corrected adequate clinical and parasitological response (ACPR)
timeFrame: Day 29 (i.e., 28 days post-first dose administration)
Secondary outcomes:
measure: PCR-corrected and uncorrected ACPR
timeFrame: Days 22 and 43 (i.e., 21 and 42 days post-first dose administration)
measure: Uncorrected ACPR
timeFrame: Day 29
measure: Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Day 43
measure: Fever Clearance Time
timeFrame: Up to Day 3
measure: Parasite Clearance Time
timeFrame: Up to Day 3
measure: Incidence rate of recrudescence and new infection
timeFrame: Days 22, 29 and 43
measure: Proportion of patients with parasitemia
timeFrame: 12, 24, 48 and 72 hours after treatment
measure: Gametocytemia
timeFrame: From baseline up to Day 43
measure: Extension phase: PCR-corrected and uncorrected ACPR
timeFrame: Day 29 of malaria episode
measure: Extension phase: KLU156-related AE/SAE incidence and severity by malaria episode
timeFrame: Up to 2 years
measure: Extension phase: Gametocyte carriage over time
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Banfora
country: Burkina Faso
facility: Novartis Investigative Site
city: Bobo Dioulasso
country: Burkina Faso
facility: Novartis Investigative Site
city: Nanoro
country: Burkina Faso
facility: Novartis Investigative Site
city: Ouagadougou
country: Burkina Faso
facility: Novartis Investigative Site
city: Sabou
country: Burkina Faso
facility: Novartis Investigative Site
city: Commune De La Kenya Lubumbashi
country: Congo, The Democratic Republic of the
facility: Novartis Investigative Site
state: Du Haut Katanga
city: Kimpese
country: Congo, The Democratic Republic of the
facility: Novartis Investigative Site
state: Kongo Central
city: Kisantu
country: Congo, The Democratic Republic of the
facility: Novartis Investigative Site
state: Kongo Central
city: Kenge
country: Congo, The Democratic Republic of the
facility: Novartis Investigative Site
state: Kwango
city: Masi Manimba
country: Congo, The Democratic Republic of the
facility: Novartis Investigative Site
state: Kwilu
city: Abidjan
country: Côte D'Ivoire
facility: Novartis Investigative Site
city: Agboville
country: Côte D'Ivoire
facility: Novartis Investigative Site
city: Azaguie
country: Côte D'Ivoire
facility: Novartis Investigative Site
city: Lambarene
country: Gabon
facility: Novartis Investigative Site
city: Libreville
country: Gabon
facility: Novartis Investigative Site
city: Kintampo
country: Ghana
facility: Novartis Investigative Site
city: Navrango
country: Ghana
facility: Novartis Investigative Site
city: Bhubaneswar
country: India
facility: Novartis Investigative Site
state: Odisha
city: Jaipur
country: India
facility: Novartis Investigative Site
state: Rajasthan
city: Darjeeling
country: India
facility: Novartis Investigative Site
state: West Bengal
city: Kombewa
country: Kenya
facility: Novartis Investigative Site
city: Nairobi
country: Kenya
facility: Novartis Investigative Site
city: Siaya
country: Kenya
facility: Novartis Investigative Site
city: Sotuba
country: Mali
facility: Novartis Investigative Site
city: Niamey
country: Niger
facility: Novartis Investigative Site
city: Gicumbi District Rwamiko
country: Rwanda
facility: Novartis Investigative Site
state: Northern Province
city: Kigali
country: Rwanda
facility: Novartis Investigative Site
city: Kigali
country: Rwanda
facility: Novartis Investigative Site
city: Rubavu
country: Rwanda
facility: Novartis Investigative Site
city: Rusizi
country: Rwanda
facility: Novartis Investigative Site
city: Bagamoyo
country: Tanzania
facility: Novartis Investigative Site
city: Korogwe Tanga
country: Tanzania
facility: Novartis Investigative Site
city: Tanga
country: Tanzania
facility: Novartis Investigative Site
city: Tororo
country: Uganda
facility: Novartis Investigative Site
city: Nchelenge
country: Zambia
facility: Novartis Investigative Site
state: Luapula
city: Ndola
country: Zambia
facility: Novartis Investigative Site
Study officials:
References: