Efficacy, Safety and Tolerability of KLU156 in Adults and Children ≥ 5 kg Body Weight With Uncomplicated P. Falciparum Malaria (KALUMA)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Uncomplicated Plasmodium Falciparum Malaria
• Intervention / Treatment: Drug: KLU156; Drug: Coartem

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.

• Study Type: Interventional
• Enrollment (Estimated): 1500
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: +41613241111; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals

Study Locations

• Congo, The Democratic Republic of the
  • Kongo Central
    • Kisantu, Kongo Central, Congo, The Democratic Republic of the
      • Recruiting
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: KLU156; KLU156 once daily (QD) for 3 days under fed conditions (light meal).	Drug: KLU156; Oral use. KLU156 (400/480 mg) is the dose for patients with a bodyweight ≥ 35kg. Patients < 35kg will take a fraction of the dose according to weight group as defined in the protocol.
Active Comparator: Coartem; Coartem twice a day (BID) for 3 days under fed conditions.	Drug: Coartem; Oral use. Dosing will be selected based on patient's body weight as per product's label.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PCR-corrected adequate clinical and parasitological response (ACPR)	To confirm the efficacy of KLU156 in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) by demonstrating that KLU156 is non-inferior to Coartem (non-inferiority margin = 5%) based on the PCR-corrected ACPR at Day 29.	Day 29 (i.e., 28 days post-first dose administration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs), and laboratory results qualifying and reported as AEs.	Day 43
PCR-corrected and uncorrected ACPR	To confirm the efficacy of KLU156 by assessing uncorrected and PCR-corrected ACPR at additional time points	Days 22 and 43 (i.e., 21 and 42 days post-first dose administration)
Uncorrected ACPR	To further confirm the efficacy of KLU156 by demonstrating non-inferiority of KLU156 to Coartem (NI margin 7.5%) based on the uncorrected ACPR at Day 29	Day 29
Fever Clearance Time	To confirm the efficacy of KLU156 by assessing fever clearance between the two treatment arms	Up to Day 3
Parasite Clearance Time	To assess parasite clearance time between the two treatment arms	Up to Day 3
Incidence rate of recrudescence and new infection	Proportion of patients with recrudescence and new infections between the two treatment arms	Days 22, 29 and 43
Proportion of patients with parasitemia	For the parasitemia assessment, blood sampling can be done by means of a finger prick except when the timing for parasitology assessments coincides with time for clinical laboratory tests, in which case, blood sample can be taken from the venous blood collected for clinical laboratory analyses.	12, 24, 48 and 72 hours after treatment
Gametocytemia	Disappearance or development of gametocytemia in patients with or without gametocytemia at baseline (pre-first dose administration), respectively	From baseline up to Day 43
Extension phase: PCR-corrected and uncorrected ACPR	To evaluate efficacy over repeated treatment with KLU156 in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) for a maximum of 2 years	Day 29 of malaria episode
Extension phase: KLU156-related AE/SAE incidence and severity by malaria episode	To assess the safety and tolerability over repeated treatment with KLU156 in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) for a maximum of 2 years	Up to 2 years
Extension phase: Gametocyte carriage over time	To assess gametocyte carriage over time by malaria episode in the extension phase	Up to 2 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: MMV, EDCTP, WANECAM

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2024
• Primary Completion (Estimated): July 7, 2025
• Study Completion (Estimated): August 11, 2027

Study Registration Dates

• First Submitted: April 24, 2023
• First Submitted That Met QC Criteria: May 3, 2023
• First Posted (Actual): May 6, 2023

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Plasmodium falciparum; malaria; artemether; lumefantrine; Coartem; ganaplacide; KLU156
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Body Weight; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Artemether, Lumefantrine Drug Combination
• Other Study ID Numbers: CKLU156A12301; 2022-002675-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No