Efficacy, Safety and Tolerability of KAF156 in Combination With Lumefantrine Solid Dispersion Formulation (LUM-SDF) in Pediatric Population With Uncomplicated Plasmodium Falciparum Malaria

NCT04546633 | Completed Phase 2 Results DMC

• 2 other identifiers: CKAF156A22032021-003583-27
• Study Type: interventional
• Target: 295
• Locations: 5 countries
• Sites: 9

Brief Summary

This study aimed to determine the efficacy, safety and tolerability of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in pediatric patients (6 months to \< 18 years of age) with uncomplicated P. falciparum malaria. There is an unmet medical need for anti-malarial treatment with a new mechanism of action to reduce the probability of developing resistance.

Conditions

Uncomplicated Plasmodium Falciparum Malaria

Keywords

Plasmodium falciparum malaria; KAF156; Lumefantrine Solid Dispersion Formulation; LUM-SDF; children

Outcome Measures

Primary Outcomes (1)

• Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) - Cohorts 1 and 2 Pooled

  PCR-corrected ACPR, defined as the absence of parasitemia(PS), was evaluated on Day29. Microscopic species identification was confirmed and determined by PCR genotyping methods to establish malaria recrudescence/reinfection.A participant was considered as PCR corrected ACPR at Day29 if the participant did not meet any of the criteria of early treatment failure (up to Day4), late clinical failure(Day5 to Day29) or late parasitological failure(Day8 to Day29), and had absence of PS on Day29 irrespective of axillary temperature unless the presence of PS after 7days(Day8 or later) was due to reinfection based on PCR genotyping.A presence of PS after 7days of treatment initiation was considered as a reinfection only if the PS was clear before Day8 and none of the parasite strain(s) detected on Day8 or later match with the parasite strain at baseline based on PCR genotyping.Given the age-independent symptoms of acute malaria, and to increase statistical power,the cohorts 1 and 2 were pooled.

  Day 29

Secondary Outcomes (14)

• PCR-corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR)

  Corrected ACPR: Day 15, Day 43; Uncorrected ACPR: Day 15, Day 29 and Day 43

• PCR-corrected Adequate Clinical and Parasitological Response (ACPR) - Run-in Cohort

  Day 29

• Parasite Clearance Time (PCT)

  up to 43 days

• Fever Clearance Times (FCT)

  up to 43 days

• Percentage Early Treatment Failure (ETF)

  From Day 1 to Day 4

Study Arms (4)

Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition

EXPERIMENTAL

KAF156 and LUM-SDF QD (once daily) for 2 days in fasted condition

Drug: KAF156; Drug: LUM-SDF

Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition

EXPERIMENTAL

KAF156 and LUM-SDF QD (once daily) for 2 days in fed condition

Drug: KAF156; Drug: LUM-SDF

Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in 3-day dose regimen

EXPERIMENTAL

KAF156 and LUM-SDF QD (once daily) in 3-day dose regimen. It was administered with a light meal and the full dose was adjusted based on patient´s body weight.

Drug: KAF156; Drug: LUM-SDF

Cohort 1/2 - Coartem® BID (twice a day) for 3 days

ACTIVE COMPARATOR

Coartem® BID twice a day for 3 days (It was administered with a light meal and doses were based on patient's body weight as per product label).

Drug: Coartem

Interventions

KAF156 DRUG

Provided as 100 mg tablets, to be taken QD 2 or 3 Days in combination with LUM-SDF, dose is based on body weight

Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in 3-day dose regimen; Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition; Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition

LUM-SDF DRUG

Provided as 120 mg or 240 mg powder in sachet, to be taken QD 2 or 3 Days in combination with KAF156, dose is based on body weight

Also known as: Lumefantrine Solid Dispersion Formulation

Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in 3-day dose regimen; Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition; Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition

Coartem DRUG

Coartem® (Artemether/Lumefantrine dispersible tablets 20/120mg in blister pack) (for Cohorts 1 and 2), dose is based on body weight

Cohort 1/2 - Coartem® BID (twice a day) for 3 days

Eligibility Criteria

• Age: 6 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• In run-in cohort: Male and female patients 12 to \< 18 years of age, with a body weight
• kg In Cohort 1: Male and female patients 2 to \< 12 years of age, with a body weight ≥ 10.0 kg In Cohort 2: Male and female patients 6 months to \< 2 years of age, with a body weight
• Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films
• P. falciparum parasitemia of ≥ 1,000 and ≤ 150,000 parasites/μL at the time of prescreening for the Run-in Cohort; and P. falciparum parasitemia of ≥ 1,500 and ≤ 150,000 parasites/μL at the time of pre-screening for Cohorts 1 and 2
• Axillary temperature ≥ 37.5 ºC or oral/tympanic/rectal temperature ≥ 38.0 ºC; or history of fever during the previous 24 hours (at least documented verbally)
• Written informed consent has been obtained from parent / legal guardian before any assessment is performed. 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 assent with parental/legal guardian consent or as per local ethical guidelines
• The patient and his/her 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

You may not qualify if:

• Mixed Plasmodium infections as per light microscopy results
• Signs and symptoms of severe malaria according to WHO 2015 (see Section 16.4)
• Significant, non-plasmodial co-infections including tuberculosis
• Patients with concurrent febrile illnesses (e.g., typhoid fever, known or suspected COVID19)
• Known relevant liver disease e.g. chronic hepatitis, cirrhosis, compensated or decompensated, history of hepatitis B or C, hepatitis B or A vaccination in last 3 months, known gallbladder or bile duct disease, acute or chronic pancreatitis
• Major congenital defects
• Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection or family history of congenital or hereditary immunodeficiency
• Immunosuppressive therapy (steroids, immune modulators or immune suppressors) within 3 months prior to recruitment. (For corticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topical steroids are allowed)
• Active duodenal ulcer, ulcerative colitis, Crohn's disease, chronic (i.e., \> 2 weeks) use of non-steroidal anti-inflammatory drugs (NSAIDs)
• Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia
• Anemia (hemoglobin level \<7 g/dL)
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (e.g., HIV patients on ART therapy or TB patients on treatment), or which may jeopardize the patient in case of participation in the study. The investigator should make this determination in consideration of the patient's medical history and/or clinical or laboratory evidence of any of the following:
• AST/ALT \> 3 x the upper limit of normal range (ULN), regardless of the level of total bilirubin
• AST/ALT \> 1.5 and ≤ 2 x ULN and total bilirubin is \> ULN Total bilirubin \> 2 x ULN regardless of the level of AST/ALT
• Resting QT interval corrected by Fridericia's formula (QTcF) \> 450 ms at screening

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• European and Developing Countries Clinical Trials Partnership (EDCTP): collaborator

Study Sites (9)

Novartis Investigative Site

Banfora, Burkina Faso

Location

Novartis Investigative Site

Bobo-Dioulasso, 01, Burkina Faso

Location

Novartis Investigative Site

Ouagadougou, Burkina Faso

Location

Novartis Investigative Site

Sabou, 06 BP 10248, Burkina Faso

Location

Novartis Investigative Site

Abidjan, 13BP972, Côte d’Ivoire

Location

Novartis Investigative Site

Lambaréné, BP 242, Gabon

Location

Novartis Investigative Site

Kati, Mali

Location

Novartis Investigative Site

Sotouba, Mali

Location

Novartis Investigative Site

Lubumbashi, Du Haut Katanga, 7010, Republic of the Congo

Location

Related Publications (1)

• Ogutu B, Yeka A, Kusemererwa S, Thompson R, Tinto H, Toure AO, Uthaisin C, Verma A, Kibuuka A, Lingani M, Lourenco C, Mombo-Ngoma G, Nduba V, N'Guessan TL, Nassa GJW, Nyantaro M, Tina LO, Singh PK, El Gaaloul M, Marrast AC, Chikoto H, Csermak K, Demin I, Mehta D, Pathan R, Risterucci C, Su G, Winnips C, Kaguthi G, Fofana B, Grobusch MP. Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial. Lancet Infect Dis. 2023 Sep;23(9):1051-1061. doi: 10.1016/S1473-3099(23)00209-8. Epub 2023 Jun 13.

  PMID: 37327809 DERIVED

MeSH Terms

Conditions

Malaria, Falciparum

Interventions

ganaplacide; Artemether, Lumefantrine Drug Combination

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Treatment and food condition during the Run-in cohort will be open to patients/patients' parents/legal guardian, investigators staff and study monitors, as well as to the Clinical Trial Team (CTT) to allow continuous review of safety, drug exposure and efficacy data in pediatric population. For Cohorts 1 and 2, treatment/food condition will be open to patients/patients' parents/legal guardian, investigators staff and study monitors but will be blinded to the Clinical Trial Team (CTT).
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 5, 2020
• First Posted: September 14, 2020
• Study Start: February 16, 2021
• Primary Completion: August 13, 2024
• Study Completion: August 28, 2024
• Last Updated: May 7, 2026
• Results First Posted: May 7, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

BU (4); GA (1); MA (2); CÔ (1); RE (1)