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 DMC

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

Brief Summary

This study aims 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)

• PCR-corrected adequate clinical and parasitological response (ACPR) at Day 29 (i.e., 28 days post-dose) (Cohorts 1 and 2 pooled).

  The primary efficacy variable is the PCR corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 (Cohorts 1 and 2 pooled). In case that Cohort 2 stops early, such as after the first 24 patients, the study objectives will be assessed based on Cohort 1 data alone. A patient is considered as PCR corrected ACPR at Day 29 if the patient does not meet any of the criteria of early treatment failure (ETF) (up to Day 4), late clinical failure (LCF) (Day 5 to Day 29) or late parasitological failure (LPF) (Day 8 to Day 29), and is absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days (Day 8 or later) is due to reinfection based on PCR genotyping. A presence of parasitaemia after 7 days of treatment initiation is considered as a reinfection only if the parasitaemia is clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later match with the parasite strain at baseline based on PCR genotyping.

  Day 29

Secondary Outcomes (15)

• Percentage of Participants with Polymerase Chain Reaction (PCR)-corrected and uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and 43

  Day 15, Day 43

• Percentage of Participants with Polymerase Chain Reaction (PCR)-corrected and uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 (Run-in Cohort)

  Day 29

• Time to parasite clearance (PCT)

  up to 43 days

• Time to fever clearance (FCT)

  up to 43 days

• Proportion of patients with Early Treatment Failure (ETF)

  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 either a 2-day or 3-day dose regimen

EXPERIMENTAL

KAF156 and LUM-SDF QD (once daily) in either a 2-day or 3-day dose regimen. Food recommendation will be issued after the Run-in Cohort based on efficacy, safety, tolerability and PK data).

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 (will be administered with food and doses will be based on patient's body weight as per product label).

Drug: Coartem

Interventions

KAF156 DRUG

Provided as 50 mg or 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 either a 2-day or 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 60 mg, 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 either a 2-day or 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® (dispersible tablets 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

Commune de La Kenya Lubumbashi, Du Haut Katanga, Democratic Republic of the Congo

Location

Novartis Investigative Site

Lambaréné, BP 242, Gabon

Location

Novartis Investigative Site

Kati, Mali

Location

Novartis Investigative Site

Sotouba, Mali

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

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

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: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a multicenter, open-label, randomized study in adolescents and children with confirmed uncomplicated P. falciparum malaria. This study will first explore the effect of food on lumefantrine and KAF156 PK in a Run-in Cohort of patients 12 to \< 18 years old with malaria caused by P. falciparum, before younger patients are assessed. Then, efficacy, safety and tolerability of the combination of KAF156 and LUM-SDF will be evaluated in younger patients, first in Cohort 1 of patients 2 to \< 12 years old and then in Cohort 2 of patients 6 months to \< 2 years old. Randomization is stratified by country for patients in the Run-in cohort, by age group (6 years to \<12 and 2 to \<6 years) and country in Cohort 1 and by country in Cohort 2.

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: September 25, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will share

Locations

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