Efficacy and Safety of KAF156 in Combination With LUM-SDF in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria

NCT03167242 | Completed Phase 2 Results DMC

• 2 other identifiers: CKAF156A22022020-003284-25
• Study Type: interventional
• Target: 524
• Locations: 9 countries
• Sites: 11

Brief Summary

This study was designed to determine the most effective and tolerable dose at the shortest dosing regimen of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in adult/adolescent and pediatric patients with uncomplicated Plasmodium falciparum malaria. There is unmet medical need for anti-malarial treatment with new mechanism of action to reduce probability of developing resistance, and for duration shorter than 3 days of treatment and/or reduced pill burden.

Conditions

Acute Uncomplicated Plasmodium Falciparum Malaria

Outcome Measures

Primary Outcomes (2)

• Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29

  PCR-corrected ACPR defined as the absence of parasitaemia was evaluated at Day 29 (i.e., 28 days post first dose) based on the short half-life of the study drugs. 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 Day 29 if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and was absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days was due to reinfection based on PCR. A presence of parasitaemia after 7 days of treatment initiation was considered as a reinfection only if the parasitaemia was clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later matched with the parasite strain at baseline based on PCR.

  28 days post first dose

• PK Run-in: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Treatment Dose (AUC0-24h) of KAF156

  Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. AUC0-24h was determined using non-compartmental methods.

  0, 1, 3, 6, 12, 18 and 24 hours post-dose

Secondary Outcomes (11)

• Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR)

  14, 28 and 42 days post first dose

• Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR)

  14 and 42 days post first dose

• Part A and Part B: Number of Participants With Recrudescence Events

  42 days post first dose

• Part A and Part B: Number of Participants With Reinfection Events

  42 days post first dose

• Part A and Part B: Fever Clearance Time (FCT)

  42 days post first dose

Study Arms (12)

Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day

EXPERIMENTAL

Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 day

EXPERIMENTAL

Participants received a single oral dose of KAF156 800 mg and LUM-SDF 960 mg

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 days

EXPERIMENTAL

Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 days

EXPERIMENTAL

Participants received KAF156 200 mg and LUM-SDF 480 mg once daily via oral administration for 3 days

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 days

EXPERIMENTAL

Participants received KAF156 400 mg and LUM-SDF 480 mg once daily via oral administration for 3 days

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 days

EXPERIMENTAL

Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part A - Cohort 7: Coartem

ACTIVE COMPARATOR

Participants received Coartem twice daily via oral administration for 3 days

Drug: Coartem

PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 day

EXPERIMENTAL

Participants received a single oral dose of KAF156 200 mg and LUM-SDF 960 mg

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day

EXPERIMENTAL

Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 days

EXPERIMENTAL

Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 days

EXPERIMENTAL

Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days

Drug: KAF156; Drug: Lumefantrine Solid Dispersion Formulation

Part B - Cohort 4: Coartem

ACTIVE COMPARATOR

Participants received Coartem twice daily via oral administration for 3 days

Drug: Coartem

Interventions

KAF156 DRUG

KAF156 comes in 100 mg tablets for oral administration. KAF156 was administered in combination with LUM-SDF once daily (QD) for 1, 2 or 3 days at 200 mg, 400 mg or 800 mg doses.

Also known as: KAF

PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 day; Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day; Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 day; Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 days; Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 days; Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 days; Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 days; Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day; Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 days; Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 days

Coartem DRUG

Coartem comes as 20/120 mg dispersible tablets or 80/480 mg tablets for oral administration. Coartem was administered twice daily for 3 days as active comparator.

Part A - Cohort 7: Coartem; Part B - Cohort 4: Coartem

Lumefantrine Solid Dispersion Formulation DRUG

LUM-SDF comes in 240 mg or 480 mg sachets for oral administration. LUM-SDF was administered in combination with KAF156 once daily (QD) for 1, 2 or 3 days at 480 mg or 960 mg doses.

Also known as: LUM-SDF and LUM

PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 day; Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day; Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 day; Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 days; Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 days; Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 days; Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 days; Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day; Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 days; Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 days

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A: male and female patients ≥ 12 years and with a body weight ≥ 35.0 kg. Part B: after determining the effective/tolerated doses and regimens in adolescent and adult patients, male and female patients ≥ 2 and \< 12 years and with a body weight ≥ 10.0 kg will be included.
• Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films.
• P. falciparum parasitaemia of more than 1000 and less than 150 000 parasites/µL at the time of pre-screening (i.e., Study Visit 1).
• Axillary temperature ≥ 37.5 ºC or oral/tympanic/rectal temperature ≥ 38.3 ºC; or similar history of fever during the previous 24 hours (history of fever must be documented).
• Written informed consent must be obtained before any assessment is performed. If the patient is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients \< 18 years old, who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines.

You may not qualify if:

• Mixed Plasmodium infections.
• Signs and symptoms of severe malaria according to WHO (World Health Organization) 2015 criteria unless characterized by high parasitaemia only.
• Patients with concurrent febrile illnesses (e.g., typhoid fever).
• Pregnant or nursing (lactating) women.
• Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia.
• Anemia (Hemoglobin level \< 8 g/dL).
• Patients with prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five (5) plasma half-lives (or within 4 weeks of screening if half-life is unknown).
• History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc (heart rate-corrected QT) interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease.
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, 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 \> 2 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• Medicines for Malaria Venture: collaborator

Study Sites (11)

Novartis Investigative Site

Nanoro, Burkina Faso

Location

Novartis Investigative Site

Lambaréné, Gabon

Location

Novartis Investigative Site

Ranchi, Jharkhand, 834009, India

Location

Novartis Investigative Site

Kombewa, Kenya

Location

Novartis Investigative Site

Siaya, 2300, Kenya

Location

Novartis Investigative Site

Sotouba, Mali

Location

Novartis Investigative Site

Chokwé, Mozambique

Location

Novartis Investigative Site

Tak, 63140, Thailand

Location

Novartis Investigative Site

Masaka, Uganda

Location

Novartis Investigative Site

Tororo, Uganda

Location

Novartis Investigative Site

Binh Phuoc Province, VNM, 830000, Vietnam

Location

Related Publications (2)

• Sangana R, Ogutu B, Yeka A, Kusemererwa S, Tinto H, Toure AO, Kibuuka A, Lingani M, Lourenco C, Mombo-Ngoma G, Nduba V, Landry N'Guessan T, Nassa GJW, Nyantaro M, Tina LO, Anvikar A, Sinha A, Kaguthi G, Fofana B, Grobusch MP, Gaaloul ME, Marrast AC, Pathan R, Chikoto H, Csermak K, Risterucci C, Su G, Winnips C, Zhang J, Zack J. Pharmacokinetics of Ganaplacide and Lumefantrine in Adults, Adolescents, and Children with Plasmodium falciparum Malaria Treated with Ganaplacide Plus Lumefantrine Solid Dispersion Formulation: Analysis of Data from a Multinational Phase 2 Study. J Clin Pharmacol. 2025 Feb;65(2):179-189. doi: 10.1002/jcph.6138. Epub 2024 Sep 29.

  PMID: 39344281 DERIVED

• 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

Interventions

ganaplacide; Artemether, Lumefantrine Drug Combination

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

• Study Director

  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
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 19, 2017
• First Posted: May 25, 2017
• Study Start: August 2, 2017
• Primary Completion: June 14, 2021
• Study Completion: June 28, 2021
• Last Updated: February 10, 2022
• Results First Posted: February 10, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will share

Locations

GA (1); MO (1); VN (1); UG (2); TH (1); BU (1); IN (1); KE (2); MA (1)