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

NCT ID: NCT03167242

Last Updated: 2022-02-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 524 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-02
• Study Completion Date: 2021-06-28

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.

Detailed Description

This was a Phase 2 multi-center and open-label study with a single cohort pharmacokinetic (PK) Run-in Part followed by 2 randomized parallel-group parts, Part A and Part B, in adults and children with confirmed and uncomplicated Plasmodium falciparum malaria. Each part (PK Run-in, Part A and Part B) had the same design structure: A screening phase of up to 24 hours where participants were evaluated for eligibility and randomized (Part A and B) into different cohorts. A treatment phase of up to 3 days where participants were treated for 1, 2 or 3 consecutive days. Finally, participants were followed up until Day 43, where the rescue medication was the local standard at the discretion of the Investigator and participants

PK Run-in part: Adult/adolescent participants (≥ 12 years old) were dosed with a single dose of 200 mg KAF156 and 960 mg LUM-SDF at Day 1. The purpose of this part was to assess potential PK interactions between the compounds when dosed together.

Part A: Adult/adolescent participants (≥ 12 years old) were randomized into one of seven cohorts in a 2:2:2:2:2:2:1 ratio: six KAF156 and LUM-SDF cohorts at starting doses of 400 mg and 480 mg once daily (QD) for 1 day respectively and a control arm (Coartem twice a day (BID) for 3 days). Upon completion of Part A, all the dosing groups were evaluated in an interim assessment to determine the effective and tolerated KAF156 and LUM-SDF dosing regimen and dosages to be used in Part B.

Part B: Children participants (2 to < 12 years old) were randomized to three KAF156 and LUM-SDF cohorts at dosages and dosing regimens selected from Part A and the control arm (Coartem) in a 2:2:2:1 ratio.

Conditions

Acute Uncomplicated Plasmodium Falciparum Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

Part A - Cohort 7: Coartem

Participants received Coartem twice daily via oral administration for 3 days

Group Type: ACTIVE_COMPARATOR

Coartem

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

KAF156

Intervention Type: 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.

Lumefantrine Solid Dispersion Formulation

Intervention Type: 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.

Part B - Cohort 4: Coartem

Participants received Coartem twice daily via oral administration for 3 days

Group Type: ACTIVE_COMPARATOR

Coartem

Intervention Type: 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.

Interventions

KAF156

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.

Intervention Type: DRUG

Coartem

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.

Intervention Type: DRUG

Lumefantrine Solid Dispersion Formulation

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.

Intervention Type: DRUG

Other Intervention Names

KAF; LUM-SDF and LUM

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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).
• Severe vomiting, defined as more than 3 times in the 24 hours prior to inclusion in the study or severe diarrhea defined as more than 3 watery stools per day.
• 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

• Minimum Eligible Age: 2 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medicines for Malaria Venture

OTHER

Sponsor Role: collaborator

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Nanoro, , Burkina Faso

Novartis Investigative Site

Lambaréné, , Gabon

Novartis Investigative Site

Ranchi, Jharkhand, India

Novartis Investigative Site

Kombewa, , Kenya

Novartis Investigative Site

Siaya, , Kenya

Novartis Investigative Site

Sotouba, , Mali

Novartis Investigative Site

Chokwé, , Mozambique

Novartis Investigative Site

Tak, , Thailand

Novartis Investigative Site

Masaka, , Uganda

Novartis Investigative Site

Tororo, , Uganda

Novartis Investigative Site

Binh Phuoc Province, VNM, Vietnam

Countries

Burkina Faso; Gabon; India; Kenya; Mali; Mozambique; Thailand; Uganda; Vietnam

References

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.

Reference Type: DERIVED

PMID: 39344281 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37327809 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2020-003284-25

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CKAF156A2202

Identifier Type: -

Identifier Source: org_study_id