Clinical trial NCT03167242: Efficacy and Safety of KAF156 in Combination With LUM-SDF in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria
Official title: A Phase 2 Interventional, Multicenter, Randomized Open Label Study to Determine the Effective and Tolerable Dose of KAF156 and Lumefantrine Solid Dispersion Formulation in Combination, Given Once Daily for 1, 2 and 3-days to Adults and Children With Uncomplicated Plasmodium Falciparum Malaria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Uncomplicated Plasmodium Falciparum Malaria
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Medicines for Malaria Venture
First posted: 2017-05-25
Enrollment: 524
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29
timeFrame: 28 days post first dose
measure: PK Run-in: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Treatment Dose (AUC0-24h) of KAF156
timeFrame: 0, 1, 3, 6, 12, 18 and 24 hours post-dose
Secondary outcomes:
measure: Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR)
timeFrame: 14, 28 and 42 days post first dose
measure: Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR)
timeFrame: 14 and 42 days post first dose
measure: Part A and Part B: Number of Participants With Recrudescence Events
timeFrame: 42 days post first dose
measure: Part A and Part B: Number of Participants With Reinfection Events
timeFrame: 42 days post first dose
measure: Part A and Part B: Fever Clearance Time (FCT)
timeFrame: 42 days post first dose
measure: PK Run-in, Part A and Part B: Parasite Clearance Time (PCT)
timeFrame: 42 days post first dose
measure: PK Run-in, Part A and Part B: Number of Participants With Parasitaemia
timeFrame: 12, 24 and 48 hours post last dose
measure: Part A and Part B: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Last Treatment Dose (AUC0-24h) of KAF156
timeFrame: 3, 6, 18 and 24 hours post last dose
measure: Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156
timeFrame: 3, 6, 18, 24, 27, 30, 48, 51, 54, 68, 72 and 168 hours post last dose
measure: PK Run-in and Part A: Elimination Half-life (T½) of KAF156
timeFrame: 0, 1, 3, 6, 12, 18, 24, 27, 30, 36, 48, 72, 96 and 168 hours post last dose
measure: PK Run-in and Part A (Cohorts 1 and 2): Time to Reach Maximum Blood Concentrations (Tmax) of KAF156
timeFrame: 0, 1, 3, 6, 12, 18, 24, 30, 48, 96 and 168 hours post last dose
Other outcomes:
Locations:
city: Nanoro
country: Burkina Faso
facility: Novartis Investigative Site
city: Lambarene
country: Gabon
facility: Novartis Investigative Site
city: Ranchi
country: India
facility: Novartis Investigative Site
state: Jharkhand
city: Kombewa
country: Kenya
facility: Novartis Investigative Site
city: Siaya
country: Kenya
facility: Novartis Investigative Site
city: Sotuba
country: Mali
facility: Novartis Investigative Site
city: Chokwe
country: Mozambique
facility: Novartis Investigative Site
city: Tak
country: Thailand
facility: Novartis Investigative Site
city: Masaka
country: Uganda
facility: Novartis Investigative Site
city: Tororo
country: Uganda
facility: Novartis Investigative Site
city: Binh Phuoc Province
country: Vietnam
facility: Novartis Investigative Site
state: VNM
Study officials:
affiliation: Novartis Pharmaceuticals
name: Study Director
role: STUDY_DIRECTOR
References: