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

Study Overview
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Brief Summary
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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.

Detailed Description
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This Phase 2 study aims to evaluate the efficacy, safety and tolerability of the investigational drug KAF156 and a Solid Dispersion Formulation of lumefantrine (LUM-SDF) when administered in combination in pediatric patients 6 months to < 18 years of age with uncomplicated Plasmodium falciparum malaria. In addition, pharmacokinetics (PK) of the drug combination will also be evaluated. There will be three age-descending cohorts: Run-in Cohort, Cohort 1 and Cohort 2. It is important to understand the impact of food on exposure. In adult healthy volunteers, LUM-SDF alone has shown a food effect whereas KAF156 does not have a food effect. This new study will first explore the effect of food on lumefantrine and KAF156 PK in malaria 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.

Official Title
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A Phase 2 Interventional, Multicenter, Randomized, Open-label Study in Three Age-descending Cohorts to Evaluate Efficacy, Safety and Tolerability of KAF156 and Lumefantrine-SDF Combination in the Treatment of Acute Uncomplicated Plasmodium Falciparum Malaria in a Pediatric Population

Conditions
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Uncomplicated Plasmodium Falciparum Malaria

Intervention / Treatment
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* Drug: KAF156
* Drug: LUM-SDF
* Drug: Coartem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In run-in cohort: Male and female patients 12 to < 18 years of age, with a body weight 35.0 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 5.0 kg 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 Exclusion Criteria: 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) Repeated 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 in the 24 hours prior to inclusion in the study) 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 Creatinine > 2 x ULN in the absence of dehydration. In case of dehydration, creatinine should be < 2 x ULN after oral/parenteral rehydration Any severe disease condition which might prohibit participation in this study Known chronic underlying disease such as sickle cell disease, and severe cardiac, renal, or hepatic impairment Known active or uncontrolled thyroid disease Inability to swallow oral medication (in tablet and/or liquid form) 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) Use of other investigational drugs within 30 days of dosing or until the expected pharmacodynamic effect has returned to baseline, whichever is longer Patients taking medications prohibited by the protocol Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance within 3 months of dosing History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes For the Run-in Cohort only: Pregnant or nursing (lactating) patients Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of investigational drug. Basic contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment Male sterilization (at least 6 m prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps). Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug. Women are considered not of child bearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. For Cohorts 1 and 2 only: Patients of child bearing potential, defined as all girls post first menarche (except for Run-in Cohort)

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition<br>KAF156 and LUM-SDF QD (once daily) for 2 days in fasted condition | Drug: KAF156<br>* 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<br>Drug: LUM-SDF<br>* 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<br>* Other names: Lumefantrine Solid Dispersion Formulation;|
| Experimental: Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition<br>KAF156 and LUM-SDF QD (once daily) for 2 days in fed condition | Drug: KAF156<br>* 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<br>Drug: LUM-SDF<br>* 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<br>* Other names: Lumefantrine Solid Dispersion Formulation;|
| Experimental: Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in either a 2-day or 3-day dose regimen<br>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<br>* 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<br>Drug: LUM-SDF<br>* 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<br>* Other names: Lumefantrine Solid Dispersion Formulation;|
| Active Comparator: Cohort 1/2 - Coartem® BID (twice a day) for 3 days<br>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<br>* Coartem® (dispersible tablets in blister pack) (for Cohorts 1 and 2), dose is based on body weight<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Polymerase Chain Reaction (PCR)-corrected and uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and 43 | A blood draw will be performed at each collection time point for parasitemia assessment. | 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) | A blood draw will be performed at Day 29 in the Run-in Cohort only for parasitemia assessment. | Day 29 | 
| Time to parasite clearance (PCT) | Parasite Clearance Time (PCT) is defined as the time from the first dose until the first total and continued disappearance of asexual parasite forms which remained at least a further 48 hours. | up to 43 days | 
| Time to fever clearance (FCT) | Fever Clearance Time (FCT) is defined as the time from the first dose until the first time the axillary body temperature decreased below and remained below 37.5°C axillary or 38.0°C oral/tympanic/rectal for at least a further 24 hours. | up to 43 days | 
| Proportion of patients with Early Treatment Failure (ETF) | ETF is defined as: Development of danger signs or severe malaria on Day 2, Day 3, Day 4 in the presence of parasitemia Parasitemia on Day 3 higher than Day 1 count irrespective of axillary temperature Parasitemia on Day 4 with axillary temperature ≥ 37.5°C Parasitemia on Day 4 equals to or more than 25% of count on Day 1 | Day 1 to Day 4 | 
| Proportion of patients with Late Clinical Failure (LCF) | LCF is defined as: Development of danger signs or severe malaria on any day from Day 5 to Day 43 in the presence of parasitemia without previously meeting any of the criteria of ETF Presence of parasitemia and axillary temperature ≥ 37.5oC on any day from Day 5 to Day 43 without previously meeting any of the criteria of ETF | Day 5 to Day 43 | 
| Proportion of patients with Late Parasitological Failure (LPF) | LPF is defined as the presence of parasitemia on any day from Day 8 to Day 43 and axillary temperature < 37.5oC without previously meeting any of the criteria of ETF or LCF | Day 8 to Day 43 | 
| Incidence rate of recrudescence and reinfection | Time to event (recrudescence or reinfection) will be calculated from the time of first study medication to the date of first event if a patient experiences the event and be censored at the time of last parasite assessment if a patient does not experience the event due to whatever reason. Reinfection is defined as appearance of asexual parasites after clearance of initial infection with a genotype different from those parasites present at baseline. Recrudescence is defined as appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at baseline. Reinfection and Recrudescence must be confirmed by PCR analysis. | Day 15, Day 29 and Day 43 | 
| Number of Participants with On-Treatments Adverse Events, Serious Adverse Events, and Deaths | Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) to demonstrate that KAF156 and Lumefantrine-SDF combination, under fasted or fed conditions is safe through the monitoring of relevant clinical and laboratory safety parameters. | Day 1 to Day 43 | 
| Pharmacokinetics of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Area Under the Plasma Concentration-time Curve (AUC) | AUC is the area under the plasma concentration-time curve. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. | From Day 1 to Day 8 | 
| Pharmacokinetic of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Maximum Observed Plasma Concentration (Cmax) | Cmax is the maximum observed plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods. | From Day 1 to Day 8 | 
| Pharmacokinetic of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Time to reach the maximum concentration after drug administration (Tmax) | Tmax is the time to reach maximum plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods. | From Day 1 to Day 8 | 
| Pharmacokinetics of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Plasma drug concentration 168 hours post first dose administration (C168h) | C168h is the plasma concentration at 168h post first dose administration. | Day 8 | 
| Pharmacokinetics of LUM from Coartem arm (Cohorts 1 and 2): Maximum Observed Plasma Concentration (Cmax) | Cmax is the maximum observed plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods. | From Day 1 to Day 8 | 
| Pharmacokinetics of LUM from Coartem arm (Cohorts 1 and 2): Plasma drug concentration 168 hours post first dose administration (C168h) | C168h is the plasma concentration at 168h post first dose administration. | Day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plasmodium falciparum malaria, KAF156, Lumefantrine Solid Dispersion Formulation, LUM-SDF, children