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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Uncomplicated Plasmodium Falciparum Malaria
• Intervention / Treatment: Drug: KAF156; Drug: LUM-SDF; Drug: Coartem

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 295
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: +41613241111; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals

Study Locations

• Burkina Faso
  • Banfora, Burkina Faso
    • Recruiting
    • Novartis Investigative Site
  • Bobo Dioulasso, Burkina Faso, 01
    • Recruiting
    • Novartis Investigative Site
  • Ouagadougou, Burkina Faso
    • Recruiting
    • Novartis Investigative Site
  • Sabou, Burkina Faso, 06 BP 10248
    • Recruiting
    • Novartis Investigative Site
• Gabon
  • Lambarene, Gabon, BP 242
    • Recruiting
    • Novartis Investigative Site
• Mali
  • Kati, Mali
    • Recruiting
    • Novartis Investigative Site
  • Sotuba, Mali
    • Recruiting
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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
2. Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films
3. 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
4. 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)
5. 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
6. 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:

1. Mixed Plasmodium infections as per light microscopy results
2. Signs and symptoms of severe malaria according to WHO 2015 (see Section 16.4)
3. Significant, non-plasmodial co-infections including tuberculosis
4. Patients with concurrent febrile illnesses (e.g., typhoid fever, known or suspected COVID19)
5. 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
6. Major congenital defects
7. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection or family history of congenital or hereditary immunodeficiency
8. 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)
9. 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)
10. Active duodenal ulcer, ulcerative colitis, Crohn's disease, chronic (i.e., > 2 weeks) use of non-steroidal anti-inflammatory drugs (NSAIDs)
11. Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia
12. Anemia (hemoglobin level <7 g/dL)

13. 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
14. Resting QT interval corrected by Fridericia's formula (QTcF) > 450 ms at screening
15. Creatinine > 2 x ULN in the absence of dehydration. In case of dehydration, creatinine should be < 2 x ULN after oral/parenteral rehydration
16. Any severe disease condition which might prohibit participation in this study
17. Known chronic underlying disease such as sickle cell disease, and severe cardiac, renal, or hepatic impairment
18. Known active or uncontrolled thyroid disease
19. Inability to swallow oral medication (in tablet and/or liquid form)
20. 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)
21. Use of other investigational drugs within 30 days of dosing or until the expected pharmacodynamic effect has returned to baseline, whichever is longer
22. Patients taking medications prohibited by the protocol
23. Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance within 3 months of dosing
24. 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
25. Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study

26. 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:

27. Pregnant or nursing (lactating) patients

28. 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:

29. Patients of child bearing potential, defined as all girls post first menarche (except for Run-in Cohort)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP)
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2021
• Primary Completion (Estimated): May 28, 2024
• Study Completion (Estimated): June 14, 2024

Study Registration Dates

• First Submitted: September 5, 2020
• First Submitted That Met QC Criteria: September 5, 2020
• First Posted (Actual): September 14, 2020

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 8, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: children; Plasmodium falciparum malaria; KAF156; Lumefantrine Solid Dispersion Formulation; LUM-SDF
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Lumefantrine; Artemether, Lumefantrine Drug Combination
• Other Study ID Numbers: CKAF156A2203; 2021-003583-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is commited to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No