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

Phase 2

Recruiting

• Conditions: Uncomplicated Plasmodium Falciparum Malaria
• Interventions: Drug: KAF156; Drug: Coartem; Drug: LUM-SDF

• Registration Number: NCT04546633
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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

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 Timeline

• Study First Submitted: 2020-09-05
• Study First Submitted QC: 2020-09-05
• Study First Posted: 2020-09-14
• Study Start: 2021-02-16
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-22
• Last Update Posted: 2024-07-23
• Primary Completion: 2024-08-19
• Study Completion: 2024-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 295

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition	KAF156	KAF156 and LUM-SDF QD (once daily) for 2 days in fasted condition
Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition	LUM-SDF	KAF156 and LUM-SDF QD (once daily) for 2 days in fasted condition
Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition	KAF156	KAF156 and LUM-SDF QD (once daily) for 2 days in fed condition
Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition	LUM-SDF	KAF156 and LUM-SDF QD (once daily) for 2 days in fed condition
Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in either a 2-day or 3-day dose regimen	LUM-SDF	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).
Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in either a 2-day or 3-day dose regimen	KAF156	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).
Cohort 1/2 - Coartem® BID (twice a day) for 3 days	Coartem	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).

Primary Outcome Measures

Name	Time	Method
PCR-corrected adequate clinical and parasitological response (ACPR) at Day 29 (i.e., 28 days post-dose) (Cohorts 1 and 2 pooled).	Day 29	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants with Polymerase Chain Reaction (PCR)-corrected and uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and 43	Day 15, Day 43	A blood draw will be performed at each collection time point for parasitemia assessment.
Percentage of Participants with Polymerase Chain Reaction (PCR)-corrected and uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 (Run-in Cohort)	Day 29	A blood draw will be performed at Day 29 in the Run-in Cohort only for parasitemia assessment.
Time to parasite clearance (PCT)	up to 43 days	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.
Time to fever clearance (FCT)	up to 43 days	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.
Proportion of patients with Late Clinical Failure (LCF)	Day 5 to Day 43	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
Proportion of patients with Late Parasitological Failure (LPF)	Day 8 to Day 43	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
Incidence rate of recrudescence and reinfection	Day 15, Day 29 and Day 43	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.
Number of Participants with On-Treatments Adverse Events, Serious Adverse Events, and Deaths	Day 1 to Day 43	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.
Pharmacokinetic of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Maximum Observed Plasma Concentration (Cmax)	From Day 1 to Day 8	Cmax is the maximum observed plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods.
Proportion of patients with Early Treatment Failure (ETF)	Day 1 to Day 4	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
Pharmacokinetics of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Area Under the Plasma Concentration-time Curve (AUC)	From Day 1 to Day 8	AUC is the area under the plasma concentration-time curve. PK parameters were calculated from plasma concentration-time data using non-compartmental methods.
Pharmacokinetic of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Time to reach the maximum concentration after drug administration (Tmax)	From Day 1 to Day 8	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.
Pharmacokinetics of KAF156 and LUM-SDF PK (Run-in Cohort, Cohort 1 and 2): Plasma drug concentration 168 hours post first dose administration (C168h)	Day 8	C168h is the plasma concentration at 168h post first dose administration.
Pharmacokinetics of LUM from Coartem arm (Cohorts 1 and 2): Maximum Observed Plasma Concentration (Cmax)	From Day 1 to Day 8	Cmax is the maximum observed plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods.
Pharmacokinetics of LUM from Coartem arm (Cohorts 1 and 2): Plasma drug concentration 168 hours post first dose administration (C168h)	Day 8	C168h is the plasma concentration at 168h post first dose administration.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇲🇱 Sotuba, Mali