Efficacy, Safety and Tolerability of KAF156 in Combination With Lumefantrine Solid Dispersion Formulation (LUM-SDF) in Pediatric Population With Uncomplicated Plasmodium Falciparum Malaria
Efficacy, Safety and Tolerability of KAF156 in Combination With Lumefantrine Solid Dispersion Formulation (LUM-SDF) in Pediatric Population With Uncomplicated Plasmodium Falciparum Malaria
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, and for a duration shorter than 3 days of
 treatment and/or reduced pill burden.
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 once daily for two days 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 with and without food, first in Cohort 1 of patients 2 to < 12
 years old and then in Cohort 2 of patients 6 months to < 2 years old.
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
 pre-screening

 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 planne

 Exclusion Criteria:

 1. Mixed Plasmodium infections as per light microscopy results

 2. Signs and symptoms of severe malaria according to WHO 2015

 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)