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

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, Under Fasted or Fed Conditions, in the Treatment of Acute Uncomplicated Plasmodium Falciparum Malaria in a Pediatric Population

ClinicalTrials.gov Identifier: NCT04546633

Novartis Reference Number: CKAF156A2203

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All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study Description

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.

Condition 
Uncomplicated Plasmodium Falciparum Malaria
Phase 
Phase 2
Overall status 
Not yet recruiting
Enrollment count 
224 participants
Start date 
Oct 22, 2020
Completion date 
Oct 26, 2021
Gender 
All
Age(s)
6 Years - 17 Years (Child)

Interventions

Drug
KAF156
Provided as 50 mg or 100 mg tablets, to be taken QD 2 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 Days in combination with KAF156, dose is based on body weight

Eligibility Criteria

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 pre-screening
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 planne

Exclusion Criteria:

Mixed Plasmodium infections as per light microscopy results
Signs and symptoms of severe malaria according to WHO 2015
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)

Contacts

Name: 
Novartis Pharmaceuticals
Phone: 
+41613241111
Name: 
Novartis Pharmaceuticals
Phone: 
Email: 

Have a question?

Call 1-999-669-6682 or email [email protected]