Efficacy and Safety of KAF156 in Combination With LUM-SDF in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria
Condition: Acute Uncomplicated Plasmodium Falciparum Malaria
MeSH terms: Malaria; Malaria, Falciparum
Intervention: KAF156; Coartem; Lumefantrine Solid Dispersion Formulation
Intervention description: KAF156 comes in 100 mg tablets for oral administration. KAF156 was administered in combination with LUM-SDF once daily (QD) for 1, 2 or 3 days at 200 mg, 400 mg or 800 mg doses.; Coartem comes as 20/120 mg dispersible tablets or 80/480 mg tablets for oral administration. Coartem was administered twice daily for 3 days as active comparator.; LUM-SDF comes in 240 mg or 480 mg sachets for oral administration. LUM-SDF was administered in combination with KAF156 once daily (QD) for 1, 2 or 3 days at 480 mg or 960 mg doses.
Intervention MeSH terms: Lumefantrine; Artemether, Lumefantrine Drug Combination
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 524.0
Sex: All
Minimum age: 2 Years
Healthy volunteers: No

Summary:

      This study was designed to determine the most effective and tolerable dose at the shortest
      dosing regimen of the investigational drug KAF156 in combination with a solid dispersion
      formulation of lumefantrine (LUM-SDF) in adult/adolescent and pediatric patients with
      uncomplicated Plasmodium falciparum malaria.

      There is unmet medical need for anti-malarial treatment with new mechanism of action to
      reduce probability of developing resistance, and for duration shorter than 3 days of
      treatment and/or reduced pill burden.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Part A: male and female patients ≥ 12 years and with a body weight ≥ 35.0 kg. Part B:
             after determining the effective/tolerated doses and regimens in adolescent and adult
             patients, male and female patients ≥ 2 and < 12 years and with a body weight ≥ 10.0 kg
             will be included.

          -  Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films.

          -  P. falciparum parasitaemia of more than 1000 and less than 150 000 parasites/µL at the
             time of pre-screening (i.e., Study Visit 1).

          -  Axillary temperature ≥ 37.5 ºC or oral/tympanic/rectal temperature ≥ 38.3 ºC; or
             similar history of fever during the previous 24 hours (history of fever must be
             documented).

          -  Written informed consent must be obtained before any assessment is performed. If the
             patient is unable to read and write, then a witnessed consent according to local
             ethical standards is permitted. Patients < 18 years old, who are capable of providing
             assent, must provide assent with parental/legal guardian consent or as per local
             ethical guidelines.

        Exclusion Criteria:

          -  Mixed Plasmodium infections.

          -  Signs and symptoms of severe malaria according to WHO (World Health Organization) 2015
             criteria unless characterized by high parasitaemia only.

          -  Patients with concurrent febrile illnesses (e.g., typhoid fever).

          -  Severe 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 per day.

          -  Pregnant or nursing (lactating) women.

          -  Clinically relevant abnormalities of electrolyte balance which require correction,
             e.g., hypokalemia, hypocalcemia or hypomagnesemia.

          -  Anemia (Hemoglobin level < 8 g/dL).

          -  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).

          -  History or family history of long QT syndrome or sudden cardiac death, or any other
             clinical condition known to prolong the QTc (heart rate-corrected QT) interval, such
             as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or
             severe heart disease.

          -  Any surgical or medical condition which might significantly alter the absorption,
             distribution, metabolism, or excretion of drugs, 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 > 2 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