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About
A randomised, double-blind single-dose study to determine the efficacy, safety, tolerability and pharmacokinetics of OZ439 (artefenomel) in combination with piperaquine (PQP) in patients > 0.5 years and <= 70 years of age with uncomplicated Plasmodium falciparum malaria in Africa and Asia (Vietnam).
Interim analyses for futility were planned. Adults and children will be included through progressive step-down in age following safety review by an independent safety monitoring board (ISMB).
If the study were to meets its efficacy objectives, this will inform dose setting for Phase III studies.
Full description
A randomised, double-blind single-dose (loose combination) study in the target patient population of children > 0.5 years and <= 5 years of age in Africa and patients of all ages in Asia (> 0.5 years and <= 70 years) with uncomplicated Plasmodium falciparum malaria. Patients > 5 years in Africa were also to be recruited in a safety age step down procedure. The underlying assumption was that children of 5 years or less in Africa and all ages in Asia will have a higher probability of having lower immunity and hence potentially require higher drug exposure to achieve efficacy and hence the study aimed to recruit 60-80% African children < = 5 years and 18-36% Asian patients (defined as the target population) and approximately 10% African patients >5 years,
Three OZ439/PQP treatment arms were to be included for patients >= 35 kg (800mg OZ439 in loose combination with PQP doses of either 640, 960, 1440 mg). Doses were scaled for patients < 35kg based on the weight to achieve similar exposures in patients >= 35kg.
The study was to test for futility and dose arms were to be dropped if the probability was >30% that PCR-adjusted ACPR at Day 28 (ACPR28) was less than 90% (the target efficacy for the study was >= 95% ACPR28). Only data from patients in Asia patients and Africa patients < 5 years were to be included in the Interim analysis, although all patients were to be included in the final analysis. Interim analyses were to occur after recruitment of approximately 50 evaluable patients per dose cohort and thereafter approximately after every 25 patients.
In a separate process, the safety of OZ439/PQP treatment arms was to be assessed at scheduled time points by an ISMB and adults and children were included through progressive step-down in age range following safety evaluation
Following Screening and informed consent, patients were to receive study drug and were to be followed for clinical signs of malaria (parasitaemia and temperature), safety assessments and pharmacokinetics up to Day 42 following dosing (Day 63 at selected sites).
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Male or female patient age >6 months <70 years.
Body weight >5 kg <90 kg.
Presence of mono-infection of P. falciparum with:
Written informed consent provided by the adult patient, or parent or legally acceptable representative (LAR) of the minor patient or by an impartial witness (if the patient or patient's LAR is illiterate), and by the medically qualified Investigator. Children will be asked to provide assent where appropriate. The age from which this will be sought will be defined by local legislation.
Exclusion criteria
Presence of severe malaria (according to World Health Organization (WHO) definition - WHO 2013)
Anti-malarial treatment:
Known history or evidence of clinically significant disorders such as, respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological, neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or other abnormality (including head trauma).
Family history of sudden death or of congenital or clinical conditions known to prolong QTcB or QTcF interval or e.g. patients with a history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.
Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failure accompanied by reduced left ventricle ejection fraction.
Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia.
Any treatment which can induce a lengthening of QT interval, such as:
Mixed Plasmodium infection
Severe vomiting, defined as more than three times in the 24 hours prior to enrolment in the study or inability to tolerate oral treatment, or severe diarrhoea defined as 3 or more watery stools per day
Severe malnutrition (defined for subjects aged ten years or less as the weight-for-height being below -3 standard deviation or less than 70% of median of the National Centre for Health Statistics (NCHS)/WHO normalised reference values, and for subjects aged greater than ten years, a body mass index (BMI) of less than 16 (WFP Manual, Chapter 1)).
Known history of hypersensitivity, allergic or adverse reactions to piperaquine or other aminoquinolones or to OZ439 or OZ277
Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab).
If Total Bilirubin is normal, exclude the patient if liver function tests Aspartate transaminase (AST)/ Alanine transaminase (ALT) ≥ 2x Upper limit of normal (ULN).
If Total Bilirubin is > 1 and ≤ 1.5xULN, exclude the patient if AST/ALT >1.5xULN.
Total Bilirubin > 1.5XULN
Haemoglobin level below 8 g/dL.
Serum creatinine levels ≥2 x ULN
Female patients of child bearing potential must be neither pregnant (as demonstrated by a negative pregnancy test) nor lactating, and must be willing to take measures not to become pregnant during the study period and safety follow-up period.
Have received an investigational drug within the past 4 weeks.
Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance.
Primary purpose
Allocation
Interventional model
Masking
448 participants in 3 patient groups
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Data sourced from clinicaltrials.gov
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