Phase II Efficacy Study of Artefenomel & Piperaquine in Adults & Children With P. Falciparum Malaria.

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Randomised Phase IIb Study of Efficacy, Safety, Tolerability & Pharmacokinetics of a Single Dose Regimen of Artefenomel (OZ439) in Loose Combination With Piperaquine in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria.

Conditions
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Uncomplicated Plasmodium Falciparum Malaria

Intervention / Treatment
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* Drug: Artefenomel 800mg: piperaquine 640mg
* Drug: Artefenomel 800mg: piperaquine 960mg
* Drug: Artefenomel 800mg: piperaquine 1440mg


Participation Criteria
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Eligibility Criteria
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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: Fever, as defined by axillary temperature ≥ 37.5°C or oral/rectal/tympanic temperature ≥ 38°C, or history of fever in the previous 24 hours (history of fever must be documented) and, Microscopically confirmed parasite infection, in range 1,000 to 100,000 asexual parasites /µL of blood. 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: With piperaquine -based compound, mefloquine, naphthoquine or sulphadoxine/pyrimethamine (SP) within the previous 6 weeks (after their inhibition of new infections has fallen below 50%). With amodiaquine or chloroquine within the previous 4 weeks. With quinine, halofantrine, lumefantrine-based compounds and any other anti-malarial treatment or antibiotics with anti-malarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones, and azithromycin) within the past 14 days. With any herbal products or traditional medicines, within the past 7 days. 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: Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol), Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine), Anti-depressive agents, certain antimicrobial agents, including agents of the following classes macrolides (e.g. erythromycin, clarithromycin), fluoroquinolones (e.g. moxifloxacin, sparfloxacin), imidazole and triazole antifungal agents, and also pentamidine and saquinavir, Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine), cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide. Anti-emetics with known QT prolongation potential such as domperidone 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.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A) Artefenomel 800mg: piperaquine 640mg<br>One single dose of Artefenomel 800mg: Piperaquine phosphate 640mg loose combination | Drug: Artefenomel 800mg: piperaquine 640mg<br>* Active, loose combination<br>* Other names: OZ439 ; PQP;|
| Experimental: B) Artefenomel 800mg: piperaquine 960mg<br>One single dose of Artefenomel 800mg: Piperaquine phosphate 960mg loose combination | Drug: Artefenomel 800mg: piperaquine 960mg<br>* Active, loose combination<br>* Other names: OZ439 ; PQP;|
| Experimental: C) Artefenomel 800mg: piperaquine 1440mg<br>One single dose of Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination | Drug: Artefenomel 800mg: piperaquine 1440mg<br>* Active, loose combination<br>* Other names: OZ439 ; PQP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR-adjusted ACPR at Day 28 in the PP Population (All Patients) | Polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. Per protocol population (PP). 95% Clopper-Pearson 2-sided Confidence Interval (CI) constructed around the single binomial proportion per treatment arm and total. | Day 28 | 
| PCR-adjusted ACPR at Day 28 in the PP Population: Asia (All Ages) | PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total. | Day 28 | 
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (All Ages) | PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total. | Day 28 | 
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (> Than 5 Years) | PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total. | Day 28 | 
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (< = 5 Years) | PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total. | Day 28 | 
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>2 to <= 5 Years) | PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total. | Day 28 | 
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>= 0.5 to <= 2 Years) | PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR - Adjusted ACPR at Day 42 in the PP Population | PCR - adjusted adequate clinical and parasitological response at Day 42 | Days 42 | 
| PCR-adjusted ACPR at Day 63 in the PP Population | PCR-adjusted adequate clinical and parasitological response at Day 63 | Day 63 | 
| Crude ACPR at Day 28 in the PP Population | Crude adequate clinical and parasitological response at Day 28 | Day 28 | 
| Crude ACPR at Day 42 in the PP Population | Crude adequate clinical and parasitological response at Day 42 | Day 42 | 
| Crude ACPR at Day 63 in the PP Population | Crude adequate clinical and parasitological response at Day 63 | Day 63 | 
| PCR-adjusted ACPR at Day 28 in the ITT Population | PCR-adjusted adequate clinical and parasitological response at Day 28. Intent to Treat ( ITT) population. | Day 28 | 
| PCR-adjusted ACPR at Day 42 in the ITT Population | PCR-adjusted adequate clinical and parasitological response at Day 42 in the ITT population | Day 42 | 
| PCR-adjusted ACPR at Day 63 in the ITT Population | PCR-adjusted adequate clinical and parasitological response at Day 63 in the ITT population | Day 63 | 
| Crude ACPR at Day 28 in the ITT Population | Crude adequate clinical and parasitological response at Day 28 in the ITT population | Day 28 | 
| Crude ACPR at Day 42 in the ITT Population | Crude adequate clinical and parasitological response at Day 42 in the ITT population | Day 42 | 
| Crude ACPR at Day 63 in the ITT Population | Crude adequate clinical and parasitological response at Day 63 in the ITT population | Day 63 | 
| Kaplan-Meier Estimate of Recurrence | Kaplan-Meier estimate of number of recurrent infections (either recrudescence or new infection) | Day 63 | 
| Kaplan-Meier Estimate of Recrudescence | Kaplan-Meier estimate of number of patients with recrudescence | Day 63 | 
| Kaplan-Meier Estimate of New Infection Rate | Kaplan-Meier estimate of number of patients with new infections | Day 63 | 
| Parasite Clearance Time | Time post dose to parasite clearance | 0, 6, 12, 18, 24, 30, 36, 48 and 72 hours post dose | 
| Fever Clearance Time | Time to fever clearance (hours) | Day 42 | 
| PRR48 | Parasite reduction ratio at 48 hours post dose | 0, 6, 12, 18, 24, 30, 36 and 48 hours post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plasmodium falciparum malaria, malaria, OZ439, piperaquine, PQP