Phase II Efficacy Study of Artefenomel & Piperaquine in A... | NCT02083380

Description Module

Detailed 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).

Label	Type	Description	Intervention Names
A) Artefenomel 800mg: piperaquine 640mg	Experimental	One single dose of Artefenomel 800mg: Piperaquine phosphate 640mg loose combination	Drug: Artefenomel 800mg: piperaquine 640mg
B) Artefenomel 800mg: piperaquine 960mg	Experimental	One single dose of Artefenomel 800mg: Piperaquine phosphate 960mg loose combination	Drug: Artefenomel 800mg: piperaquine 960mg
C) Artefenomel 800mg: piperaquine 1440mg	Experimental	One single dose of Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination	Drug: Artefenomel 800mg: piperaquine 1440mg

Name	Type	Description	Arm Group Labels	Other Names
Artefenomel 800mg: piperaquine 640mg	Drug	Active, loose combination	A) Artefenomel 800mg: piperaquine 640mg

Outcomes Module

Primary Outcomes

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.

Secondary Outcomes

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

Other Outcomes

Measure	Description	Time Frame
Piperaquine: Cday7 Asia (All Ages)	Piperaquine concentration at Day7 in Asian patients all ages	Day 7
Piperaquine: Cday7 Africa (> 5 Years)	Piperaquine concentration at Day7 in African patients > 5 years

Eligibility Module

Eligibility Criteria

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:
1. 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,
2. 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:
1. 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%).
2. With amodiaquine or chloroquine within the previous 4 weeks.
3. 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.
4. 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:
1. Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol),
2. Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine),
3. 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,
4. Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine), cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide.
5. 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.

Name	Affiliation	Role
Fiona Macintyre, PhD	Medicines for Malaria Venture	Study Director
Michael Ramharter, MD	CERMEL (Centre de Recherches Médicale de Lambaréné)	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Centre D'Étude Et de Recherchesur Le Paludisme Associé À La Grossesse Et À L'Enfance (Cerpage) Cerpage		Cotonou		FSS 01 BP 188	Benin

PubMed Identifier	Type	Citation	Retractions
30967148	Derived	Leroy D, Macintyre F, Adoke Y, Ouoba S, Barry A, Mombo-Ngoma G, Ndong Ngomo JM, Varo R, Dossou Y, Tshefu AK, Duong TT, Phuc BQ, Laurijssens B, Klopper R, Khim N, Legrand E, Menard D. African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker. Malar J. 2019 Apr 10;18(1):126. doi: 10.1186/s12936-019-2756-4.
28988541

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
FG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Primary analysis population was the per protocol population defined as all patients comprising the ITT set and without major protocol deviations. Including insufficient evidence of study indication, no baseline parasitemia and non-compliance with study drug administration.

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: piperaquine 640mg: Active, loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants	OG000106 OG001117 OG002117

Title

Denominators

Categories

Title	Measurements
	OG00070.8(61.13 to 79.19) OG00168.4(59.13 to 76.66) OG00278.6(70.09 to 85.67)

Primary

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.

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg

Primary

PCR-adjusted ACPR at Day 28 in the PP Population: Africa (All Ages)

95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg

Primary

PCR-adjusted ACPR at Day 28 in the PP Population: Africa (> Than 5 Years)

95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg

Primary

PCR-adjusted ACPR at Day 28 in the PP Population: Africa (< = 5 Years)

95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg

Primary

PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>2 to <= 5 Years)

95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg

Primary

PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>= 0.5 to <= 2 Years)

95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg

Secondary

PCR - Adjusted ACPR at Day 42 in the PP Population

PCR - adjusted adequate clinical and parasitological response at Day 42

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Days 42

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

PCR-adjusted ACPR at Day 63 in the PP Population

PCR-adjusted adequate clinical and parasitological response at Day 63

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 63

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

Crude ACPR at Day 28 in the PP Population

Crude adequate clinical and parasitological response at Day 28

Posted

Number

95% Confidence Interval

% ACPR unadjusted (crude)

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	C) Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts

Secondary

Crude ACPR at Day 42 in the PP Population

Crude adequate clinical and parasitological response at Day 42

Posted

Number

95% Confidence Interval

% ACPR unajusted (crude)

Day 42

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

Crude ACPR at Day 63 in the PP Population

Crude adequate clinical and parasitological response at Day 63

Posted

Number

95% Confidence Interval

% ACPR unadjusted (crude)

Day 63

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts

Secondary

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.

Intent to Treat (ITT) population : all patients who provided written informed consent, were randomised, received the single dose combination of OZ439/PQP study drug (or part thereof), and had a confirmed positive blood film for P. falciparum asexual parasitaemia at inclusion.

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts

Secondary

PCR-adjusted ACPR at Day 42 in the ITT Population

PCR-adjusted adequate clinical and parasitological response at Day 42 in the ITT population

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 42

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts

Secondary

PCR-adjusted ACPR at Day 63 in the ITT Population

PCR-adjusted adequate clinical and parasitological response at Day 63 in the ITT population

Posted

Number

95% Confidence Interval

% ACPR PCR-adjusted

Day 63

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts

Secondary

Crude ACPR at Day 28 in the ITT Population

Crude adequate clinical and parasitological response at Day 28 in the ITT population

Posted

Number

95% Confidence Interval

% ACPR unadjusted (crude)

Day 28

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

Crude ACPR at Day 42 in the ITT Population

Crude adequate clinical and parasitological response at Day 42 in the ITT population

Posted

Number

95% Confidence Interval

% ACPR unadjusted (crude)

Day 42

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

Crude ACPR at Day 63 in the ITT Population

Crude adequate clinical and parasitological response at Day 63 in the ITT population

Posted

Number

95% Confidence Interval

% ACPR unadjusted (crude)

Day 63

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

Kaplan-Meier Estimate of Recurrence

Kaplan-Meier estimate of number of recurrent infections (either recrudescence or new infection)

modified Intent to Treat (mITT) population : all patients who provided written informed consent, were randomised, were compliant with the single dose combination of OZ439/PQP study drug and had a confirmed positive blood film for P. falciparum asexual parasitaemia at inclusion.

Posted

Number

% population recurring

Day 63

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

Kaplan-Meier Estimate of Recrudescence

Kaplan-Meier estimate of number of patients with recrudescence

Posted

Number

% patients with recrudescence

Day 63

ID	Title	Description
OG000	A) Arttefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

Kaplan-Meier Estimate of New Infection Rate

Kaplan-Meier estimate of number of patients with new infections

Posted

Number

% population with new infection

Day 63

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

Parasite Clearance Time

Time post dose to parasite clearance

Posted

Median

95% Confidence Interval

hours

0, 6, 12, 18, 24, 30, 36, 48 and 72 hours post dose

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

Fever Clearance Time

Time to fever clearance (hours)

Posted

Median

95% Confidence Interval

hours

Day 42

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Secondary

PRR48

Parasite reduction ratio at 48 hours post dose

Posted

Median

Inter-Quartile Range

ratio

0, 6, 12, 18, 24, 30, 36 and 48 hours post dose

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants

Other Pre-specified

Piperaquine: Cday7 Asia (All Ages)

Piperaquine concentration at Day7 in Asian patients all ages

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 7

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants	OG000

Other Pre-specified

Piperaquine: Cday7 Africa (> 5 Years)

Piperaquine concentration at Day7 in African patients > 5 years

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 7

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants	OG000

Other Pre-specified

Piperaquine: Cday7 Africa (>2 to <= 5 Years)

Piperaquine concentration at Day7 in African patients > 2 and <= 5years

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 7

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants	OG000

Other Pre-specified

Piperaquine: Cday7 Africa (>=0.5 to <= 2 Years)

Piperaquine concentration at Day7 in African patients >= 0.5 and <= 2 years

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 7

ID	Title	Description
OG000	A) Artefenomel 800mg: Piperaquine 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
OG001	B) Artefenomel 800mg: Piperaquine 960mg	Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
OG002	C) Artefenomel 800mg: Piperaquine 1440mg	Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Units	Counts
Participants	OG000

Other Pre-specified

Artefenomel Cday7 Asian Patients (All Ages)

Artefenomel concentration on Day 7 in Asian Patients (all ages). All Treatment arms.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 7

ID	Title	Description
OG000	A) Artefenomel 800mg: PQP 640mg, 960mg & 1440mg	Artefenomel 800mg: Piperaquine phosphate 640mg, 960mg & 1440mg combined Artefenomel 800mg: PQP 640mg, 960mg & 1440mg

Units	Counts
Participants	OG00082

Other Pre-specified

Artefenomel Cday7 African Patients (> 5 Years)

Artefenomel concentration on Day 7 in African Patients > 5 years. All Treatment arms.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 7

ID	Title	Description
OG000	A) Artefenomel 800mg: PQP 640mg, 960mg & 1440mg	Artefenomel 800mg: Piperaquine phosphate 640mg, 960mg & 1440mg combined

Units	Counts
Participants	OG00064

Title

Other Pre-specified

Artefenomel Cday7 African Patients (>2 to <= 5 Years)

Artefenomel concentration on Day 7 in African Patients >2 to <= 5 years. All Treatment arms.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 7

ID	Title	Description
OG000	A) Artefenomel 800mg: PQP 640mg, 960mg & 1440mg	Artefenomel 800mg: Piperaquine phosphate 640mg, 960mg & 1440mg combined

Units	Counts
Participants	OG000120

Other Pre-specified

Artefenomel Cday7 African Patients (>=0.5 to <= 2 Years)

Artefenomel concentration on Day 7 in African Patients >= 0.5 to <=2 years. All Treatment arms.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 7

ID	Title	Description
OG000	A) Artefenomel 800mg: PQP 640mg, 960mg & 1440mg	Artefenomel 800mg: Piperaquine phosphate 640mg, 960mg & 1440mg combined

Units	Counts
Participants	OG000161

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
malaria	Infections and infestations	MedDRA (Unspecified)	Systematic Assessment	EG00034 events34 affected146 at risk EG00148 events45 affected148 at risk EG00244 events43 affected143 at risk
Bronchitis	Infections and infestations	MedDRA (Unspecified)	Non-systematic Assessment	EG00011 events10 affected146 at risk EG00119 events13 affected148 at risk EG00216 events13 affected143 at risk
Rhinitis	Infections and infestations	MedDRA (Unspecified)	Non-systematic Assessment	EG00010 events10 affected146 at risk EG00110 events9 affected148 at risk EG00211 events11 affected143 at risk
Plasmodium Falciparum Infection	Infections and infestations	MedDRA (Unspecified)	Systematic Assessment	EG0007 events7 affected146 at risk EG00110 events10 affected148 at risk EG0029 events9 affected143 at risk
Electrocardiumgram QT prolonged	Investigations	MedDRA (Unspecified)	Systematic Assessment	EG00056 events44 affected146 at risk EG00148 events41 affected148 at risk EG00229 events27 affected143 at risk
Neutrophil count decreased	Investigations	MedDRA (Unspecified)	Systematic Assessment	EG00013 events12 affected146 at risk EG00111 events11 affected148 at risk EG00218 events18 affected143 at risk
Haemoglobin decreased	Investigations	MedDRA (Unspecified)	Systematic Assessment	EG00011 events11 affected146 at risk EG00122 events20 affected148 at risk EG0029 events9 affected143 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG00020 events20 affected146 at risk EG00121 events21 affected148 at risk EG00212 events11 affected143 at risk
Vomiting	Gastrointestinal disorders	MedDRA (Unspecified)	Systematic Assessment	EG00016 events16 affected146 at risk EG00120 events20 affected148 at risk EG00214 events14 affected143 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG00013 events12 affected146 at risk EG0019 events8 affected148 at risk EG0025 events5 affected143 at risk
Pyrexia	General disorders	MedDRA (Unspecified)	Systematic Assessment	EG00011 events9 affected146 at risk EG00113 events12 affected148 at risk EG0025 events5 affected143 at risk

ID	Term
D011528	Protozoan Infections
D010272	Parasitic Diseases
D007239	Infections
D000096724	Mosquito-Borne Diseases
D000079426	Vector Borne Diseases

ID	Title	Description
BG000	A) Artefenomel 800mg: PQP 640mg	Artefenomel 800mg: Piperaquine 640mg
BG001	B) Artefenomel 800mg: PQP 960mg	Artefenomel 800mg: Piperaquine 960mg
BG002	C) Artefenomel 800mg: PQP 1440mg	Artefenomel 800mg: Piperaquine 1440mg
BG003	Total	Total of all reporting groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	A) Artefenomel 800mg: PQP 640mg	Artefenomel 800mg: Piperaquine phosphate 640mg	1	146	122	146
EG001	B) Artefenomel 800mg: PQP 960mg	Artefenomel 800mg: Piperaquine 960mg	1	148	127	148
EG002	C) Artefenomel 800mg: PQP 1440mg	Artefenomel 800mg: Piperaquine 1440mg	2	143	115	143

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Transaminase elevation	Investigations	MedDRA (Unspecified)	Systematic Assessment	Two reversible SAEs of possibly related reversible transaminase elevation in one subject	EG0000 events0 affected146 at risk EG0010 events0 affected148 at risk EG0022 events1 affected143 at risk
Anemia	Investigations	MedDRA (Unspecified)	Systematic Assessment		EG0000 events0 affected146 at risk EG0010 events0 affected148 at risk EG0021 events1 affected143 at risk
Febrile convulsion	Nervous system disorders	MedDRA (Unspecified)	Non-systematic Assessment		EG0000 events0 affected146 at risk EG0011 events1 affected148 at risk EG0020 events0 affected143 at risk
Hemoglobin drop < 5 g/dL	Investigations	MedDRA (Unspecified)	Systematic Assessment		EG0001 events1 affected146 at risk EG0010 events0 affected148 at risk EG0020 events0 affected143 at risk