Uncomplicated Plasmodium Falciparum Malaria
Conditions
Keywords
Plasmodium falciparum malaria, malaria, OZ439, piperaquine, PQP
Brief summary
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
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).
Interventions
DRUGArtefenomel 800mg: piperaquine 640mg
Active, loose combination
DRUGArtefenomel 800mg: piperaquine 960mg
Active, loose combination
DRUGArtefenomel 800mg: piperaquine 1440mg
Active, loose combination
Sponsors
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patient age \>6 months \<70 years. 2. Body weight \>5 kg \<90 kg. 3. 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. 4. 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
1. Presence of severe malaria (according to World Health Organization (WHO) definition - WHO 2013) 2. 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. 3. 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). 4. 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. 5. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. 6. 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. 7. Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia. 8. 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 9. Mixed Plasmodium infection 10. 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 11. 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)). 12. Known history of hypersensitivity, allergic or adverse reactions to piperaquine or other aminoquinolones or to OZ439 or OZ277 13. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab). 14. If Total Bilirubin is normal, exclude the patient if liver function tests Aspartate transaminase (AST)/ Alanine transaminase (ALT) ≥ 2x Upper limit of normal (ULN). 15. If Total Bilirubin is \> 1 and ≤ 1.5xULN, exclude the patient if AST/ALT \>1.5xULN. 16. Total Bilirubin \> 1.5XULN 17. Haemoglobin level below 8 g/dL. 18. Serum creatinine levels ≥2 x ULN 19. 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. 20. Have received an investigational drug within the past 4 weeks. 21. Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>2 to <= 5 Years) | Day 28 | 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. |
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (< = 5 Years) | Day 28 | 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. |
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (> Than 5 Years) | Day 28 | 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. |
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (All Ages) | Day 28 | 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. |
| PCR-adjusted ACPR at Day 28 in the PP Population: Asia (All Ages) | Day 28 | 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. |
| PCR-adjusted ACPR at Day 28 in the PP Population (All Patients) | Day 28 | 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. |
| PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>= 0.5 to <= 2 Years) | Day 28 | 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
| Measure | Time frame | Description |
|---|---|---|
| PCR-adjusted ACPR at Day 42 in the ITT Population | Day 42 | PCR-adjusted adequate clinical and parasitological response at Day 42 in the ITT population |
| PCR-adjusted ACPR at Day 63 in the ITT Population | Day 63 | PCR-adjusted adequate clinical and parasitological response at Day 63 in the ITT population |
| Crude ACPR at Day 28 in the ITT Population | Day 28 | Crude adequate clinical and parasitological response at Day 28 in the ITT population |
| PCR - Adjusted ACPR at Day 42 in the PP Population | Days 42 | PCR - adjusted adequate clinical and parasitological response at Day 42 |
| PCR-adjusted ACPR at Day 63 in the PP Population | Day 63 | PCR-adjusted adequate clinical and parasitological response at Day 63 |
| Crude ACPR at Day 28 in the PP Population | Day 28 | Crude adequate clinical and parasitological response at Day 28 |
| Crude ACPR at Day 42 in the PP Population | Day 42 | Crude adequate clinical and parasitological response at Day 42 |
| Crude ACPR at Day 63 in the PP Population | Day 63 | Crude adequate clinical and parasitological response at Day 63 |
| PCR-adjusted ACPR at Day 28 in the ITT Population | Day 28 | PCR-adjusted adequate clinical and parasitological response at Day 28. Intent to Treat ( ITT) population. |
| Crude ACPR at Day 42 in the ITT Population | Day 42 | Crude adequate clinical and parasitological response at Day 42 in the ITT population |
| Crude ACPR at Day 63 in the ITT Population | Day 63 | Crude adequate clinical and parasitological response at Day 63 in the ITT population |
| Kaplan-Meier Estimate of Recurrence | Day 63 | Kaplan-Meier estimate of number of recurrent infections (either recrudescence or new infection) |
| Kaplan-Meier Estimate of Recrudescence | Day 63 | Kaplan-Meier estimate of number of patients with recrudescence |
| Kaplan-Meier Estimate of New Infection Rate | Day 63 | Kaplan-Meier estimate of number of patients with new infections |
| Parasite Clearance Time | 0, 6, 12, 18, 24, 30, 36, 48 and 72 hours post dose | Time post dose to parasite clearance |
| Fever Clearance Time | Day 42 | Time to fever clearance (hours) |
| PRR48 | 0, 6, 12, 18, 24, 30, 36 and 48 hours post dose | Parasite reduction ratio at 48 hours post dose |
Other
| Measure | Time frame | Description |
|---|---|---|
| Piperaquine: Cday7 Africa (>2 to <= 5 Years) | Day 7 | Piperaquine concentration at Day7 in African patients \> 2 and \<= 5years |
| Piperaquine: Cday7 Asia (All Ages) | Day 7 | Piperaquine concentration at Day7 in Asian patients all ages |
| Artefenomel Cday7 African Patients (>=0.5 to <= 2 Years) | Day 7 | Artefenomel concentration on Day 7 in African Patients \>= 0.5 to \<=2 years. All Treatment arms. |
| Artefenomel Cday7 African Patients (>2 to <= 5 Years) | Day 7 | Artefenomel concentration on Day 7 in African Patients \>2 to \<= 5 years. All Treatment arms. |
| Artefenomel Cday7 African Patients (> 5 Years) | Day 7 | Artefenomel concentration on Day 7 in African Patients \> 5 years. All Treatment arms. |
| Artefenomel Cday7 Asian Patients (All Ages) | Day 7 | Artefenomel concentration on Day 7 in Asian Patients (all ages). All Treatment arms. |
| Piperaquine: Cday7 Africa (>=0.5 to <= 2 Years) | Day 7 | Piperaquine concentration at Day7 in African patients \>= 0.5 and \<= 2 years |
| Piperaquine: Cday7 Africa (> 5 Years) | Day 7 | Piperaquine concentration at Day7 in African patients \> 5 years |
Countries
Benin, Burkina Faso, Democratic Republic of the Congo, Gabon, Mozambique, Uganda, Vietnam
Participant flow
Recruitment details
Randomized double blind study. Conduct was July 2014-August 2015 in Africa (Benin, Burkina Faso, Democratic Republic of Congo, Gabon, Mozambique and Uganda) and Vietnam. Following informed consent patients were recruited to the study. Patients below the age to give legal Informed Consent were consented according local customs / legal requirements.
Pre-assignment details
Patients were assigned a screening number and underwent screening procedures to assess eligibility. Eligible patients were randomized through an Interactive web-response system and followed for efficacy and safety up to 42 days post dose and 63 days at selected centers. Patients were consented separately to remain in the study up to Day 63.
Participants by arm
| Arm | Count |
|---|---|
| A) Artefenomel 800mg: PQP 640mg Artefenomel 800mg: Piperaquine 640mg | 143 |
| B) Artefenomel 800mg: PQP 960mg Artefenomel 800mg: Piperaquine 960mg | 148 |
| C) Artefenomel 800mg: PQP 1440mg Artefenomel 800mg: Piperaquine 1440mg | 146 |
| Total | 437 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 68 | 79 | 64 |
| Overall Study | Lost to Follow-up | 5 | 3 | 3 |
| Overall Study | Other | 8 | 4 | 6 |
| Overall Study | Physician Decision | 1 | 6 | 3 |
| Overall Study | Withdrawal by Subject | 9 | 3 | 7 |
Baseline characteristics
| Characteristic | Total | C) Artefenomel 800mg: PQP 1440mg | B) Artefenomel 800mg: PQP 960mg | A) Artefenomel 800mg: PQP 640mg |
|---|---|---|---|---|
| Age, Customized >= 0.5 to <= 2 years | 77 participants | 26 participants | 26 participants | 25 participants |
| Age, Customized > 15 years | 124 participants | 41 participants | 42 participants | 41 participants |
| Age, Customized > 2 to <= 5 years | 211 participants | 70 participants | 72 participants | 69 participants |
| Age, Customized > 5 to <= 15 years | 25 participants | 9 participants | 8 participants | 8 participants |
| Sex: Female, Male Female | 266 Participants | 98 Participants | 85 Participants | 83 Participants |
| Sex: Female, Male Male | 171 Participants | 48 Participants | 63 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 122 / 146 | 127 / 148 | 115 / 143 |
| serious Total, serious adverse events | 1 / 146 | 1 / 148 | 2 / 143 |
Outcome results
Primary
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.
Time frame: Day 28
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>= 0.5 to <= 2 Years) | 61.1 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>= 0.5 to <= 2 Years) | 38.1 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>= 0.5 to <= 2 Years) | 62.5 % ACPR PCR-adjusted |
Primary
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.
Time frame: Day 28
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>2 to <= 5 Years) | 75.6 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>2 to <= 5 Years) | 74.0 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>2 to <= 5 Years) | 83.6 % ACPR PCR-adjusted |
Primary
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.
Time frame: Day 28
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (< = 5 Years) | 71.4 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (< = 5 Years) | 63.4 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (< = 5 Years) | 78.9 % ACPR PCR-adjusted |
Primary
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.
Time frame: Day 28
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (All Ages) | 72.8 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (All Ages) | 69.6 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (All Ages) | 81.1 % ACPR PCR-adjusted |
Primary
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.
Time frame: Day 28
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (> Than 5 Years) | 77.8 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (> Than 5 Years) | 90.5 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 28 in the PP Population: Africa (> Than 5 Years) | 89.5 % ACPR PCR-adjusted |
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.
Time frame: Day 28
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 28 in the PP Population (All Patients) | 70.8 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 28 in the PP Population (All Patients) | 68.4 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 28 in the PP Population (All Patients) | 78.6 % ACPR PCR-adjusted |
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.
Time frame: Day 28
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 28 in the PP Population: Asia (All Ages) | 64 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 28 in the PP Population: Asia (All Ages) | 64 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 28 in the PP Population: Asia (All Ages) | 70.4 % ACPR PCR-adjusted |
Secondary
Crude ACPR at Day 28 in the ITT Population
Crude adequate clinical and parasitological response at Day 28 in the ITT population
Time frame: Day 28
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Crude ACPR at Day 28 in the ITT Population | 53.1 % ACPR unadjusted (crude) |
| B) Artefenomel 800mg: Piperaquine 960mg | Crude ACPR at Day 28 in the ITT Population | 53.4 % ACPR unadjusted (crude) |
| C) Artefenomel 800mg: Piperaquine 1440mg | Crude ACPR at Day 28 in the ITT Population | 63.0 % ACPR unadjusted (crude) |
Secondary
Crude ACPR at Day 28 in the PP Population
Crude adequate clinical and parasitological response at Day 28
Time frame: Day 28
Population: 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. The PP population comprised 93.3% of the randomized population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Crude ACPR at Day 28 in the PP Population | 57.4 % ACPR unadjusted (crude) |
| B) Artefenomel 800mg: Piperaquine 960mg | Crude ACPR at Day 28 in the PP Population | 56.6 % ACPR unadjusted (crude) |
| C) Artefenomel 800mg: Piperaquine 1440mg | Crude ACPR at Day 28 in the PP Population | 66.9 % ACPR unadjusted (crude) |
Secondary
Crude ACPR at Day 42 in the ITT Population
Crude adequate clinical and parasitological response at Day 42 in the ITT population
Time frame: Day 42
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Crude ACPR at Day 42 in the ITT Population | 44.1 % ACPR unadjusted (crude) |
| B) Artefenomel 800mg: Piperaquine 960mg | Crude ACPR at Day 42 in the ITT Population | 44.6 % ACPR unadjusted (crude) |
| C) Artefenomel 800mg: Piperaquine 1440mg | Crude ACPR at Day 42 in the ITT Population | 46.6 % ACPR unadjusted (crude) |
Secondary
Crude ACPR at Day 42 in the PP Population
Crude adequate clinical and parasitological response at Day 42
Time frame: Day 42
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Crude ACPR at Day 42 in the PP Population | 48.0 % ACPR unajusted (crude) |
| B) Artefenomel 800mg: Piperaquine 960mg | Crude ACPR at Day 42 in the PP Population | 48.5 % ACPR unajusted (crude) |
| C) Artefenomel 800mg: Piperaquine 1440mg | Crude ACPR at Day 42 in the PP Population | 51.5 % ACPR unajusted (crude) |
Secondary
Crude ACPR at Day 63 in the ITT Population
Crude adequate clinical and parasitological response at Day 63 in the ITT population
Time frame: Day 63
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Crude ACPR at Day 63 in the ITT Population | 36.8 % ACPR unadjusted (crude) |
| B) Artefenomel 800mg: Piperaquine 960mg | Crude ACPR at Day 63 in the ITT Population | 35.0 % ACPR unadjusted (crude) |
| C) Artefenomel 800mg: Piperaquine 1440mg | Crude ACPR at Day 63 in the ITT Population | 43.0 % ACPR unadjusted (crude) |
Secondary
Crude ACPR at Day 63 in the PP Population
Crude adequate clinical and parasitological response at Day 63
Time frame: Day 63
Population: 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. The PP population comprised 93.3% of the randomized population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Crude ACPR at Day 63 in the PP Population | 42.1 % ACPR unadjusted (crude) |
| B) Artefenomel 800mg: Piperaquine 960mg | Crude ACPR at Day 63 in the PP Population | 39.3 % ACPR unadjusted (crude) |
| C) Artefenomel 800mg: Piperaquine 1440mg | Crude ACPR at Day 63 in the PP Population | 49.1 % ACPR unadjusted (crude) |
Secondary
Fever Clearance Time
Time to fever clearance (hours)
Time frame: Day 42
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Fever Clearance Time | 1.0 hours |
| B) Artefenomel 800mg: Piperaquine 960mg | Fever Clearance Time | 1.2 hours |
| C) Artefenomel 800mg: Piperaquine 1440mg | Fever Clearance Time | 1.1 hours |
Secondary
Kaplan-Meier Estimate of New Infection Rate
Kaplan-Meier estimate of number of patients with new infections
Time frame: Day 63
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Kaplan-Meier Estimate of New Infection Rate | 11.3 % population with new infection |
| B) Artefenomel 800mg: Piperaquine 960mg | Kaplan-Meier Estimate of New Infection Rate | 16.3 % population with new infection |
| C) Artefenomel 800mg: Piperaquine 1440mg | Kaplan-Meier Estimate of New Infection Rate | 13.6 % population with new infection |
Secondary
Kaplan-Meier Estimate of Recrudescence
Kaplan-Meier estimate of number of patients with recrudescence
Time frame: Day 63
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Kaplan-Meier Estimate of Recrudescence | 22.7 % patients with recrudescence |
| B) Artefenomel 800mg: Piperaquine 960mg | Kaplan-Meier Estimate of Recrudescence | 29.1 % patients with recrudescence |
| C) Artefenomel 800mg: Piperaquine 1440mg | Kaplan-Meier Estimate of Recrudescence | 18.6 % patients with recrudescence |
Secondary
Kaplan-Meier Estimate of Recurrence
Kaplan-Meier estimate of number of recurrent infections (either recrudescence or new infection)
Time frame: Day 63
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Kaplan-Meier Estimate of Recurrence | 44.7 % population recurring |
| B) Artefenomel 800mg: Piperaquine 960mg | Kaplan-Meier Estimate of Recurrence | 54.6 % population recurring |
| C) Artefenomel 800mg: Piperaquine 1440mg | Kaplan-Meier Estimate of Recurrence | 43.6 % population recurring |
Secondary
Parasite Clearance Time
Time post dose to parasite clearance
Time frame: 0, 6, 12, 18, 24, 30, 36, 48 and 72 hours post dose
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Parasite Clearance Time | 36.1 hours |
| B) Artefenomel 800mg: Piperaquine 960mg | Parasite Clearance Time | 36.0 hours |
| C) Artefenomel 800mg: Piperaquine 1440mg | Parasite Clearance Time | 36.1 hours |
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.
Time frame: Day 28
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 28 in the ITT Population | 53.8 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 28 in the ITT Population | 55.4 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 28 in the ITT Population | 65.1 % ACPR PCR-adjusted |
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
Time frame: Day 42
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 42 in the ITT Population | 46.9 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 42 in the ITT Population | 48.6 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 42 in the ITT Population | 50.0 % ACPR PCR-adjusted |
Secondary
PCR - Adjusted ACPR at Day 42 in the PP Population
PCR - adjusted adequate clinical and parasitological response at Day 42
Time frame: Days 42
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR - Adjusted ACPR at Day 42 in the PP Population | 65.0 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR - Adjusted ACPR at Day 42 in the PP Population | 65.7 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR - Adjusted ACPR at Day 42 in the PP Population | 72.0 % ACPR PCR-adjusted |
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
Time frame: Day 63
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 63 in the ITT Population | 36.8 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 63 in the ITT Population | 38.6 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 63 in the ITT Population | 43.7 % ACPR PCR-adjusted |
Secondary
PCR-adjusted ACPR at Day 63 in the PP Population
PCR-adjusted adequate clinical and parasitological response at Day 63
Time frame: Day 63
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PCR-adjusted ACPR at Day 63 in the PP Population | 57.8 % ACPR PCR-adjusted |
| B) Artefenomel 800mg: Piperaquine 960mg | PCR-adjusted ACPR at Day 63 in the PP Population | 58.9 % ACPR PCR-adjusted |
| C) Artefenomel 800mg: Piperaquine 1440mg | PCR-adjusted ACPR at Day 63 in the PP Population | 69.0 % ACPR PCR-adjusted |
Secondary
PRR48
Parasite reduction ratio at 48 hours post dose
Time frame: 0, 6, 12, 18, 24, 30, 36 and 48 hours post dose
Population: 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. Subjects with sufficient data points to determine PRR48
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | PRR48 | 9.120 ratio |
| B) Artefenomel 800mg: Piperaquine 960mg | PRR48 | 9.300 ratio |
| C) Artefenomel 800mg: Piperaquine 1440mg | PRR48 | 8.690 ratio |
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.
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Artefenomel Cday7 African Patients (>=0.5 to <= 2 Years) | 2.0 ng/mL | Geometric Coefficient of Variation 147 |
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.
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Artefenomel Cday7 African Patients (>2 to <= 5 Years) | 3.3 ng/mL | Geometric Coefficient of Variation 142 |
Other Pre-specified
Artefenomel Cday7 African Patients (> 5 Years)
Artefenomel concentration on Day 7 in African Patients \> 5 years. All Treatment arms.
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Artefenomel Cday7 African Patients (> 5 Years) | 3.3 ng/mL | Geometric Coefficient of Variation 141 |
Other Pre-specified
Artefenomel Cday7 Asian Patients (All Ages)
Artefenomel concentration on Day 7 in Asian Patients (all ages). All Treatment arms.
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Artefenomel Cday7 Asian Patients (All Ages) | 5.1 ng/mL | Geometric Coefficient of Variation 95 |
Other Pre-specified
Piperaquine: Cday7 Africa (>=0.5 to <= 2 Years)
Piperaquine concentration at Day7 in African patients \>= 0.5 and \<= 2 years
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Piperaquine: Cday7 Africa (>=0.5 to <= 2 Years) | 5.0 ng/mL | Geometric Coefficient of Variation 63 |
| B) Artefenomel 800mg: Piperaquine 960mg | Piperaquine: Cday7 Africa (>=0.5 to <= 2 Years) | 5.9 ng/mL | Geometric Coefficient of Variation 70 |
| C) Artefenomel 800mg: Piperaquine 1440mg | Piperaquine: Cday7 Africa (>=0.5 to <= 2 Years) | 9.0 ng/mL | Geometric Coefficient of Variation 94 |
Other Pre-specified
Piperaquine: Cday7 Africa (>2 to <= 5 Years)
Piperaquine concentration at Day7 in African patients \> 2 and \<= 5years
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Piperaquine: Cday7 Africa (>2 to <= 5 Years) | 6.3 ng/mL | Geometric Coefficient of Variation 71 |
| B) Artefenomel 800mg: Piperaquine 960mg | Piperaquine: Cday7 Africa (>2 to <= 5 Years) | 9.2 ng/mL | Geometric Coefficient of Variation 87 |
| C) Artefenomel 800mg: Piperaquine 1440mg | Piperaquine: Cday7 Africa (>2 to <= 5 Years) | 10.9 ng/mL | Geometric Coefficient of Variation 92 |
Other Pre-specified
Piperaquine: Cday7 Africa (> 5 Years)
Piperaquine concentration at Day7 in African patients \> 5 years
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Piperaquine: Cday7 Africa (> 5 Years) | 5.6 ng/mL | Geometric Coefficient of Variation 113 |
| B) Artefenomel 800mg: Piperaquine 960mg | Piperaquine: Cday7 Africa (> 5 Years) | 8.8 ng/mL | Geometric Coefficient of Variation 105 |
| C) Artefenomel 800mg: Piperaquine 1440mg | Piperaquine: Cday7 Africa (> 5 Years) | 12.1 ng/mL | Geometric Coefficient of Variation 103 |
Other Pre-specified
Piperaquine: Cday7 Asia (All Ages)
Piperaquine concentration at Day7 in Asian patients all ages
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| A) Artefenomel 800mg: Piperaquine 640mg | Piperaquine: Cday7 Asia (All Ages) | 4.2 ng/mL | Geometric Coefficient of Variation 72 |
| B) Artefenomel 800mg: Piperaquine 960mg | Piperaquine: Cday7 Asia (All Ages) | 6.9 ng/mL | Geometric Coefficient of Variation 61 |
| C) Artefenomel 800mg: Piperaquine 1440mg | Piperaquine: Cday7 Asia (All Ages) | 9.3 ng/mL | Geometric Coefficient of Variation 78 |