The purpose of this study is to compare the efficacy and safety of the fixed combination of pyronaridine artesunate (Pyramax®, PA) (180:60 mg) with that of standard chloroquine therapy in children and adults with acute, uncomplicated Plasmodium vivax malaria.
This is a multi-centre, randomised, double-blind, double-dummy, parallel-group, non-inferiority study comparing the efficacy and safety of the fixed combination of pyronaridine/artesunate (ie, PP/AS \[PA\]) (180:60 mg) with that of standard chloroquine therapy in children and adults with acute uncomplicated P. vivax malaria. The study population will include 456 patients, comprising male and female children (≥20 kg body weight) and adults recruited from study sites in South East Asia and India. Patients will be randomised in a 1:1 ratio to receive either oral PA (180:60 mg tablets) plus chloroquine-placebo or oral chloroquine (155 mg tablets).plus PA-placebo, once a day for 3 consecutive days (Days 0, 1, and 2). For PA, posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The dose range covered by this regimen is 7.2:2.4 mg/kg to 13.8:4.6 mg/kg, which has been shown to be effective and safe in Phase I and II studies. The chloroquine daily dose is 10 mg/kg on Days 0 and 1 and 5 mg/kg on Day 2 for children, and 620 mg on Days 0 and 1 and 310 mg on Day 2 for adults. Patients will be confined to the study facility for ≥4 days (Days 0,1,2 \& 3) and ideally remain near the study site for ≥7 days, or once fever and parasite clearance has been confirmed for ≥24 hours - whichever occurs later. The primary efficacy end point for the study is the crude cure rate on Day 14, which is defined as the absence of P. vivax parasitaemia on Day 14. Scheduled follow-up visits will continue until completion of the study at Day 42. In the case of adverse events reported and unresolved at Day 42, patients will be followed up for a further 30 days, or until resolution of the event. For patients who complete the study up to Day 28 and who have normal glucose-6-phosphate dehydrogenase (G-6-PD) activity, a 14-day course of primaquine (15 mg/day for adults and 0.3 mg/kg/day for children) will be administered starting on Day 28 to complete their radical cure. Subjects who are deficient in G-6-PD and who completed the study up to Day 28 will be treated per country policy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
456
Pailin Referral Hospital
Pailin, Pailin, Cambodia
Wentlock District Hospital
Mangalore, India
RSUD TC Hillers
Maumere, Nusa Tenggara Timur, Indonesia
MaeLamad District Hospital
Mae Ramat, Changwat Tak, Thailand
Crude Cure Rate on Day 14
Cure rate on Day 14 is defined as the absence of P. vivax parasitaemia on Day 14 irrespective of temperature (axillary, oral, tympanic, rectal) without previously meeting any of the criteria of treatment failure throughout the follow-up period.
Time frame: Day 14
Crude Cure Rate on Days 21 and 28.
Cure on Day 21 and 28 is defined as the absence of P. vivax parasitaemia on Day 21 and 28 irrespective of temperature (axillary, oral, tympanic, rectal) without previously meeting any of the criteria of treatment failure throughout the follow-up period.
Time frame: Day 21 and 28
Parasite Clearance Time
Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart.
Time frame: Days 0 to 42
Fever Clearance Time
Fever clearance time is defined as the time from first dosing to the first normal reading of temperature (\<37.5°C for axillary/tympanic or \<38°C for oral/rectal) for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.
Time frame: Days 0 to 42
Percentage of Subjects With Parasite Clearance on Days 1, 2, and 3
Percentage of subjects with parasite clearance on Day 1 (24 hours after first dose), Day 2 (48 hours after first dose), and Day 3 (72 hours after first dose).
Time frame: Days 1, 2, and 3
Percentage of Subjects With Fever Clearance on Days 1, 2, and 3
Percentage of subjects with fever clearance on Day 1 (24 hours after first dose), Day 2 (48 hours after first dose), and Day 3 (72 hours after first dose).
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MaeSod General Hospital
Mae Sot, Changwat Tak, Thailand
Time frame: Day 1, 2, and 3
Number of Participants With Adverse Events
Number of participants with adverse events, including clinically significant laboratory results, ECG, vital signs or physical examination abnormalities.
Time frame: Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier