Pyronaridine Artesunate (3:1) in Children and Adults With Acute Plasmodium Vivax Malaria

• Sponsor: Medicines for Malaria Venture (Other)
• Overall Status: Completed
• CT.gov ID: NCT00440999
• Collaborator: Shin Poong Pharmaceuticals (Industry)
• Enrollment: 456
• Locations: 5
• Arms: 2
• Duration (Months): 18.1
• Patients Per Site: 91.2
• Patients Per Site Per Month: 5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: Pyronaridine artesunate; Drug: Chloroquine	Phase 3

Detailed Description

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 Design

• Study Type: Interventional
• Actual Enrollment: 456 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III Comparative (Double-blind, Double-dummy) Randomised Multicentre Study to Assess the Safety & Efficacy of Oral Pyronaridine Artesunate (180:60 mg) Versus Chloroquine (155 mg) in Children & Adult Patients With Acute Vivax Malaria
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: pyronaridine artesunate The tablet strength is 180:60 mg oral PA plus chloroquine-placebo. Depending on their body weight, patients receive 1 to 4 tablets once a day, for 3 days. The actual dose-level range covered by this regimen is 7.2: 2.4 mg/kg to 13.8:4.6 mg/kg pyronaridine artesunate.	Drug: Pyronaridine artesunate; Other Names: Pyramax
Active Comparator: chloroquine The tablet strength is 155 mg oral chloroquine plus PA-placebo. Patients receive: For adults: 620 mg (i.e. 4 tablets) on Days 0 and 1 and 310 mg (i.e. 2 tablets) on Day 2. For children: 10 mg/kg on Days 0 and 1 and 5 mg/kg on Day 2.	Drug: Chloroquine

Outcome Measures

Primary Outcome Measures

1. Crude Cure Rate on Day 14 [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.

Secondary Outcome Measures

1. Crude Cure Rate on Days 21 and 28. [Day 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.

2. Parasite Clearance Time [Days 0 to 42]

   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.

3. Fever Clearance Time [Days 0 to 42]

   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.

4. Percentage of Subjects With Parasite Clearance on Days 1, 2, and 3 [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).

5. Percentage of Subjects With Fever Clearance on Days 1, 2, and 3 [Day 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).

6. Number of Participants With Adverse Events [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]

   Number of participants with adverse events, including clinically significant laboratory results, ECG, vital signs or physical examination abnormalities.

Other Outcome Measures

1. Percentage of Subjects With PCR-corrected Cure Rate on Days 14, 21, and 28 [Day 14, 21, and 28]

   Cure on Days 14, 21, and 28 is defined as the absence of P. vivax parasitaemia on Days 14, 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.

2. Percentage of Subjects With Crude and PCR-corrected Cure Rate on Day 42 [Day 42]

   Cure on Day 42 is defined as the absence of P. vivax parasitaemia on Day 42 irrespective of temperature (axillary, oral, tympanic, rectal) without previously meeting any of the criteria of treatment failure throughout the follow-up period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female patients between the age of 3 and 60 years, inclusive.

2. Body weight between 20 kg and 90 kg with no clinical evidence of severe malnutrition.

3. Presence of acute uncomplicated P. vivax mono-infection confirmed by:

• Fever, as defined by axillary/tympanic temperature ≥37.5°C or oral/rectal temperature ≥38°C, or history of fever in the previous 24 hours (history of fever must be documented) and,

• Positive microscopy of P. vivax with parasite density ≥250/ mcL of blood (including at least 50% of asexual parasites).

1. Written informed consent, in accordance with local practice, provided by patient and/or parent/guardian/spouse. If the patient is unable to write, witnessed consent is permitted according to local ethical considerations.

2. Ability to swallow oral medication.

3. Ability and willingness to participate based on information given to patient or parent or guardian and access to health facility.

Exclusion Criteria:

1. Presence of a mixed Plasmodium infection.

2. Presence of other clinical condition requiring hospitalization.

3. Presence of significant anaemia, as defined by Hb <8 g/dL.

4. Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTc interval ≥450 msec), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other abnormality (including recent head trauma).

5. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, chloroquine or artesunate or other artemisinins.

6. Known history of hypersensitivity, allergic or adverse reactions to chloroquine, primaquine and related agents.

7. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab).

8. Known seropositive HIV antibody.

9. Have received any antimalarial treatment in the preceding 2 weeks, as determined by history and, whenever feasible, by screening test.

10. Have received antibacterial with known antimalarial activity in the preceding 2 weeks.

11. Have received any investigational drug within the past 4 weeks.

12. Liver function tests (AST/ALT levels) >2.5 times the upper limit of normal range.

13. Known significant renal impairment as indicated by serum creatinine levels of >1.4 mg/dL.

14. 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 to not become pregnant during the study period.

15. Previous participation in the present clinical trial with PA.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pailin Referral Hospital	Pailin	Pailin Province	Cambodia
2	Wentlock District Hospital	Mangalore		India
3	RSUD TC Hillers	Maumere	Nusa Tenggara Timur	Indonesia	86113
4	MaeLamad District Hospital	Mae Ramat	Tak Province	Thailand
5	MaeSod General Hospital	Mae Sot	Tak Province	Thailand

Sponsors and Collaborators

• Medicines for Malaria Venture
• Shin Poong Pharmaceuticals

Investigators

• Study Director: Isabelle Borghini Fuhrer, PhD, Medicines for Malaria Venture

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Medicines for Malaria Venture

Publications

None provided.

• Responsible Party: Medicines for Malaria Venture
• ClinicalTrials.gov Identifier: NCT00440999
• Other Study ID Numbers: SP-C-006-06
• First Posted: Feb 27, 2007
• Last Update Posted: Nov 2, 2021
• Last Verified: Oct 1, 2021

• Keywords provided by Medicines for Malaria Venture: P vivax; malaria; artemisinin based combination therapy (ACT); antimalarial; pyronaridine artesunate (Pyramax)
• Additional relevant MeSH terms: Malaria; Malaria, Vivax; Artesunate; Chloroquine; Pyronaridine

Study Results

Participant Flow

Arm/Group Title	Pyronaridine - Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (D0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (D0, 1, and 2). The 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.
Period Title: Overall Study
STARTED	228	228
COMPLETED	193	187
NOT COMPLETED	35	41

Baseline Characteristics

Arm/Group Title	Pyronaridine - Artesunate	Chloroquine	Total
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (D0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (D0, 1, and 2). The 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.	Total of all reporting groups
Overall Participants	228	228	456
Age (years) [Mean (Standard Deviation) ]
Total	27.0 (11.7)	26.4 (10.93)	26.7 (11.04)
Cambodia	21.0 (8.93)	23.0 (9.92)	22.0 (9.46)
India	31.5 (12.20)	27.9 (11.99)	29.7 (12.15)
Indonesia/Maumere	26.7 (10.59)	18.6 (9.07)	23.0 (10.54)
Thailand/Mae Sot	29.6 (11.15)	29.6 (9.80)	29.6 (10.44)
Thailand/Mae Ramat	30.5 (9.93)	29.0 (11.04)	29.7 (10.47)
Age, Customized (Count of Participants)
≤12 years	14 6.1%	13 5.7%	27 5.9%
>12 years	214 93.9%	215 94.3%	429 94.1%
Sex: Female, Male (Count of Participants)
Female	56 24.6%	64 28.1%	120 26.3%
Male	172 75.4%	164 71.9%	336 73.7%
Female	25 11%	27 11.8%	52 11.4%
Male	52 22.8%	50 21.9%	102 22.4%
Female	5 2.2%	7 3.1%	12 2.6%
Male	34 14.9%	34 14.9%	68 14.9%
Female	6 2.6%	3 1.3%	9 2%
Male	7 3.1%	8 3.5%	15 3.3%
Female	11 4.8%	11 4.8%	22 4.8%
Male	38 16.7%	39 17.1%	77 16.9%
Female	9 3.9%	16 7%	25 5.5%
Male	41 18%	33 14.5%	74 16.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	228 100%	228 100%	456 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Cambodia	77 33.8%	77 33.8%	154 33.8%
Thailand	99 43.4%	99 43.4%	198 43.4%
India	39 17.1%	41 18%	80 17.5%
Indonesia	13 5.7%	11 4.8%	24 5.3%

Outcome Measures

1. Primary Outcome

Title	Crude Cure Rate on Day 14
Description	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

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

Arm/Group Title	Pyronaridine Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (Day 0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (Day 0, 1, and 2). The 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.
Measure Participants	218	209
Total cured	217 95.2%	209 91.7%
Cambodia	75 32.9%	73 32%
India	33 14.5%	33 14.5%
Indonesia/Maumere	11 4.8%	10 4.4%
Thailand/Mae Sot	49 21.5%	46 20.2%
Thailand/Mae Ramat	50 21.9%	47 20.6%
baseline P. vivax = 250-5,000/uL	69 30.3%	80 35.1%
baseline P. vivax = >5,000/uL-10,000/uL	58 25.4%	59 25.9%
baseline P. vivax = >10,000/uL	89 39%	70 30.7%
age ≤ 12 years	13 5.7%	11 4.8%
age ≥ 12 years	204 89.5%	198 86.8%
Gender - Male	164 71.9%	148 64.9%
Gender - Female	53 23.2%	61 26.8%
Previous P. vivax episode in the past = no	107 46.9%	93 40.8%
Previous P. vivax episode in the past = yes	110 48.2%	116 50.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pyronaridine Artesunate, Chloroquine
	Comments	Null hypothesis: The cure rate on Day 14 for the PA group is inferior to the cure rate on Day 14 for the chloroquine group by more than 10%. Was tested against the alternative: Alternative hypothesis: The cure rate on Day 14 for the PA group was not inferior to the cure rate on Day 14 for the chloroquine group by more than 10%.
	Type of Statistical Test	Non-Inferiority
	Comments	The primary efficacy analysis tested the non-inferiority of the PA group compared to the comparator group with regard to the crude cure rate on Day 14 using the 2-sided 95% confidence interval (CI) (Newcombe-Wilson score method without continuity correction) and a 10% non-inferiority margin. Non-inferiority was claimed if the lower limit of the 2-sided 95% CI for the difference in cure rates on Day 14 was >10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in cure rate
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -2.6 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Conclusion: non-inferiority between PA & chloroquine.

2. Secondary Outcome

Title	Crude Cure Rate on Days 21 and 28.
Description	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

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

Arm/Group Title	Pyronaridine Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (Day 0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (Day 0, 1, and 2). The 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.
Measure Participants	218	209
Cure rate (%) at Day 21	99.5	99.5
Cure rate (%) at Day 28	97.1	98.0

3. Secondary Outcome

Title	Parasite Clearance Time
Description	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

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

Arm/Group Title	Pyronaridine Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (Day 0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (Day 0, 1, and 2). The 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.
Measure Participants	218	209
Median (95% Confidence Interval) [hours]	23.1	32.0

4. Secondary Outcome

Title	Fever Clearance Time
Description	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

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

Arm/Group Title	Pyronaridine Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (Day 0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (Day 0, 1, and 2). The 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.
Measure Participants	168	154
Median (95% Confidence Interval) [hours]	15.8	23.8

5. Secondary Outcome

Title	Percentage of Subjects With Parasite Clearance on Days 1, 2, and 3
Description	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

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

Arm/Group Title	Pyronaridine Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (D0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (D0, 1, and 2). The 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.
Measure Participants	218	209
Clearance rate (%) at Day 1 (24h after first dose)	71.6	30.6
Clearance rate (%) at Day 2 (48h after first dose)	99.5	88.0
Clearance rate (%) at Day 3 (72h after first dose)	100.0	96.7

6. Secondary Outcome

Title	Percentage of Subjects With Fever Clearance on Days 1, 2, and 3
Description	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).
Time Frame	Day 1, 2, and 3

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

Arm/Group Title	Pyronaridine Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (Day 0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (Day 0, 1, and 2). The 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.
Measure Participants	168	154
Clearance rate (%) at Day 1 (24h after first dose)	78.6	58.4
Clearance rate (%) at Day 2 (48h after first dose)	89.9	88.3
Clearance rate (%) at Day 3 (72h after first dose)	97.0	97.4

7. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

Safety population consists of all randomized subjects who received any amount of study medication, subjects were analyzed as treated.

Arm/Group Title	Pyronaridine Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (Day 0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (Day 0, 1, and 2). The 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.
Measure Participants	228	228
Nr subj. with ≥1 AE	92 40.4%	72 31.6%
Nr subj. with ≥1 treatment-related AE	27 11.8%	23 10.1%
Nr subj. with ≥1 SAE	2 0.9%	0 0%
Nr subj. with ≥1 treatment-related SAE	0 0%	0 0%
Nr subj. with ≥1 severe or life-threatening AE	0 0%	2 0.9%
Nr subj. with ≥1 AE leading to death	0 0%	0 0%
Nr subj. ≥1 AE leading to study drug discontinuation	0 0%	2 0.9%
Nr subj. with ≥1 AE leading to study withdrawal	0 0%	2 0.9%

8. Other Pre-specified Outcome

Title	Percentage of Subjects With PCR-corrected Cure Rate on Days 14, 21, and 28
Description	Cure on Days 14, 21, and 28 is defined as the absence of P. vivax parasitaemia on Days 14, 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 14, 21, and 28

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

Arm/Group Title	Pyronaridine Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (Day 0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (Day 0, 1, and 2). The 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.
Measure Participants	216	200
Cure rate (%) at Day 14	100.0	99.5
Cure rate (%) at Day 21	100.0	99.5
Cure rate (%) at Day 28	98.1	97.9

9. Other Pre-specified Outcome

Title	Percentage of Subjects With Crude and PCR-corrected Cure Rate on Day 42
Description	Cure on Day 42 is defined as the absence of P. vivax parasitaemia on Day 42 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 42

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

Arm/Group Title	Pyronaridine Artesunate	Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (Day 0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (Day 0, 1, and 2). The 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.
Measure Participants	216	200
Crude cure rate (%)	95.5	92.1
PCR-corrected cure rate (%)	95.0	94.1

Adverse Events

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
Arm/Group Title	Pyronaridine Artesunate		Chloroquine
Arm/Group Description	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (D0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.		Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (D0, 1, and 2). The 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.
All Cause Mortality
	Pyronaridine Artesunate		Chloroquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/228 (0.9%)		0/228 (0%)
Serious Adverse Events
	Pyronaridine Artesunate		Chloroquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/228 (0.9%)		0/228 (0%)
General disorders
Pyrexia	1/228 (0.4%)	1	0/228 (0%)	0
Infections and infestations
Typhoid fever	1/228 (0.4%)	1	0/228 (0%)	0
Other (Not Including Serious) Adverse Events
	Pyronaridine Artesunate		Chloroquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/228 (39.5%)		72/228 (31.6%)
General disorders
Fatigue	12/228 (5.3%)	12	11/228 (4.8%)	11
Infections and infestations
Nasopharyngitis	13/228 (5.7%)	15	6/228 (2.6%)	7
Metabolism and nutrition disorders
Anorexia	19/228 (8.3%)	19	10/228 (4.4%)	10
Musculoskeletal and connective tissue disorders
Myalgia	30/228 (13.2%)	30	21/228 (9.2%)	22
Nervous system disorders
Headache	45/228 (19.7%)	52	34/228 (14.9%)	40

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.