Pyronaridine Artesunate 3:1 Granule Formulation vs. Coartem© Crushed Tablets in P. Falciparum Malaria Pediatric Patients

• Sponsor: Medicines for Malaria Venture (Other)
• Overall Status: Completed
• CT.gov ID: NCT00541385
• Collaborator: Shin Poong Pharmaceuticals (Industry)
• Enrollment: 535
• Locations: 8
• Arms: 2
• Duration (Months): 13
• Patients Per Site: 66.9
• Patients Per Site Per Month: 5.1

Study Details

Study Description

Brief Summary

The primary objective of this Phase III clinical study is to demonstrate the efficacy of the fixed combination of pyronaridine artesunate (PA) granule formulation (60:20 mg; pediatric PYRAMAX®) by showing a PCR-corrected adequate clinical and parasitological cure rate (ACPR) of more than 90%.

Secondary objectives of this clinical study are to compare the efficacy (non-inferiority) and safety of the PA granule formulation compared to Coartem® (ie, the combination of artemether/lumefantrine [AL]) crushed tablets in a paediatric population and to assess the safety of the PA granule formulation.

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: pyronaridine artesunate; Drug: arthemeter lumefantrine	Phase 3

Detailed Description

This is a multi-centre, comparative, randomised, open-label, parallel-group study of the efficacy and safety of a 3-day regimen of a fixed combination of PA (3:1) versus AL in the treatment of acute uncomplicated Plasmodium falciparum mono-infection. The study population will include 534 patients, comprising male and female infants and children (body weight ≥5 and <25 kg) recruited from study sites in East, Central, and West Africa and South East Asia (max. 150 patients/site).

Patients will be randomised in a 2:1 ratio to receive either oral PA (60:20 mg granules) once a day for 3 consecutive days (Days 0, 1, and 2) or AL (20:120 mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). The study drug will be administered by a Third Party Investigator unblinded to the study treatment, while the Investigator will remain blinded. For PA, the dose range covered by this regimen is 7.0:2.3 mg to 13.3:4.4 mg, which has been shown to be effective and safe in Phase I and II studies. Posology will be based on body weight ranges for both the PA and AL regimens.

Patients will be confined to the study facility ≥4 days (Days 0, 1, 2, and 3) and remain near the study site for ≥7 days, or once fever and parasite clearance has been confirmed for ≥24 hours - whichever occurs earlier.

The primary efficacy end point for this study is the proportion of subjects with PCR-corrected ACPR on Day 28. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 535 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III Comparative, Open-labelled, Randomised, Clinical Study to Assess a Fixed Dose of Oral Pyronaridine Artesunate Granule Formulation vs. Coartem® Crushed Tablets in Infants With Acute Uncomplicated Plasmodium Falciparum Malaria
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PA group Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Drug: pyronaridine artesunate; The strength of the granule formulation is 60:20 mg pyronaridine artesunate per sachet. Depending on their body weight, patients will receive between 1 to 3 pyronaridine artesunate sachets per day, for 3 consecutive days The actual dose-range covered by this regimen is 7.0:2.3 mg/kg to 13.3:4.4 mg/kg pyronaridine artesunate, which has shown to be effective and safe in the phase II studies conducted in children and adults.; Other Names: Pyramax
Active Comparator: AL group Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Drug: arthemeter lumefantrine; The strength of the tablet is 20 mg artemether and 120 mg lumefantrine. Depending on their body weight, patients will receive either 1 or 2 crushed tablets twice a day (≥5 to <15 = 1 tablet, 15 to <25 kg = 2 tablets), for 3 consecutive days.; Other Names: Coartem

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With PCR-Corrected ACPR on Day 28 [Day 28]

   Percentage of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. The PCR-corrected ACPR on Day 28 is defined as the absence of parasitaemia on Day 28 without the patient's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure

Secondary Outcome Measures

1. Percentage of Participants With PCR-Corrected ACPR on Day 14 [Day 14]

   Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 14. The PCR-corrected ACPR on Day 14 is defined as the absence of parasitaemia on Day 14 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure

2. Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28 [Days 14 and 28]

   Percentage of subjects with adequate clinical and parasitological response (ACPR) on Day 14 and 28, without correction by PCR. Crude ACPR on Day 14 and 28 is defined as the absence of parasitaemia on Day 14 and 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure

3. Parasite Clearance Time [Days 0, 3, 7, 14, 21, 28, 35, and 42 or on any other day if the subject spontaneously returned within the 42-day study period]

   Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance was defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart

4. Fever Clearance Time [Day 0 and every 8 hours over ≥72 hours following first study drug administration or temperature normalization for ≥2 readings between 7 and 25 hours apart, then at each visit and as clinically indicated (within the 42-day study period)]

   Fever clearance time is defined as the time from first dosing to the first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.

5. Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 [Days 1, 2, and 3]

   Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance was defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart

6. Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 [Days 1, 2, and 3]

   Fever clearance time is defined as the time from first dosing to the first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart

7. Number of Subjects With ≥1 Adverse Event [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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female patients ≤12 years of age.

2. Body weight ≥ 5 kg and < 25 kg with no clinical evidence of severe malnutrition (defined as a child whose weight-for-height is below -3 standard deviations or <70% of the median of the NCHS/WHO normalised reference values).

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

4. Fever, as defined by axillary temperature ≥37.5°C or oral/tympanic/rectal temperature ≥38°C, or documented history of fever in the previous 24 hours and,

5. Positive microscopy of P. falciparum with parasite density between 1,000 and 200,000 asexual parasite count/µl of blood.

6. Written informed consent, in accordance with local practice, provided by parent/guardian. If the parent/guardian is unable to write, witnessed consent is permitted according to local ethical considerations. Where possible, patient assent will be sought.

7. Ability to swallow whole volume of liquid in which medication is suspended.

8. 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.

9. Ability and willingness to participate based on information given to parent or guardian and access to health facility. The patient is to comply with all scheduled follow up visits until D42.

Exclusion Criteria:

1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000 [Attachment 3].

2. Mixed Plasmodium infection.

3. Severe vomiting, defined as >3 times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or severe diarrhoea defined as ≥3 watery stools per day.

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

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

6. Presence of febrile conditions caused by diseases other than malaria.

7. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, lumefantrine or artesunate or other artemisinins.

8. Patients with known disturbances of electrolytes balance, e.g. hypokalaemia or hypomagnesaemia.

9. Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by reported patient history.

10. Pregnant or breastfeeding.

11. Patients taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (flecainide, metoprol, imipramine, amitriptyline, clomipramine).

12. Received an investigational drug within the past 4 weeks.

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

14. Known positive for HIV antibody.

15. Liver function tests [ASAT/ALAT levels] >2.5 times upper limit of normal range.

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

17. Previous participation in any clinical study with pyronaridine artesunate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centre National de Recherche et de Formation sur le Paludisme	Ouagadougou		Burkina Faso
2	Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa	Kinshasa		Congo, The Democratic Republic of the
3	Unité de Paludologie de l'Institut Pasteur d'Abidjan	Abidjan		Côte D'Ivoire
4	Medical Research Unit, Albert Schweitzer Hospital	Lambaréné		Gabon
5	Siaya District Hospital, Medical Superintendent's office	Siaya		Kenya
6	Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie	Bamako		Mali
7	Instituto Nacional de Saude, Ministero de Saude	Maputo		Mozambique
8	Puerto Princesa General Hospital	Puerto Princesa		Philippines

Sponsors and Collaborators

• Medicines for Malaria Venture
• Shin Poong Pharmaceuticals

Investigators

• Study Director: Claude Oeuvray, 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: NCT00541385
• Other Study ID Numbers: SP-C-007-07
• First Posted: Oct 10, 2007
• Last Update Posted: Nov 22, 2021
• Last Verified: Oct 1, 2021

• Keywords provided by Medicines for Malaria Venture: Falciparum malaria; pediatric; Coartem; artesunate; lumefantrine; pyronaridine; Pyramax
• Additional relevant MeSH terms: Malaria; Malaria, Falciparum; Artesunate; Lumefantrine; Pyronaridine

Study Results

Participant Flow

Arm/Group Title	PA Group	AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Period Title: Overall Study
STARTED	355	180
COMPLETED	274	142
NOT COMPLETED	81	38

Baseline Characteristics

Arm/Group Title	PA Group	AL Group	Total
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Total of all reporting groups
Overall Participants	355	180	535
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.9 (2.47)	5.3 (2.52)	5.0 (2.49)
Age, Customized (Count of Participants)
<1 year	12 3.4%	3 1.7%	15 2.8%
1-<5 years	148 41.7%	69 38.3%	217 40.6%
5-12 years	195 54.9%	108 60%	303 56.6%
Sex: Female, Male (Count of Participants)
Female	178 50.1%	96 53.3%	274 51.2%
Male	177 49.9%	84 46.7%	261 48.8%
Race/Ethnicity, Customized (Count of Participants)
Black	342 96.3%	172 95.6%	514 96.1%
Asian/Oriental	13 3.7%	8 4.4%	21 3.9%
Region of Enrollment (participants) [Number]
Gabon	53 14.9%	27 15%	80 15%
Burkina Faso	19 5.4%	9 5%	28 5.2%
Mali	86 24.2%	44 24.4%	130 24.3%
Philippines	13 3.7%	7 3.9%	20 3.7%
Congo, The Democratic Republic of the	56 15.8%	28 15.6%	84 15.7%
Côte D'Ivoire	72 20.3%	35 19.4%	107 20%
Kenya	56 15.8%	30 16.7%	86 16.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With PCR-Corrected ACPR on Day 28
Description	Percentage of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. The PCR-corrected ACPR on Day 28 is defined as the absence of parasitaemia on Day 28 without the patient's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: patients who completed a full course of study medication and had a known primary efficacy endpoint at D28; did not miss a dose; did not use concomitant medication, except acetaminophen; did not have a concomitant disease which may interfere with the clear classification of the treatment outcome; did not have a major protocol deviation.C

Arm/Group Title	PA Group	AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Measure Participants	337	167
Number (95% Confidence Interval) [percentage of cured subjects]	97.6	98.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PA Group
	Comments
	Type of Statistical Test	Other
	Comments	Analysis of the PCR-corrected ACPR response rate on Day 28 for the PA group. Null hypothesis: The PCR-corrected ACPR response rate on Day 28 for the PA group is ≤90%. Was tested versus the alternative: Alternative hypothesis: The PCR-corrected ACPR response rate on Day 28 for the PA group is >90%.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The threshold for significance was ≤0.025.
	Method	Exact binomial test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PA Group, AL Group
	Comments	Null hypothesis: The PCR-corrected ACPR response rate on Day 28 for the PA group is inferior to the PCR-corrected ACPR response rate for the AL group. Was tested versus the alternative: Alternative hypothesis: The PCR-corrected ACPR response rate on Day 28 for the PA group is not inferior to the PCR-corrected ACPR response rate for the AL group.
	Type of Statistical Test	Non-Inferiority
	Comments	The secondary efficacy analysis tested the non-inferiority of PA compared to the AL group with regard to the PCR-corrected ACPR response rate on Day 28 using a 2-sided 95% confidence interval (Newcombe Wilson score method without continuity correction) and a 10% non-inferiority margin for the EE population. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% confidence interval for the difference in 28-day PCR-corrected ACPR was not lower than 10%.
Statistical Test of Hypothesis	p-Value	0.3728
	Comments	If non-inferiority of PA was demonstrated, the p-value associated with a superiority test was calculated based on a 2-sided Chi-Square test. If the calculated p-value was <0.05, then the superiority of PA over AL was statistically demonstrated.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	ACPR percent difference
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -3.6 to 2.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With PCR-Corrected ACPR on Day 14
Description	Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 14. The PCR-corrected ACPR on Day 14 is defined as the absence of parasitaemia on Day 14 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: patients who completed a full course of study medication and had a known primary efficacy endpoint at D28; did not miss a dose; did not use concomitant medication, except acetaminophen; did not have a concomitant disease which may interfere with the clear classification of the treatment outcome; did not have a major protocol deviation.

Arm/Group Title	PA Group	AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Measure Participants	337	167
Number (95% Confidence Interval) [percentage of subjects]	100.0	100.0

3. Secondary Outcome

Title	Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28
Description	Percentage of subjects with adequate clinical and parasitological response (ACPR) on Day 14 and 28, without correction by PCR. Crude ACPR on Day 14 and 28 is defined as the absence of parasitaemia on Day 14 and 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure
Time Frame	Days 14 and 28

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: patients who completed a full course of study medication and had a known primary efficacy endpoint at D28; did not miss a dose; did not use concomitant medication, except acetaminophen; did not have a concomitant disease which may interfere with the clear classification of the treatment outcome; did not have a major protocol deviation.

Arm/Group Title	PA Group	AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Measure Participants	337	167
Percentage of Participants with ACPR at Day 14	100	100
Percentage of Participants with ACPR at Day 28	90.2	89.2

4. 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 was defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart
Time Frame	Days 0, 3, 7, 14, 21, 28, 35, and 42 or on any other day if the subject spontaneously returned within the 42-day study period

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: patients who completed a full course of study medication and had a known primary efficacy endpoint at D28; did not miss a dose; did not use concomitant medication, except acetaminophen; did not have a concomitant disease which may interfere with the clear classification of the treatment outcome; did not have a major protocol deviation.

Arm/Group Title	PA Group	AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Measure Participants	337	167
Median (95% Confidence Interval) [hours]	24.1	24.2

5. 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 for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.
Time Frame	Day 0 and every 8 hours over ≥72 hours following first study drug administration or temperature normalization for ≥2 readings between 7 and 25 hours apart, then at each visit and as clinically indicated (within the 42-day study period)

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population*: patients who completed a full course of study medication and had a known primary efficacy endpoint at D28; did not miss a dose; did not use concomitant medication, except acetaminophen; did not have a concomitant disease which may interfere with the clear classification of the treatment outcome; did not have a major protocol deviation. *does not include subjects initially included on history of fever.

Arm/Group Title	PA Group	AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Measure Participants	264	126
Median (95% Confidence Interval) [hours]	8.1	8.1

6. Secondary Outcome

Title	Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3
Description	Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance was defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart
Time Frame	Days 1, 2, and 3

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population: patients who completed a full course of study medication and had a known primary efficacy endpoint at D28; did not miss a dose; did not use concomitant medication, except acetaminophen; did not have a concomitant disease which may interfere with the clear classification of the treatment outcome; did not have a major protocol deviation.

Arm/Group Title	PA Group	AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Measure Participants	337	167
Percentage of Participants with parasite clearance at Day 1 (24h after first dose)	49.9	43.7
Percentage of Participants with parasite clearance at Day 2 (48h after first dose)	95.5	95.2
Percentage of Participants with parasite clearance at Day 3 (72h after first dose)	97.0	98.8

7. Secondary Outcome

Title	Proportion of Subjects With Fever Cleared on Days 1, 2, and 3
Description	Fever clearance time is defined as the time from first dosing to the first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart
Time Frame	Days 1, 2, and 3

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population*: patients who completed a full course of study medication and had a known primary efficacy endpoint at D28; did not miss a dose; did not use concomitant medication, except acetaminophen; did not have a concomitant disease which may interfere with the clear classification of the treatment outcome; did not have a major protocol deviation. *does not include subjects initially included on history of fever.

Arm/Group Title	PA Group	AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Measure Participants	264	126
Percentage of Participants with fever clearance at Day 1 (24h after first dose)	87.1	81.0
Percentage of Participants with fever clearance at Day 2 (48h after first dose)	98.5	96.8
Percentage of Participants with fever clearance at Day 3 (48h after first dose)	99.6	98.4

8. Secondary Outcome

Title	Number of Subjects With ≥1 Adverse Event
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: all randomized subjects who received any amount of study medication. Subjects were analyzed as treated

Arm/Group Title	PA Group	AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Measure Participants	355	180
Nr subj. with ≥1 AE	285 80.3%	143 79.4%
Nr subj. with ≥1 treatment-related AE	132 37.2%	80 44.4%
Nr subj. with ≥1 SAE	1 0.3%	0 0%
Nr subj. with ≥1 treatment-related SAE	0 0%	0 0%
Nr subj. with ≥1 severe or life-threatening AE	2 0.6%	2 1.1%
Nr subj. with ≥1 AE leading to death	0 0%	0 0%
Nr subj. ≥1 AE leading to drug discontinuation	6 1.7%	3 1.7%
Nr subj. with ≥1 AE leading to study withdrawal	6 1.7%	3 1.7%

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	PA Group		AL Group
Arm/Group Description	Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology was based on body weight ranges. Subjects were randomized in a 2:1 ratio to receive either PA or AL.		Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology was based on body weight ranges. Subjects were randomized in a 2:1 ratio to receive either PA or AL.
All Cause Mortality
	PA Group		AL Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/355 (0%)		0/180 (0%)
Serious Adverse Events
	PA Group		AL Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/355 (0.3%)		0/180 (0%)
Infections and infestations
Malaria	1/355 (0.3%)	1	0/180 (0%)	0
Other (Not Including Serious) Adverse Events
	PA Group		AL Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	285/355 (80.3%)		143/180 (79.4%)
Blood and lymphatic system disorders
Anaemia	34/355 (9.6%)	36	14/180 (7.8%)	14
Splenomegaly	8/355 (2.3%)	8	4/180 (2.2%)	5
Gastrointestinal disorders
Vomiting	25/355 (7%)	27	8/180 (4.4%)	9
Abdominal pain	11/355 (3.1%)	11	8/180 (4.4%)	8
General disorders
Pyrexia	23/355 (6.5%)	24	8/180 (4.4%)	8
Influenza like illness	19/355 (5.4%)	19	8/180 (4.4%)	8
Infections and infestations
Upper respiratory tract infection	42/355 (11.8%)	44	19/180 (10.6%)	19
Bronchitis	28/355 (7.9%)	31	10/180 (5.6%)	10
Helminthic infection	11/355 (3.1%)	11	3/180 (1.7%)	4
Nasopharyngitis	9/355 (2.5%)	10	3/180 (1.7%)	3
Rhinitis	8/355 (2.3%)	10	3/180 (1.7%)	3
Tinea capitis	7/355 (2%)	7	1/180 (0.6%)	1
Pneumonia	4/355 (1.1%)	4	5/180 (2.8%)	5
Tonsillitis	2/355 (0.6%)	2	4/180 (2.2%)	4
Investigations
Platelet count increased	33/355 (9.3%)	33	19/180 (10.6%)	19
Blood glucose decreased	32/355 (9%)	32	19/180 (10.6%)	19
Blood albumin decreased	21/355 (5.9%)	21	16/180 (8.9%)	16
Aspartate aminotransferase increased	17/355 (4.8%)	17	8/180 (4.4%)	8
Blood potassium increased	16/355 (4.5%)	16	6/180 (3.3%)	6
Haematocrit decreased	16/355 (4.5%)	16	5/180 (2.8%)	5
Haemoglobin decreased	15/355 (4.2%)	15	5/180 (2.8%)	5
White blood cell count increased	9/355 (2.5%)	9	2/180 (1.1%)	2
Alanine aminotransferase increased	7/355 (2%)	7	2/180 (1.1%)	2
Blood creatinine decreased	7/355 (2%)	7	7/180 (3.9%)	7
Platelet count decreased	7/355 (2%)	7	1/180 (0.6%)	1
Nervous system disorders
Headache	13/355 (3.7%)	14	5/180 (2.8%)	5
Respiratory, thoracic and mediastinal disorders
Cough	44/355 (12.4%)	48	28/180 (15.6%)	30
Productive cough	6/355 (1.7%)	6	4/180 (2.2%)	4

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.