Phase II Dose-ranging Study of Pyronaridine/Artesunate in Adults Patients With Plasmodium Falciparum Malaria

• Sponsor: Medicines for Malaria Venture (Other)
• Overall Status: Completed
• CT.gov ID: NCT01594931
• Collaborator: Shin Poong Pharmaceutical Co. Ltd. (Industry)
• Enrollment: 477
• Locations: 6
• Arms: 3
• Duration (Months): 9
• Patients Per Site: 79.5
• Patients Per Site Per Month: 8.8

Study Details

Study Description

Brief Summary

The primary trial objective is to determine the clinically effective dose of orally administered pyronaridine/artesunate (Pyramax®, PA) with a 3:1 ratio to treat adults with acute, symptomatic, uncomplicated P. falciparum malaria in South East Asia and Africa. Secondary trial objectives are to determine the safety of once-daily dosing for 3 days of PA and to explore possible ethnic differences in safety or efficacy.

Condition or Disease	Intervention/Treatment	Phase
Plasmodium Falciparum Malaria	Drug: pyronaridine/artesunate	Phase 2

Detailed Description

This is a double-blind, multicentre, randomized, parallel group, dose-finding study of the efficacy, safety and tolerability of a once-daily 3-day regimen of PA with a 3:1 weight/weight ratio for patients with acute, symptomatic, uncomplicated P. falciparum malaria. Patients will be recruited from 5 to 7 study sites in endemic regions of South East Asia and Africa and will be randomized to 1 of 3 treatment groups differing in dosage, with 160 patients per group (n-480). Randomization will be balanced within each study site across all 3 study groups in pre-assigned treatment blocks.

The first dose will be administered on Day 0 and patients will remain hospitalized for at least 4 days whilst undertaking the 3-day regimen. Patients will remain near the study site for a minimum of 7 days or once fever and parasite clearance is confirmed (assessed by 3 negative readings of fever and/or slide).

The primary efficacy end point is the cure rate on Day 28 - the proportion of patients with PCR-corrected adequate clinical and parasitological response (ACPR). Despite this Day 28 end point, the relatively long half-life of pyronaridine necessitates follow-up until 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: 477 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomised, Multi-Centre, Phase II, Dose-ranging Clinical Study to Assess the Safety and Efficacy of Fixed Dose, Orally Administered Pyronaridine and Artesunate (3:1) in Adult Patients With Acute Uncomplicated Plasmodium Falciparum Malaria
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Mar 1, 2006
• Actual Study Completion Date: Apr 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: pyronaridine/artesunate (6:2 mg/kg) pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg	Drug: pyronaridine/artesunate; Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.; Other Names: Pyramax
Experimental: pyronaridine/artesunate (9:3 mg/kg) pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg	Drug: pyronaridine/artesunate; Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.; Other Names: Pyramax
Experimental: pyronaridine/artesunate (12:4 mg/kg) pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg	Drug: pyronaridine/artesunate; Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.; Other Names: Pyramax

Outcome Measures

Primary Outcome Measures

1. PCR-Corrected ACPR at Day 28 [Day 28]

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

Secondary Outcome Measures

1. PCR-Corrected ACPR at Day 14 [Day 14]

   Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 14, defined as 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. Parasite Clearance Time [Thick blood slides were examined every 8 hours until at least 72 hours or until a negative smear was recorded]

   Parasite clearance time was defined as the time (in hours) from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of parasites for two consecutive negative readings eight hours apart, with confirmed negative reading at 24 hours after the first negative slide

3. Fever Clearance Time [Every 8 hours for at least 72 hours after the first dose]

   Fever clearance time was defined as the time (in hours) from first dosing to the first normal reading with fever clearance (2 consecutive assessments without fever (<37.5°C)). The method of temperature measurement was the same (ie, axillary, tympanic, oral or rectal) for each subject. Any subjects with a documented history of fever at inclusion, but who did not subsequently have a documented temperature reading >37.5°C during the 24 hours after initial dosing, were not included in this end point analysis.

4. Parasite Clearance [Days 1, 2, and 3]

   Parasite clearance is defined as zero presence of parasites for 2 consecutive negative readings 8 hours apart, with confirmed negative reading at 24 hours after the first negative slide. The proportion of subjects with parasite clearance was summarized at Days 1, 2, and 3.

5. Fever Clearance [Days 1, 2 and 3]

   Fever clearance was defined as a subject without fever for 2 consecutive assessments, plus confirmed normal temperature at 24 hours. The proportion of subjects with fever clearance was summarized at Days 1, 2, and 3.

6. Adverse Events (AEs) [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]

   An AE was defined as any unfavourable and unintended sign, symptom, syndrome, or illness that developed or worsened during the period of observation in the clinical study

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female patients between the age of 15 and 60 years of age inclusive

2. 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

3. Absence of severe malnutrition (defined as the weight-for-height being below -3 standard deviations or <70% of the median of the NCHS/WHO normalized reference values)

4. Weight of between 35 kg and 75 kg inclusive

5. Presence of acute symptomatic uncomplicated P. falciparum malaria with a diagnosis confirmed by a positive blood smear with asexual forms of P. falciparum only (i.e. no mixed infection) plus history of fever within the previous 24 hours or a measured temperature of ≥37.5°C (depending on method of measurement):

• the acceptable range is between 1,000 and 100,000 asexual parasite count/μl of blood and

• axillary/tympanic temperature of ≥ 37.5°C or oral/rectal temperature of ≥ 38.0°C

1. Ability to swallow oral medication

2. Ability to comply with study visit schedule: patients will be hospitalised for at least 4 days and will be required to remain in the vicinity of the trial site for a minimum of 7 days or until clearance of fever and parasite for at least 24 hours, whichever is the later. The patient is to return to the study site or to make themselves available for all scheduled follow up visits, until discharge at Day 42.

3. Females must not be pregnant or lactating and be willing to take measures to not become pregnant during the study period

4. Willingness and ability to comply with the study protocol for the duration of the study

Exclusion Criteria:

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

2. Mixed Plasmodium infection

3. Severe vomiting, defined as >3 times in the 24 hours prior to inclusion in the trial or inability to tolerate oral treatment

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

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

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

7. Evidence of use of any other antimalarial agent within 2 weeks prior to the start of the study confirmed by a negative urine test or using Eggelte dipsticks

8. Positive urine pregnancy test or lactating

9. Received an investigational drug within the past 4 weeks

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

11. Known seropositive HIV antibody

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

13. Known significant renal impairment as indicated by a serum creatinine of ≥ 1.4 mg/dl

14. Previous participation in this clinical trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pailin General Hospital	Pailin		Cambodia
2	Farafenni Field Station, c/o MRC Laboratories	Farafenni		Gambia
3	Bethesday Hospital	Tomohon	North Sulawesi	Indonesia
4	Centre de santé du roi Baudoin	Guediawaye		Senegal
5	Faculty of Tropical Medicine, Mahidol University	Bangkok		Thailand
6	MSF Epicentre	Mbarara		Uganda

Sponsors and Collaborators

• Medicines for Malaria Venture
• Shin Poong Pharmaceutical Co. Ltd.

Investigators

• Principal Investigator: Sornchai Looareesuwan, MD, Hospital of Tropical Diseases, Mahidol University, Bangkok, Thailand
• Principal Investigator: Duong Socheat, MD, Nat. Centre for Parasitol., Entomol. and Malaria Control, Phnom Penh, Cambodia
• Principal Investigator: Emiliana Tjitra, PhD, Bethesda Hospital, Tomohon, North Sulawasi, Indonesia
• Principal Investigator: Kalifa Bojang, MD, MRC Laboratories, Faraffeni, The Gambia
• Principal Investigator: Patrice Piola, MD, Epicentre, Mbarara, Uganda
• Principal Investigator: Oumar Gaye, MD, Centre de santé Roi Baudouin, Guediawaye, Senegal

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Medicines for Malaria Venture
• ClinicalTrials.gov Identifier: NCT01594931
• Other Study ID Numbers: SP-C-002-05
• First Posted: May 9, 2012
• Last Update Posted: Nov 2, 2021
• Last Verified: Oct 1, 2021

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

Study Results

Participant Flow

Arm/Group Title	Group A: Pyronaridine/Artesunate (6:2 mg/kg)	Group B: Pyronaridine/Artesunate (9:3 mg/kg)	Group C: Pyronaridine/Artesunate (12:4 mg/kg)
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1
Period Title: Overall Study
STARTED	160	157	160
COMPLETED	131	145	146
NOT COMPLETED	29	12	14

Baseline Characteristics

Arm/Group Title	Group A: Pyronaridine/Artesunate (6:2 mg/kg)	Group B: Pyronaridine/Artesunate (9:3 mg/kg)	Group C: Pyronaridine/Artesunate (12:4 mg/kg)	Total
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Total of all reporting groups
Overall Participants	160	157	160	477
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.0 (10.9)	27.4 (10.9)	28.9 (11.4)	27.8 (11.1)
Sex: Female, Male (Count of Participants)
Female	43 26.9%	37 23.6%	40 25%	120 25.2%
Male	117 73.1%	120 76.4%	119 74.4%	356 74.6%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	0 0%	0 0%	0 0%	0 0%
Black	49 30.6%	47 29.9%	48 30%	144 30.2%
Asian/Oriental	111 69.4%	110 70.1%	111 69.4%	332 69.6%
Region of Enrollment (participants) [Number]
Cambodia	10 6.3%	9 5.7%	10 6.3%	29 6.1%
Senegal	32 20%	32 20.4%	30 18.8%	94 19.7%
Gambia	12 7.5%	10 6.4%	13 8.1%	35 7.3%
Uganda	5 3.1%	5 3.2%	6 3.8%	16 3.4%
Thailand	80 50%	80 51%	80 50%	160 33.5%
Indonesia	21 13.1%	21 13.4%	21 13.1%	63 13.2%

Outcome Measures

1. Primary Outcome

Title	PCR-Corrected ACPR at Day 28
Description	Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28, defined as absence of parasitaemia on Day 28 without the subject'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

Subjects meeting the following: completed a full course of study medication and had known efficacy endpoints; no missed dose due to vomiting (except at D0); no concom. medication, except acetaminophen; no concom. disease that could have interfered with treatment outcome; no major protocol violation with respect to entry eligibility criteria.

Arm/Group Title	Group A: Pyronaridine/Artesunate (6:2 mg/kg)	Group B: Pyronaridine/Artesunate (9:3 mg/kg)	Group C: Pyronaridine/Artesunate (12:4 mg/kg)
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1
Measure Participants	101	103	102
Number (90% Confidence Interval) [percentage of subjects]	95	99	99

2. Secondary Outcome

Title	PCR-Corrected ACPR at Day 14
Description	Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 14, defined as 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

Subjects meeting the following: completed a full course of study medication and had known efficacy endpoints; no missed dose due to vomiting (except at D0); no concom. medication, except acetaminophen; no concom. disease that could have interfered with treatment outcome; no major protocol violation with respect to entry eligibility criteria.

Arm/Group Title	Group A: Pyronaridine/Artesunate (6:2 mg/kg)	Group B: Pyronaridine/Artesunate (9:3 mg/kg)	Group C: Pyronaridine/Artesunate (12:4 mg/kg)
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1
Measure Participants	105	107	106
Number (90% Confidence Interval) [percentage of subjects]	100	100	100

3. Secondary Outcome

Title	Parasite Clearance Time
Description	Parasite clearance time was defined as the time (in hours) from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of parasites for two consecutive negative readings eight hours apart, with confirmed negative reading at 24 hours after the first negative slide
Time Frame	Thick blood slides were examined every 8 hours until at least 72 hours or until a negative smear was recorded

Outcome Measure Data

Analysis Population Description

Subjects meeting the following: completed a full course of study medication and had known efficacy endpoints; no missed dose due to vomiting (except at D0); no concom. medication, except acetaminophen; no concom. disease that could have interfered with treatment outcome; no major protocol violation with respect to entry eligibility criteria.

Arm/Group Title	Group A: Pyronaridine/Artesunate (6:2 mg/kg)	Group B: Pyronaridine/Artesunate (9:3 mg/kg)	Group C: Pyronaridine/Artesunate (12:4 mg/kg)
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1
Measure Participants	108	109	109
Mean (Standard Deviation) [hours]	36.9 (20.73)	33.6 (17.08)	30.8 (14.96)

4. Secondary Outcome

Title	Fever Clearance Time
Description	Fever clearance time was defined as the time (in hours) from first dosing to the first normal reading with fever clearance (2 consecutive assessments without fever (<37.5°C)). The method of temperature measurement was the same (ie, axillary, tympanic, oral or rectal) for each subject. Any subjects with a documented history of fever at inclusion, but who did not subsequently have a documented temperature reading >37.5°C during the 24 hours after initial dosing, were not included in this end point analysis.
Time Frame	Every 8 hours for at least 72 hours after the first dose

Outcome Measure Data

Analysis Population Description

Subjects meeting the following: completed a full course of study medication and had known efficacy endpoints; no missed dose due to vomiting (except at D0); no concom. medication, except acetaminophen; no concom. disease that could have interfered with treatment outcome; no major protocol violation with respect to entry eligibility criteria.

Arm/Group Title	Group A: Pyronaridine/Artesunate (6:2 mg/kg)	Group B: Pyronaridine/Artesunate (9:3 mg/kg)	Group C: Pyronaridine/Artesunate (12:4 mg/kg)
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1
Measure Participants	84	93	93
Mean (Standard Deviation) [hours]	16.8 (12.75)	24.0 (25.99)	17.0 (12.90)

5. Secondary Outcome

Title	Parasite Clearance
Description	Parasite clearance is defined as zero presence of parasites for 2 consecutive negative readings 8 hours apart, with confirmed negative reading at 24 hours after the first negative slide. The proportion of subjects with parasite clearance was summarized at Days 1, 2, and 3.
Time Frame	Days 1, 2, and 3

Outcome Measure Data

Analysis Population Description

Subjects meeting the following: completed a full course of study medication and had known efficacy endpoints; no missed dose due to vomiting (except at D0); no concom. medication, except acetaminophen; no concom. disease that could have interfered with treatment outcome; no major protocol violation with respect to entry eligibility criteria.

Arm/Group Title	Group A: Pyronaridine/Artesunate (6:2 mg/kg)	Group B: Pyronaridine/Artesunate (9:3 mg/kg)	Group C: Pyronaridine/Artesunate (12:4 mg/kg)
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1
Measure Participants	108	109	109
Clearance rate (%) at Day 1 (24h after first dose)	74	82	84
Clearance rate (%) at Day 2 (48h after first dose)	93	96	95
Clearance rate (%) at Day 3 (72h after first dose)	96	98	99

6. Secondary Outcome

Title	Fever Clearance
Description	Fever clearance was defined as a subject without fever for 2 consecutive assessments, plus confirmed normal temperature at 24 hours. The proportion of subjects with fever clearance was summarized at Days 1, 2, and 3.
Time Frame	Days 1, 2 and 3

Outcome Measure Data

Analysis Population Description

Subjects meeting the following: completed a full course of study medication and had known efficacy endpoints; no missed dose due to vomiting (except at D0); no concom. medication, except acetaminophen; no concom. disease that could have interfered with treatment outcome; no major protocol violation with respect to entry eligibility criteria.

Arm/Group Title	Group A: Pyronaridine/Artesunate (6:2 mg/kg)	Group B: Pyronaridine/Artesunate (9:3 mg/kg)	Group C: Pyronaridine/Artesunate (12:4 mg/kg)
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1
Measure Participants	108	109	109
Clearance rate (%) at Day 1 (24h after first dose)	96	91	96
Clearance rate (%) at Day 2 (48h after first dose)	99	96	100
Clearance rate (%) at Day 3 (72h after first dose)	99	96	100

7. Secondary Outcome

Title	Adverse Events (AEs)
Description	An AE was defined as any unfavourable and unintended sign, symptom, syndrome, or illness that developed or worsened during the period of observation in the clinical study
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

The safety population includes all subjects who were randomized and received any study medication, regardless of the amount.

Arm/Group Title	Group A: Pyronaridine/Artesunate (6:2 mg/kg)	Group B: Pyronaridine/Artesunate (9:3 mg/kg)	Group C: Pyronaridine/Artesunate (12:4 mg/kg)
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1	Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1
Measure Participants	160	157	159
Nr subj. with ≥1 AE	106 66.3%	90 57.3%	91 56.9%
Nr subj. with ≥1 treatment-related AE	35 21.9%	33 21%	36 22.5%
Nr subj. with ≥1 SAE	3 1.9%	0 0%	1 0.6%
Nr subj. with ≥1 treatment-related SAE	0 0%	0 0%	1 0.6%
Nr subj. with ≥1 AE leading to death	0 0%	0 0%	0 0%
Nr subj. with ≥1 AE leading to study withdrawal	3 1.9%	1 0.6%	1 0.6%

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	Group A: Pyronaridine/Artesunate (6:2 mg/kg)		Group B: Pyronaridine/Artesunate (9:3 mg/kg)		Group C: Pyronaridine/Artesunate (12:4 mg/kg)
Arm/Group Description	Pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1		Pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1		Pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Pyronaridine/artesunate: Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1
All Cause Mortality
	Group A: Pyronaridine/Artesunate (6:2 mg/kg)		Group B: Pyronaridine/Artesunate (9:3 mg/kg)		Group C: Pyronaridine/Artesunate (12:4 mg/kg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/160 (0%)		0/157 (0%)		0/159 (0%)
Serious Adverse Events
	Group A: Pyronaridine/Artesunate (6:2 mg/kg)		Group B: Pyronaridine/Artesunate (9:3 mg/kg)		Group C: Pyronaridine/Artesunate (12:4 mg/kg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/160 (1.9%)		0/157 (0%)		1/159 (0.6%)
Cardiac disorders
Cardiac failure	1/160 (0.6%)	1	0/157 (0%)	0	0/159 (0%)	0
Infections and infestations
Abscess Limb	1/160 (0.6%)	1	0/157 (0%)	0	0/159 (0%)	0
Malaria	1/160 (0.6%)	1	0/157 (0%)	0	0/159 (0%)	0
Urinary tract infection	0/160 (0%)	0	0/157 (0%)	0	1/159 (0.6%)	1
Investigations
Hepatic enzyme increased	0/160 (0%)	0	0/157 (0%)	0	1/159 (0.6%)	1
Pregnancy, puerperium and perinatal conditions
Abortion incomplete	0/160 (0%)	0	0/157 (0%)	0	1/159 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Group A: Pyronaridine/Artesunate (6:2 mg/kg)		Group B: Pyronaridine/Artesunate (9:3 mg/kg)		Group C: Pyronaridine/Artesunate (12:4 mg/kg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/160 (66.3%)		90/157 (57.3%)		91/159 (57.2%)
Blood and lymphatic system disorders
Anaemia	16/160 (10%)	16	15/157 (9.6%)	15	13/159 (8.2%)	13
Eosinophilia	6/160 (3.8%)	6	7/157 (4.5%)	7	5/159 (3.1%)	5
Neutropenia	4/160 (2.5%)	4	0/157 (0%)	0	1/159 (0.6%)	1
Cardiac disorders
Arrhythmia	2/160 (1.3%)	2	0/157 (0%)	0	0/159 (0%)	0
Bradycardia	10/160 (6.3%)	10	7/157 (4.5%)	9	8/159 (5%)	8
Congenital, familial and genetic disorders
Fatigue	3/160 (1.9%)	3	4/157 (2.5%)	5	3/159 (1.9%)	3
Ear and labyrinth disorders
Vertigo	2/160 (1.3%)	2	1/157 (0.6%)	1	0/159 (0%)	0
Gastrointestinal disorders
Abdominal pain	8/160 (5%)	8	6/157 (3.8%)	6	4/159 (2.5%)	4
Abdominal pain upper	3/160 (1.9%)	4	4/157 (2.5%)	4	2/159 (1.3%)	3
Diarrhoea	3/160 (1.9%)	3	1/157 (0.6%)	1	2/159 (1.3%)	2
Dyspepsia	2/160 (1.3%)	2	2/157 (1.3%)	2	3/159 (1.9%)	3
Gastritis	2/160 (1.3%)	2	0/157 (0%)	0	0/159 (0%)	0
Nausea	4/160 (2.5%)	4	4/157 (2.5%)	4	3/159 (1.9%)	4
Toothache	2/160 (1.3%)	2	1/157 (0.6%)	1	0/159 (0%)	0
Vomiting	12/160 (7.5%)	12	8/157 (5.1%)	8	8/159 (5%)	9
General disorders
Asthenia	2/160 (1.3%)	2	4/157 (2.5%)	4	0/159 (0%)	0
Chest pain	0/160 (0%)	0	3/157 (1.9%)	3	0/159 (0%)	0
Chills	0/160 (0%)	0	2/157 (1.3%)	2	1/159 (0.6%)	1
Infections and infestations
Bronchitis	1/160 (0.6%)	1	3/157 (1.9%)	3	2/159 (1.3%)	2
Malaria	12/160 (7.5%)	12	8/157 (5.1%)	8	7/159 (4.4%)	7
Nasopharyngitis	2/160 (1.3%)	2	3/157 (1.9%)	4	3/159 (1.9%)	3
Otitis media acute	2/160 (1.3%)	2	0/157 (0%)	0	0/159 (0%)	0
Parasitic infection intestinal	4/160 (2.5%)	4	2/157 (1.3%)	2	4/159 (2.5%)	4
Plasmodium falciparum infection	6/160 (3.8%)	6	2/157 (1.3%)	2	2/159 (1.3%)	2
Upper respiratory tract infection	7/160 (4.4%)	8	4/157 (2.5%)	4	7/159 (4.4%)	8
Injury, poisoning and procedural complications
Wound	0/160 (0%)	0	2/157 (1.3%)	2	1/159 (0.6%)	1
Investigations
Alanine aminotransferase increased	4/160 (2.5%)	4	6/157 (3.8%)	6	6/159 (3.8%)	6
Aspartate aminotransferase increased	2/160 (1.3%)	2	1/157 (0.6%)	1	2/159 (1.3%)	2
Blood alkaline phosphatase increased	2/160 (1.3%)	2	1/157 (0.6%)	1	1/159 (0.6%)	1
Eosinophil count increased	17/160 (10.6%)	18	14/157 (8.9%)	15	14/159 (8.8%)	14
Transaminases increased	4/160 (2.5%)	4	3/157 (1.9%)	3	6/159 (3.8%)	6
Metabolism and nutrition disorders
Anorexia	5/160 (3.1%)	5	1/157 (0.6%)	1	4/159 (2.5%)	4
Dehydration	2/160 (1.3%)	2	2/157 (1.3%)	2	1/159 (0.6%)	1
Hypokalaemia	1/160 (0.6%)	1	5/157 (3.2%)	5	1/159 (0.6%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/160 (0.6%)	1	6/157 (3.8%)	6	4/159 (2.5%)	4
Myalgia	5/160 (3.1%)	5	8/157 (5.1%)	10	4/159 (2.5%)	4
Nervous system disorders
Dizziness	2/160 (1.3%)	2	3/157 (1.9%)	3	2/159 (1.3%)	2
Headache	22/160 (13.8%)	24	19/157 (12.1%)	21	17/159 (10.7%)	18
Paraesthesia	0/160 (0%)	0	2/157 (1.3%)	2	1/159 (0.6%)	1
Renal and urinary disorders
Proteinuria	3/160 (1.9%)	3	2/157 (1.3%)	2	3/159 (1.9%)	3
Reproductive system and breast disorders
Pelvic pain	2/160 (1.3%)	2	0/157 (0%)	0	1/159 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
Cough	13/160 (8.1%)	13	7/157 (4.5%)	7	13/159 (8.2%)	14
Nasal congestion	0/160 (0%)	0	2/157 (1.3%)	2	1/159 (0.6%)	1
Rhinorrhoea	1/160 (0.6%)	1	0/157 (0%)	0	3/159 (1.9%)	3
Rash	0/160 (0%)	0	1/157 (0.6%)	1	2/159 (1.3%)	2
Skin and subcutaneous tissue disorders
Hyperhidrosis	3/160 (1.9%)	3	2/157 (1.3%)	2	3/159 (1.9%)	3
Pruritus	2/160 (1.3%)	2	2/157 (1.3%)	2	0/159 (0%)	0

Limitations/Caveats

[Not Specified]

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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.