Plasmodium Falciparum Malaria
Conditions
Keywords
malaria, antimalarial, artemisinin based combination therapy (ACT), pyronaridine artesunate (Pyramax)
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.
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.
Interventions
DRUGpyronaridine/artesunate
Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.
Sponsors
Shin Poong Pharmaceutical Co. Ltd.
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
15 Years to 60 Years
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 6. Ability to swallow oral medication 7. 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. 8. Females must not be pregnant or lactating and be willing to take measures to not become pregnant during the study period 9. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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 |
| 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. |
| 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 |
| 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. |
Countries
Cambodia, Indonesia, Senegal, Thailand, The Gambia, Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) 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 | 160 |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) 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 | 157 |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) 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 | 160 |
| Total | 477 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 1 |
| Overall Study | Lack of Efficacy | 7 | 2 | 2 |
| Overall Study | Lost to Follow-up | 4 | 3 | 3 |
| Overall Study | No defiined | 11 | 4 | 7 |
| Overall Study | Protocol Violation | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|
| Age, Continuous | 27.0 years STANDARD_DEVIATION 10.9 | 27.4 years STANDARD_DEVIATION 10.9 | 28.9 years STANDARD_DEVIATION 11.4 | 27.8 years STANDARD_DEVIATION 11.1 |
| Race/Ethnicity, Customized Asian/Oriental | 111 Participants | 110 Participants | 111 Participants | 332 Participants |
| Race/Ethnicity, Customized Black | 49 Participants | 47 Participants | 48 Participants | 144 Participants |
| Race/Ethnicity, Customized White/Caucasian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Cambodia | 10 participants | 9 participants | 10 participants | 29 participants |
| Region of Enrollment Gambia | 12 participants | 10 participants | 13 participants | 35 participants |
| Region of Enrollment Indonesia | 21 participants | 21 participants | 21 participants | 63 participants |
| Region of Enrollment Senegal | 32 participants | 32 participants | 30 participants | 94 participants |
| Region of Enrollment Thailand | 80 participants | 80 participants | 80 participants | 160 participants |
| Region of Enrollment Uganda | 5 participants | 5 participants | 6 participants | 16 participants |
| Sex: Female, Male Female | 43 Participants | 37 Participants | 40 Participants | 120 Participants |
| Sex: Female, Male Male | 117 Participants | 120 Participants | 119 Participants | 356 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 160 | 0 / 157 | 0 / 159 |
| other Total, other adverse events | 106 / 160 | 90 / 157 | 91 / 159 |
| serious Total, serious adverse events | 3 / 160 | 0 / 157 | 1 / 159 |
Outcome results
Primary
PCR-Corrected ACPR at 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
Time frame: Day 28
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | PCR-Corrected ACPR at Day 28 | 95 percentage of subjects |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | PCR-Corrected ACPR at Day 28 | 99 percentage of subjects |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | PCR-Corrected ACPR at Day 28 | 99 percentage of subjects |
Secondary
Adverse Events (AEs)
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
Population: The safety population includes all subjects who were randomized and received any study medication, regardless of the amount.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 treatment-related SAE | 0 Participants |
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 AE leading to study withdrawal | 3 Participants |
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 AE | 106 Participants |
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 AE leading to death | 0 Participants |
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 treatment-related AE | 35 Participants |
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 SAE | 3 Participants |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 SAE | 0 Participants |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 treatment-related SAE | 0 Participants |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 treatment-related AE | 33 Participants |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 AE leading to death | 0 Participants |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 AE leading to study withdrawal | 1 Participants |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 AE | 90 Participants |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 AE leading to study withdrawal | 1 Participants |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 AE | 91 Participants |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 SAE | 1 Participants |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 treatment-related SAE | 1 Participants |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 treatment-related AE | 36 Participants |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Adverse Events (AEs) | Nr subj. with ≥1 AE leading to death | 0 Participants |
Secondary
Fever Clearance
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Fever Clearance | Clearance rate (%) at Day 3 (72h after first dose) | 99 percentage of subjects |
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Fever Clearance | Clearance rate (%) at Day 1 (24h after first dose) | 96 percentage of subjects |
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Fever Clearance | Clearance rate (%) at Day 2 (48h after first dose) | 99 percentage of subjects |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Fever Clearance | Clearance rate (%) at Day 1 (24h after first dose) | 91 percentage of subjects |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Fever Clearance | Clearance rate (%) at Day 3 (72h after first dose) | 96 percentage of subjects |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Fever Clearance | Clearance rate (%) at Day 2 (48h after first dose) | 96 percentage of subjects |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Fever Clearance | Clearance rate (%) at Day 1 (24h after first dose) | 96 percentage of subjects |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Fever Clearance | Clearance rate (%) at Day 2 (48h after first dose) | 100 percentage of subjects |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Fever Clearance | Clearance rate (%) at Day 3 (72h after first dose) | 100 percentage of subjects |
Secondary
Fever Clearance Time
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Fever Clearance Time | 16.8 hours | Standard Deviation 12.75 |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Fever Clearance Time | 24.0 hours | Standard Deviation 25.99 |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Fever Clearance Time | 17.0 hours | Standard Deviation 12.9 |
Secondary
Parasite Clearance
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Parasite Clearance | Clearance rate (%) at Day 2 (48h after first dose) | 93 percentage of subjects |
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Parasite Clearance | Clearance rate (%) at Day 3 (72h after first dose) | 96 percentage of subjects |
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Parasite Clearance | Clearance rate (%) at Day 1 (24h after first dose) | 74 percentage of subjects |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Parasite Clearance | Clearance rate (%) at Day 1 (24h after first dose) | 82 percentage of subjects |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Parasite Clearance | Clearance rate (%) at Day 2 (48h after first dose) | 96 percentage of subjects |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Parasite Clearance | Clearance rate (%) at Day 3 (72h after first dose) | 98 percentage of subjects |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Parasite Clearance | Clearance rate (%) at Day 1 (24h after first dose) | 84 percentage of subjects |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Parasite Clearance | Clearance rate (%) at Day 3 (72h after first dose) | 99 percentage of subjects |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Parasite Clearance | Clearance rate (%) at Day 2 (48h after first dose) | 95 percentage of subjects |
Secondary
Parasite Clearance Time
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | Parasite Clearance Time | 36.9 hours | Standard Deviation 20.73 |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | Parasite Clearance Time | 33.6 hours | Standard Deviation 17.08 |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | Parasite Clearance Time | 30.8 hours | Standard Deviation 14.96 |
Secondary
PCR-Corrected ACPR at 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
Time frame: Day 14
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Group A: Pyronaridine/Artesunate (6:2 mg/kg) | PCR-Corrected ACPR at Day 14 | 100 percentage of subjects |
| Group B: Pyronaridine/Artesunate (9:3 mg/kg) | PCR-Corrected ACPR at Day 14 | 100 percentage of subjects |
| Group C: Pyronaridine/Artesunate (12:4 mg/kg) | PCR-Corrected ACPR at Day 14 | 100 percentage of subjects |