Malaria
Conditions
Keywords
Falciparum malaria, pediatric, Coartem, artesunate, lumefantrine, pyronaridine, Pyramax
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.
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.
Interventions
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.
DRUGarthemeter 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.
Sponsors
Shin Poong Pharmaceuticals
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 12 Years
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: 1. 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, 2. Positive microscopy of P. falciparum with parasite density between 1,000 and 200,000 asexual parasite count/µl of blood. 4. 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. 5. Ability to swallow whole volume of liquid in which medication is suspended. 6. 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. 7. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. |
| 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 |
| 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 |
| 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 | — |
| 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 |
Countries
Burkina Faso, Côte d’Ivoire, Democratic Republic of the Congo, Gabon, Kenya, Mali, Mozambique, Philippines
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 355 |
| 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. | 180 |
| Total | 535 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 3 |
| Overall Study | Lost to Follow-up | 6 | 1 |
| Overall Study | Parasite reappearance/malaria | 67 | 32 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | PA Group | Total | AL Group |
|---|---|---|---|
| Age, Continuous | 4.9 years STANDARD_DEVIATION 2.47 | 5.0 years STANDARD_DEVIATION 2.49 | 5.3 years STANDARD_DEVIATION 2.52 |
| Age, Customized 1-<5 years | 148 Participants | 217 Participants | 69 Participants |
| Age, Customized <1 year | 12 Participants | 15 Participants | 3 Participants |
| Age, Customized 5-12 years | 195 Participants | 303 Participants | 108 Participants |
| Race/Ethnicity, Customized Asian/Oriental | 13 Participants | 21 Participants | 8 Participants |
| Race/Ethnicity, Customized Black | 342 Participants | 514 Participants | 172 Participants |
| Region of Enrollment Burkina Faso | 19 participants | 28 participants | 9 participants |
| Region of Enrollment Congo, The Democratic Republic of the | 56 participants | 84 participants | 28 participants |
| Region of Enrollment Côte D'Ivoire | 72 participants | 107 participants | 35 participants |
| Region of Enrollment Gabon | 53 participants | 80 participants | 27 participants |
| Region of Enrollment Kenya | 56 participants | 86 participants | 30 participants |
| Region of Enrollment Mali | 86 participants | 130 participants | 44 participants |
| Region of Enrollment Philippines | 13 participants | 20 participants | 7 participants |
| Sex: Female, Male Female | 178 Participants | 274 Participants | 96 Participants |
| Sex: Female, Male Male | 177 Participants | 261 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 355 | 0 / 180 |
| other Total, other adverse events | 285 / 355 | 143 / 180 |
| serious Total, serious adverse events | 1 / 355 | 0 / 180 |
Outcome results
Primary
Percentage of Participants With PCR-Corrected ACPR on 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
Time frame: Day 28
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| PA Group | Percentage of Participants With PCR-Corrected ACPR on Day 28 | 97.6 percentage of cured subjects |
| AL Group | Percentage of Participants With PCR-Corrected ACPR on Day 28 | 98.8 percentage of cured subjects |
p-value: <0.0001Exact binomial test
Comparison: 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.p-value: 0.372895% CI: [-3.6, 2.1]Chi-squared
Secondary
Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 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
Time frame: Days 14 and 28
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PA Group | Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28 | Percentage of Participants with ACPR at Day 14 | 100 percentage of subjects |
| PA Group | Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28 | Percentage of Participants with ACPR at Day 28 | 90.2 percentage of subjects |
| AL Group | Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28 | Percentage of Participants with ACPR at Day 14 | 100 percentage of subjects |
| AL Group | Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28 | Percentage of Participants with ACPR at Day 28 | 89.2 percentage of subjects |
Secondary
Fever Clearance Time
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)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| PA Group | Fever Clearance Time | 8.1 hours |
| AL Group | Fever Clearance Time | 8.1 hours |
Secondary
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
Population: Safety population: all randomized subjects who received any amount of study medication. Subjects were analyzed as treated
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PA Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 AE | 285 Participants |
| PA Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 treatment-related AE | 132 Participants |
| PA Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 SAE | 1 Participants |
| PA Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 treatment-related SAE | 0 Participants |
| PA Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 severe or life-threatening AE | 2 Participants |
| PA Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 AE leading to death | 0 Participants |
| PA Group | Number of Subjects With ≥1 Adverse Event | Nr subj. ≥1 AE leading to drug discontinuation | 6 Participants |
| PA Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 AE leading to study withdrawal | 6 Participants |
| AL Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 AE leading to study withdrawal | 3 Participants |
| AL Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 AE | 143 Participants |
| AL Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 severe or life-threatening AE | 2 Participants |
| AL Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 treatment-related AE | 80 Participants |
| AL Group | Number of Subjects With ≥1 Adverse Event | Nr subj. ≥1 AE leading to drug discontinuation | 3 Participants |
| AL Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 SAE | 0 Participants |
| AL Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 AE leading to death | 0 Participants |
| AL Group | Number of Subjects With ≥1 Adverse Event | Nr subj. with ≥1 treatment-related SAE | 0 Participants |
Secondary
Parasite Clearance Time
Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance 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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| PA Group | Parasite Clearance Time | 24.1 hours |
| AL Group | Parasite Clearance Time | 24.2 hours |
Secondary
Percentage of Participants With PCR-Corrected ACPR on 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
Time frame: Day 14
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| PA Group | Percentage of Participants With PCR-Corrected ACPR on Day 14 | 100.0 percentage of subjects |
| AL Group | Percentage of Participants With PCR-Corrected ACPR on Day 14 | 100.0 percentage of subjects |
Secondary
Proportion of Subjects With Cleared Parasites on 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
Time frame: Days 1, 2, and 3
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PA Group | Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 | Percentage of Participants with parasite clearance at Day 1 (24h after first dose) | 49.9 percentage of subjects |
| PA Group | Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 | Percentage of Participants with parasite clearance at Day 2 (48h after first dose) | 95.5 percentage of subjects |
| PA Group | Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 | Percentage of Participants with parasite clearance at Day 3 (72h after first dose) | 97.0 percentage of subjects |
| AL Group | Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 | Percentage of Participants with parasite clearance at Day 1 (24h after first dose) | 43.7 percentage of subjects |
| AL Group | Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 | Percentage of Participants with parasite clearance at Day 2 (48h after first dose) | 95.2 percentage of subjects |
| AL Group | Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 | Percentage of Participants with parasite clearance at Day 3 (72h after first dose) | 98.8 percentage of subjects |
Secondary
Proportion of Subjects With Fever Cleared on 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
Time frame: Days 1, 2, and 3
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PA Group | Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 | Percentage of Participants with fever clearance at Day 1 (24h after first dose) | 87.1 percentage of subjects |
| PA Group | Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 | Percentage of Participants with fever clearance at Day 2 (48h after first dose) | 98.5 percentage of subjects |
| PA Group | Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 | Percentage of Participants with fever clearance at Day 3 (48h after first dose) | 99.6 percentage of subjects |
| AL Group | Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 | Percentage of Participants with fever clearance at Day 1 (24h after first dose) | 81.0 percentage of subjects |
| AL Group | Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 | Percentage of Participants with fever clearance at Day 2 (48h after first dose) | 96.8 percentage of subjects |
| AL Group | Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 | Percentage of Participants with fever clearance at Day 3 (48h after first dose) | 98.4 percentage of subjects |