Malaria
Conditions
Keywords
malaria, antimalarial, artemisinin based combination therapy (ACT), P. falciparum, pyronaridine artesunate (Pyramax)
Brief summary
The primary objective of this phase III study is to compare the efficacy and safety of the fixed combination of pyronaridine artesunate (Pyramax®, PA) with that of Coartem® (artemether lumefantrine, AL) in children and adults with uncomplicated P falciparum malaria in Africa and South East Asia.
Detailed description
This is a multi-centre, comparative, randomised, (double-blind, double-dummy), parallel-group, non-inferiority study comparing the efficacy and safety of the fixed combination of PA with that of AL in the treatment of acute, uncomplicated P. falciparum malaria. The study population will include 1269 patients, comprising male and female children (≥20 kg body weight) and adults recruited from study sites in Africa and South East Asia. Patients will be randomised to receive either oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Days 0, 1, and 2) or AL twice a day plus PA-placebo (once a day) for 3 consecutive days (Days 0, 1, and 2) in a 2:1 ratio. The dose range of PA covered by this regimen is 7.2:2.4 mg/kg to 13.8:4.6 mg/kg, respectively, 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 for ≥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 later. The primary efficacy end point for the study is the proportion of patients with PCR-corrected adequate clinical and parasitological response (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
Oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Day 0, 1, and 2)
DRUGCoartem® (artemether lumefantrine)
AL (20:120mg tablets) twice a day plus PA-placebo (once a day) for 3 consecutive days (Day 0, 1, and 2)
Sponsors
Shin Poong Pharmaceuticals
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients between the age of 3 and 60 years, inclusive. * Body weight between 20 kg and 90 kg with no clinical evidence of severe malnutrition. * Presence of acute uncomplicated P. falciparum mono-infection confirmed by: 1. Fever, as defined by axillary/tympanic temperature ≥ 37.5°C or oral/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 100,000 asexual parasite count/μl of blood. * Written informed consent, in accordance with local practice, provided by patient and/or parent/guardian/spouse. * Ability to swallow oral medication.
Exclusion criteria
* Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000. * Mixed Plasmodium infection. * Severe vomiting or severe diarrhoea. * Known history or evidence of clinically significant disorders. * Presence of significant anaemia, as defined by Hb \<8 g/dL. * Presence of febrile conditions caused by diseases other than malaria. * Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, lumefantrine or artesunate or other artemisinins. * Patients with known disturbances of electrolytes balance, e.g., hypokalaemia or hypomagnesaemia. * Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by a positive urine test. * 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. * Patients taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (flecainide, metoprol, imipramine, amitriptyline, clomipramine). * Received an investigational drug within the past 4 weeks. * Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen. (HBsAg) or Hepatitis C antibody (HCV Ab). * Known seropositive HIV antibody. * Liver function tests \[ASAT/ALAT levels\] \>2.5 times the upper limit of normal range. * Known significant renal impairment as indicated by serum creatinine \>1.4 mg/dL.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on 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 |
|---|---|---|
| Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28 | Day 14 and 28 | Percentage of subjects with adequate clinical and parasitological response (ACPR) on Day 28, without correction by PCR, 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. |
| Parasite Clearance Time | Days 0, 3, 7, 14, 21, 28, 35, and 42 (or on any other day if the subject spontaneously returned) | Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart. |
| 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 | Fever clearance time is defined as the time from first dosing to first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart |
| PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on 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. |
| Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 | Days 1, 2, 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. |
| Adverse Events and Clinically Significant Laboratory Results | 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 | Incidence of adverse events and of clinically significant laboratory results, ECG, vital signs or physical examination abnormalities. |
| Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Days 1, 2, 3 | Fever clearance time is defined as the time from first dosing to first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart. |
Countries
Democratic Republic of the Congo, Ghana, Indonesia, Kenya, Mali, Mozambique, Philippines, Senegal, The Gambia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PA Group Pyronaridine artesunate (PA)
Pyronaridine artesunate: Oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Day 0, 1, and 2) | 849 |
| AL Group Arthemether lumefantrine (AL)
Coartem® (artemether lumefantrine): AL twice a day plus PA-placebo (once a day) for 3 consecutive days (Day 0, 1, and 2) | 423 |
| Total | 1,272 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 21 | 7 |
| Overall Study | Cyesis | 1 | 0 |
| Overall Study | Lack of Efficacy | 40 | 42 |
| Overall Study | Lost to Follow-up | 14 | 9 |
| Overall Study | Non-compliance | 1 | 0 |
| Overall Study | Not defined | 1 | 1 |
| Overall Study | Protocol Violation | 4 | 1 |
| Overall Study | P. vivax infection | 3 | 6 |
| Overall Study | Re-location | 0 | 1 |
| Overall Study | Withdrawal by Subject | 12 | 9 |
| Overall Study | Withdrawn from study accidentally | 1 | 0 |
Baseline characteristics
| Characteristic | PA Group | AL Group | Total |
|---|---|---|---|
| Age, Continuous | 17.2 years STANDARD_DEVIATION 11.12 | 18.0 years STANDARD_DEVIATION 11.41 | 17.5 years STANDARD_DEVIATION 11.22 |
| Race/Ethnicity, Customized Asian/Oriental | 127 Participants | 65 Participants | 192 Participants |
| Race/Ethnicity, Customized Black | 722 Participants | 358 Participants | 1080 Participants |
| Region of Enrollment Congo, The Democratic Republic of the | 199 participants | 99 participants | 298 participants |
| Region of Enrollment Gambia | 72 participants | 34 participants | 106 participants |
| Region of Enrollment Ghana | 4 participants | 3 participants | 7 participants |
| Region of Enrollment Indonesia | 60 participants | 29 participants | 89 participants |
| Region of Enrollment Kenya | 88 participants | 44 participants | 132 participants |
| Region of Enrollment Mali | 132 participants | 66 participants | 198 participants |
| Region of Enrollment Mozambique | 89 participants | 44 participants | 133 participants |
| Region of Enrollment Philippines | 67 participants | 36 participants | 103 participants |
| Region of Enrollment Senegal | 138 participants | 68 participants | 206 participants |
| Sex: Female, Male Female | 359 Participants | 192 Participants | 551 Participants |
| Sex: Female, Male Male | 490 Participants | 231 Participants | 721 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 849 | 0 / 423 |
| other Total, other adverse events | 506 / 849 | 239 / 423 |
| serious Total, serious adverse events | 3 / 849 | 2 / 423 |
Outcome results
Primary
PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on 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: Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PA Group | PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on Day 28 | 99.5 percentage of subjects |
| AL Group | PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on Day 28 | 99.2 percentage of subjects |
Comparison: Null hypothesis: The PCR-corrected ACPR response rate at Day 28 for the PA group is inferior to the PCR-corrected ACPR response rate at Day 28 for the comparator group (AL) by more than 5%.~Was tested versus the alternative:~Alternative hypothesis: The PCR-corrected ACPR response rate at Day 28 for the PA group is not inferior to the PCR-corrected ACPR response rate at Day 28 for the comparator group (AL) by more than -5%.p-value: 0.57895% CI: [-0.7, 1.8]Chi-squared
Secondary
Adverse Events and Clinically Significant Laboratory Results
Incidence of adverse events and of clinically significant laboratory results, ECG, vital signs or physical examination abnormalities.
Time frame: Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Population: The safety population consists of all randomized subjects who received any amount of study medication; subjects were analyzed as treated.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PA Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE | 509 Participants |
| PA Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 severe or life-threatening AE | 10 Participants |
| PA Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 SAE | 3 Participants |
| PA Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE leading to death | 0 Participants |
| PA Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 treatment-related AE | 275 Participants |
| PA Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. ≥1 AE leading to drug discontinuation | 16 Participants |
| PA Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE leading to study withdrawal | 19 Participants |
| PA Group | Adverse Events and Clinically Significant Laboratory Results | Nr pat with ≥1 treatment-related SAE | 0 Participants |
| AL Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE leading to study withdrawal | 6 Participants |
| AL Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE | 241 Participants |
| AL Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 treatment-related AE | 123 Participants |
| AL Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 SAE | 2 Participants |
| AL Group | Adverse Events and Clinically Significant Laboratory Results | Nr pat with ≥1 treatment-related SAE | 0 Participants |
| AL Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 severe or life-threatening AE | 5 Participants |
| AL Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE leading to death | 0 Participants |
| AL Group | Adverse Events and Clinically Significant Laboratory Results | Nr subj. ≥1 AE leading to drug discontinuation | 5 Participants |
Secondary
Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28
Percentage of subjects with adequate clinical and parasitological response (ACPR) on Day 28, without correction by PCR, 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 14 and 28
Population: Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PA Group | Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28 | Cure rate (%) at Day 14 | 100 percentage of subjects |
| PA Group | Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28 | Cure rate (%) at Day 28 | 98.9 percentage of subjects |
| AL Group | Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28 | Cure rate (%) at Day 28 | 97.2 percentage of subjects |
| AL Group | Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28 | Cure rate (%) at Day 14 | 100 percentage of subjects |
Secondary
Fever Clearance Time
Fever clearance time is defined as the time from first dosing to 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
Population: Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PA Group | Fever Clearance Time | 7.9 hours |
| AL Group | Fever Clearance Time | 8.0 hours |
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 is 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)
Population: Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PA Group | Parasite Clearance Time | 23.9 hours |
| AL Group | Parasite Clearance Time | 24.0 hours |
Secondary
PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on 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: Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PA Group | PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 14 | 99.9 percentage of subjects |
| AL Group | PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 14 | 100 percentage of subjects |
Secondary
Percentage of Patients With Fever Clearance at Day 1, 2 and 3
Fever clearance time is defined as the time from first dosing to first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.
Time frame: Days 1, 2, 3
Population: Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PA Group | Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 88.7 percentage of subjects |
| PA Group | Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 99.0 percentage of subjects |
| PA Group | Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 3 (72h after first dose) | 99.5 percentage of subjects |
| AL Group | Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 87.0 percentage of subjects |
| AL Group | Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 98.7 percentage of subjects |
| AL Group | Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 3 (72h after first dose) | 99.3 percentage of subjects |
Secondary
Proportion of Patients With Parasite Clearance at Day 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, 3
Population: Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PA Group | Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 68.1 percentage of subjects |
| PA Group | Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 98.1 percentage of subjects |
| PA Group | Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 3 (72h after first dose) | 99.5 percentage of subjects |
| AL Group | Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 52.8 percentage of subjects |
| AL Group | Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 97.2 percentage of subjects |
| AL Group | Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 3 (72h after first dose) | 99.7 percentage of subjects |