Falciparum Malaria
Conditions
Keywords
malaria, antimalarial, P falciparum, pyronaridine, artesunate, artemisinin based combination therapy (ACT), pyronaridine artesunate (Pyramax)
Brief summary
The primary objective of this phase III clinical study is to compare the efficacy and safety of the fixed combination of pyronaridine artesunate (Pyramax®, PA) with that of the combination of mefloquine plus artesunate (MQ + AS) in children and adults with uncomplicated P falciparum malaria in South East Asia, India and Africa.
Detailed description
This is a multi-centre, comparative, randomised, open-label, parallel-group, non-inferiority study comparing the efficacy and safety of a fixed combination of PA to a loose combination of MQ + AS for patients with acute, symptomatic, uncomplicated P. falciparum malaria. The study population will include 1271 patients, comprising male and female children (≥20 kg body weight) and adults, recruited from study sites in South East Asia, India and Africa. Patients will be randomised in a 2:1 ratio to receive either oral PA (180:60mg tablets) or MQ (250mg tablets) plus AS (100mg tablets) once 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 remains blinded. Patients will be confined to the 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. The primary efficacy end point for the study is the proportion of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28 (defined as the absence of parasitaemia without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure). 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
once a day for 3 days
once a day for 3 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
3 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients between the ages 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 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, mefloquine or artesunate or other artemisinins. * Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by 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. * Presence of significant renal or hepatic impairment. * Receipt of an investigational drug within the past 4 weeks. * Known active Hepatitis A IgM, Hepatitis B surface antigen or Hepatitis C antibody. * Known seropositive HIV antibody. * Previous participation in any clinical study with PA.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) 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 on Days 14 and 28 | Days 14 and 28 | Percentage of subjects with adequate clinical and parasitological response (ACPR) on Days 14 and 28, without correction by PCR, defined as absence of parasitaemia on Days 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 | Thick blood films were examined every 8 hours until ≥72 hours or until 2 consecutive negative readings occurred 7 to 25 hours apart, and on Days 3, 7, 14, 21, 28, 35, and 42 (or any other day if the subject returned). | Parasite clearance time was defined as the time from first dosing to 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 | Every 8 hours over ≥72 hours following first study drug administration or temperature normalisation for ≥2 readings between 7 and 25 hours apart, then at each visit. | Fever clearance time was defined as the time from first dosing to first normal reading of temperature (\<37.5°C taken axillary or tympanic; \<38°C taken oral or rectal) for 2 consecutive normal temperature readings taken between 7 and 25 hours apart. |
| PCR-corrected 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 |
| Fever Clearance at Day 1, 2 and 3 | Days 1, 2 and 3 | Fever clearance time was defined as the time for at least 2 consecutive normal body temperature measurements (\<37.5°C axillary/tympanic or \<38.0°C oral/rectal) to be obtained within an interval of 7 to 25 hours post-dosing. |
| 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 | Cases and severity of adverse events and of clinically significant laboratory results, ECG, vital signs or physical examination abnormalities |
| Parasite Clearance at Day 1, 2 and 3 | Days 1, 2 and 3 | Parasite clearance time was 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, Cambodia, Côte d’Ivoire, India, Tanzania, Thailand, Vietnam
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pyronaridine - Artesunate Pyronaridine - artesunate (180:60mg) once a day for 3 days. Posology was based on body weight ranges. | 848 |
| Mefloquine Plus Artesunate Mefloquine (250mg) plus artesunate (100mg) once a day for 3 days. Posology was based on body weight ranges. | 423 |
| Total | 1,271 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 4 |
| Overall Study | Gametocyte re-appearance | 1 | 1 |
| Overall Study | Lost to Follow-up | 49 | 25 |
| Overall Study | Mixed infection with P. falciparum | 1 | 0 |
| Overall Study | Mixed infection with P. vivax | 2 | 0 |
| Overall Study | P. ovale infection | 1 | 0 |
| Overall Study | P. vivax infection | 26 | 4 |
| Overall Study | P. vivax infection at screening | 1 | 0 |
| Overall Study | Re-appearance of P. falciparum | 34 | 25 |
| Overall Study | Withdrawal by Subject | 5 | 6 |
| Overall Study | Withdrawn from study accidentally | 0 | 1 |
Baseline characteristics
| Characteristic | Pyronaridine - Artesunate | Mefloquine Plus Artesunate | Total |
|---|---|---|---|
| Age, Continuous | 23 years | 23.0 years | 23.0 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 689 Participants | 344 Participants | 1033 Participants |
| Race (NIH/OMB) Black or African American | 159 Participants | 79 Participants | 238 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Burkina Faso | 83 participants | 39 participants | 122 participants |
| Region of Enrollment Cambodia | 140 participants | 71 participants | 211 participants |
| Region of Enrollment Côte D'Ivoire | 51 participants | 27 participants | 78 participants |
| Region of Enrollment India | 39 participants | 20 participants | 59 participants |
| Region of Enrollment Tanzania | 25 participants | 13 participants | 38 participants |
| Region of Enrollment Thailand | 402 participants | 198 participants | 600 participants |
| Region of Enrollment Vietnam | 108 participants | 55 participants | 163 participants |
| Sex: Female, Male Female | 214 Participants | 93 Participants | 307 Participants |
| Sex: Female, Male Male | 634 Participants | 330 Participants | 964 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 848 | 0 / 423 |
| other Total, other adverse events | 389 / 848 | 190 / 423 |
| serious Total, serious adverse events | 6 / 848 | 3 / 423 |
Outcome results
Primary
Percentage of Subjects With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) 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 med., did not miss a dose, did not use a concomitant med. that may have interfered with the treatment outcome up to D14, 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) |
|---|---|---|
| Pyronaridine - Artesunate | Percentage of Subjects With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 28 | 99.2 percentage of subjects |
| Mefloquine Plus Artesunate | Percentage of Subjects With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 28 | 98.1 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 (MQ + AS) 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 (MQ + AS) by more than -5%.p-value: 0.10695% CI: [-0.2, 3.1]Chi-squared
Secondary
Adverse Events and Clinically Significant Laboratory Results
Cases and severity 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 consisted of all randomised subjects who received any amount of study medication; subjects were analysed as treated.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pyronaridine - Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE | 389 Participants |
| Pyronaridine - Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 treatment-related AE | 153 Participants |
| Pyronaridine - Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 SAE | 6 Participants |
| Pyronaridine - Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 treatment-related SAE | 0 Participants |
| Pyronaridine - Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 severe or life threatenining AE | 24 Participants |
| Pyronaridine - Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE leading to death | 0 Participants |
| Pyronaridine - Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj with ≥1 AE leading to drug discontinuation | 5 Participants |
| Pyronaridine - Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE leading to study withdrawal | 5 Participants |
| Mefloquine Plus Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE leading to study withdrawal | 4 Participants |
| Mefloquine Plus Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE | 190 Participants |
| Mefloquine Plus Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 severe or life threatenining AE | 23 Participants |
| Mefloquine Plus Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 treatment-related AE | 94 Participants |
| Mefloquine Plus Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj with ≥1 AE leading to drug discontinuation | 4 Participants |
| Mefloquine Plus Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 SAE | 3 Participants |
| Mefloquine Plus Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 AE leading to death | 0 Participants |
| Mefloquine Plus Artesunate | Adverse Events and Clinically Significant Laboratory Results | Nr subj. with ≥1 treatment-related SAE | 2 Participants |
Secondary
Crude ACPR on Days 14 and 28
Percentage of subjects with adequate clinical and parasitological response (ACPR) on Days 14 and 28, without correction by PCR, defined as absence of parasitaemia on Days 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 subjects completed a full course of study med., did not miss a dose, did not use a concomitant med. that may have interfered with the treatment outcome up to D14, 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) |
|---|---|---|---|
| Pyronaridine - Artesunate | Crude ACPR on Days 14 and 28 | Cure rate (%) on Day 14 | 99.9 percentage of subjects |
| Pyronaridine - Artesunate | Crude ACPR on Days 14 and 28 | Cure rate (%) on Day 28 | 98.7 percentage of subjects |
| Mefloquine Plus Artesunate | Crude ACPR on Days 14 and 28 | Cure rate (%) on Day 14 | 99.5 percentage of subjects |
| Mefloquine Plus Artesunate | Crude ACPR on Days 14 and 28 | Cure rate (%) on Day 28 | 96.7 percentage of subjects |
Secondary
Fever Clearance at Day 1, 2 and 3
Fever clearance time was defined as the time for at least 2 consecutive normal body temperature measurements (\<37.5°C axillary/tympanic or \<38.0°C oral/rectal) to be obtained within an interval of 7 to 25 hours post-dosing.
Time frame: Days 1, 2 and 3
Population: Efficacy evaluable population subjects completed a full course of study med., did not miss a dose, did not use a concomitant med. that may have interfered with the treatment outcome up to D14, 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) |
|---|---|---|---|
| Pyronaridine - Artesunate | Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 78.5 percentage of subjects |
| Pyronaridine - Artesunate | Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 95.9 percentage of subjects |
| Pyronaridine - Artesunate | Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 3 (72h after first dose) | 99.2 percentage of subjects |
| Mefloquine Plus Artesunate | Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 78.9 percentage of subjects |
| Mefloquine Plus Artesunate | Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 96.2 percentage of subjects |
| Mefloquine Plus Artesunate | Fever Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 3 (72h after first dose) | 98.4 percentage of subjects |
Secondary
Fever Clearance Time
Fever clearance time was defined as the time from first dosing to first normal reading of temperature (\<37.5°C taken axillary or tympanic; \<38°C taken oral or rectal) for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.
Time frame: Every 8 hours over ≥72 hours following first study drug administration or temperature normalisation for ≥2 readings between 7 and 25 hours apart, then at each visit.
Population: Efficacy evaluable population subjects completed a full course of study med., did not miss a dose, did not use a concomitant med. that may have interfered with the treatment outcome up to D14, 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) |
|---|---|---|
| Pyronaridine - Artesunate | Fever Clearance Time | 15.9 hours |
| Mefloquine Plus Artesunate | Fever Clearance Time | 16.0 hours |
Secondary
Parasite Clearance at Day 1, 2 and 3
Parasite clearance time was 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 subjects completed a full course of study med., did not miss a dose, did not use a concomitant med. that may have interfered with the treatment outcome up to D14, 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) |
|---|---|---|---|
| Pyronaridine - Artesunate | Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 38.5 percentage of subjects |
| Pyronaridine - Artesunate | Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 83.8 percentage of subjects |
| Pyronaridine - Artesunate | Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 3 (48h after first dose) | 91.5 percentage of subjects |
| Mefloquine Plus Artesunate | Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 31.6 percentage of subjects |
| Mefloquine Plus Artesunate | Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 79.8 percentage of subjects |
| Mefloquine Plus Artesunate | Parasite Clearance at Day 1, 2 and 3 | Clearance rate (%) at Day 3 (48h after first dose) | 90.5 percentage of subjects |
Secondary
Parasite Clearance Time
Parasite clearance time was defined as the time from first dosing to 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: Thick blood films were examined every 8 hours until ≥72 hours or until 2 consecutive negative readings occurred 7 to 25 hours apart, and on Days 3, 7, 14, 21, 28, 35, and 42 (or any other day if the subject returned).
Population: Efficacy evaluable population subjects completed a full course of study med., did not miss a dose, did not use a concomitant med. that may have interfered with the treatment outcome up to D14, 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) |
|---|---|---|
| Pyronaridine - Artesunate | Parasite Clearance Time | 31.7 hours |
| Mefloquine Plus Artesunate | Parasite Clearance Time | 32.0 hours |
Secondary
PCR-corrected 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 med., did not miss a dose, did not use a concomitant med. that may have interfered with the treatment outcome up to D14, 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 (MEAN) |
|---|---|---|
| Pyronaridine - Artesunate | PCR-corrected ACPR on Day 14 | 99.9 percentage of subjects |
| Mefloquine Plus Artesunate | PCR-corrected ACPR on Day 14 | 99.5 percentage of subjects |