Malaria
Conditions
Keywords
Artemisinin-based combination therapy (ACT), Pyramax, Pyronaridine artesunate, Chloroquine, Children, Adults, Plasmodium vivax, Republic of Korea
Brief summary
The primary objective of this clinical study is to compare the efficacy and safety of the fixed combination of pyronaridine artesunate (180:60 mg) with that of standard chloroquine therapy in children and adults with acute, uncomplicated Plasmodium vivax (P. vivax) malaria
Detailed description
This is a multi-centre, randomised, double-blind, double-dummy, parallel group, comparative trial. It is a Phase III study designed to meet the regulatory requirements for registration of pyronaridine artesunate (PA) in Korea. Chloroquine will be used as a comparator, which is recognized as an effective and well-tolerated anti-malarial therapy, and is standard blood-stage therapy for patients with P. vivax malaria in Korea. This study will be conducted in a total of 40 male and female children (≥20 kg body weight) and adult patients suffering from acute symptomatic uncomplicated P. vivax malaria recruited from study sites in Korea. Patients will be randomised in a 1:1 ratio to receive either oral PA (180:60-mg tablets) plus chloroquine-placebo or oral chloroquine (155 mg tablets) plus PA-placebo, once a day for 3 consecutive days (Days 0, 1, and 2). For PA, posology will be based on body weight ranges, with patients receiving 1 to 4 tablets per day depending on their body weight. The actual dose range covered by this regimen is 7.2:2.4 mg/kg to 13.8:4.6 mg/kg per day, which has been shown to be effective and safe in Phase I and II studies. The chloroquine daily dose is 10 mg/kg on Days 0 and 1 and 5 mg/kg on Day 2 for children and 620 mg on Days 0 and 1 and 310 mg on Day 2 for adults. 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 crude cure rate on Day 14. 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. It is anticipated that the study results will be pooled with the results of study SP-C-006-06 entitled A Phase III Comparative (Double-blind, Double-dummy) Randomized Multicentre Study to Assess the Safety & Efficacy of Oral Pyronaridine Artesunate (180:60 mg) Versus Chloroquine (155 mg) in Children & Adult Patients with Acute Vivax Malaria for a formal non-inferiority analysis.
Interventions
Oral pyronaridine artesunate (180:60 mg tablets), plus chloroquine-placebo once a day for 3 consecutive days.
DRUGChloroquine
Oral chloroquine (155 mg tablets), plus pyronaridine artesunate-placebo, once a day for 3 consecutive days.
Sponsors
Shin Poong Pharmaceuticals
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients between the age of 3 and 60 years, inclusive. 2. Body weight between 20 kg and 90 kg with no clinical evidence of severe malnutrition. 3. Presence of acute uncomplicated P. vivax mono-infection confirmed by: 1. Fever, as defined by axillary/tympanic temperature ≥37.5°C or oral/rectal temperature ≥38°C, or history of fever in the previous 24 hours (history of fever must be documented) and, 2. Positive microscopy of P. vivax with parasite density ≥250/ μL of blood (including at least 50% of asexual parasites). 4. 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. 5. Ability to swallow oral medication. 6. Ability and willingness to participate based on information given to patient or parent or guardian and access to health facility.
Exclusion criteria
1. Presence of a mixed Plasmodium infection. 2. Presence of other clinical condition requiring hospitalization. 3. Presence of significant anaemia, as defined by Hb \<8 g/dL. 4. Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTc interval greater than or equal to 450 msec), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other abnormality (including recent head trauma). 5. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, chloroquine or artesunate or other artemisinins. 6. Known history of hypersensitivity, allergic or adverse reactions to chloroquine, primaquine and related agents. 7. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab). 8. Known seropositive HIV antibody. 9. Have received any antimalarial treatment in the preceding 2 weeks, as determined by history and, whenever feasible, by screening test. 10. Have received antibacterial with known antimalarial activity in the preceding 2 weeks. 11. Have received any investigational drug within the past 4 weeks. 12. Liver function tests (AST/ALT levels) \>2.5 times the upper limit of normal range. 13. Known significant renal impairment as indicated by serum creatinine levels of \>1.4 mg/dL. 14. 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. 15. Previous participation in the present clinical trial with pyronaridine artesunate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Crude Cure Rate on Day 14 | Day 14 | Percentage of subjects with crude cure rate at Day 14, defined as absence of parasitaemia on Day 14, irrespective of body temperature without previously meeting any of the criteria of treatment failure |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Crude Cure Rate on Day 28 | Day 28 | Percentage of subjects with crude cure rate at Day 28, defined as absence of parasitaemia on Day 28, irrespective of body temperature without previously meeting any of the criteria of treatment failure |
| Parasite Clearance Time (PCT) | Days 0, 3, 7, 14, 21, 28, 35, and 42 (or on any other day if the subject spontaneously returned within the 42-day 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 (FCT) | 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 (Days 7, 14, 28 and 42) | 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 Patients Who Had Cleared Fever on Days 1, 2, and 3 | Days 1, 2, and 3 | Fever clearance is defined as at least 2 consecutive normal body temperature measurements (\<37.5 C axillary/tympanic or \<38.0 C oral/rectal) obtained within an interval of 7 to 25 hours postdosing |
| Number of Participants With 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 | Number of Participants with AEs, including clinically significant laboratory results, electrocardiogram (ECG), vital signs or physical examination abnormalities |
| Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3 | Days 1, 2, and 3 | Parasite clearance is defined as at least 2 consecutive negative smears for asexual parasites obtained within an interval of 7 to 25 hours post-dosing |
Other
| Measure | Time frame | Description |
|---|---|---|
| Crude Cure Rate on Day 42 | Day 42 | Proportion of subjects with crude cure rate at Day 42, defined as absence of parasitaemia on Day 42, irrespective of body temperature without previously meeting any of the criteria of treatment failure |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pyronaridine - Artesunate Oral pyronaridine artesunate (180:60 mg tablets), plus chloroquine-placebo once a day for 3 consecutive days.
For patients who complete the study up to Day 28 and who have normal G-6-PD activity, a 14-day course of primaquine (15 mg/day) shall be administered starting on Day 28, after all required assessments have been performed, to complete their radical cure. Patients who are deficient in G-6-PD and who complete the study up to Day 28 will be treated as per country policy.
Pyronaridine - artesunate: Oral pyronaridine artesunate (180:60 mg tablets), plus chloroquine-placebo once a day for 3 consecutive days. | 15 |
| Chloroquine Oral chloroquine (155 mg tablets), plus pyronaridine artesunate-placebo, once a day for 3 consecutive days.
For patients who complete the study up to Day 28 and who have normal G-6-PD activity, a 14-day course of primaquine (15 mg/day) shall be administered starting on Day 28, after all required assessments have been performed, to complete their radical cure. Patients who are deficient in G-6-PD and who complete the study up to Day 28 will be treated as per country policy.
Chloroquine: Oral chloroquine (155 mg tablets), plus pyronaridine artesunate-placebo, once a day for 3 consecutive days. | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Pyronaridine - Artesunate | Chloroquine | Total |
|---|---|---|---|
| Age, Continuous | 38.2 years STANDARD_DEVIATION 14.03 | 42.3 years STANDARD_DEVIATION 11.79 | 40.3 years STANDARD_DEVIATION 12.9 |
| Race/Ethnicity, Customized Asian/Oriental | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 13 Participants | 11 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 10 / 15 | 10 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
Crude Cure Rate on Day 14
Percentage of subjects with crude cure rate at Day 14, defined as absence of parasitaemia on Day 14, irrespective of body temperature without previously meeting any of the criteria of treatment failure
Time frame: Day 14
Population: Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication 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, did not have major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pyronaridine - Artesunate | Crude Cure Rate on Day 14 | 100 percentage of participants |
| Chloroquine | Crude Cure Rate on Day 14 | 100 percentage of participants |
Secondary
Crude Cure Rate on Day 28
Percentage of subjects with crude cure rate at Day 28, defined as absence of parasitaemia on Day 28, irrespective of body temperature without previously meeting any of the criteria of treatment failure
Time frame: Day 28
Population: Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication 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, did not have major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pyronaridine - Artesunate | Crude Cure Rate on Day 28 | 100 percentage of participants |
| Chloroquine | Crude Cure Rate on Day 28 | 100 percentage of participants |
Secondary
Fever Clearance Time (FCT)
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 (Days 7, 14, 28 and 42)
Population: Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication 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, did not have major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pyronaridine - Artesunate | Fever Clearance Time (FCT) | 16.0 hours |
| Chloroquine | Fever Clearance Time (FCT) | 31.9 hours |
Secondary
Number of Participants With Adverse Events (AEs)
Number of Participants with AEs, including clinically significant laboratory results, electrocardiogram (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
Population: Safety population, consisting 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 | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 AE | 10 Participants |
| Pyronaridine - Artesunate | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 treatment-related AE | 7 Participants |
| Pyronaridine - Artesunate | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 SAE | 0 Participants |
| Pyronaridine - Artesunate | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 treatment-related SAE | 0 Participants |
| Pyronaridine - Artesunate | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 severe or life-threatening AE | 0 Participants |
| Pyronaridine - Artesunate | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 AE leading to death | 0 Participants |
| Pyronaridine - Artesunate | Number of Participants With Adverse Events (AEs) | Nr subj. with≥1 AE leading to drug discontinuation | 0 Participants |
| Pyronaridine - Artesunate | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 AE leading to study withdrawal | 0 Participants |
| Chloroquine | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 AE leading to study withdrawal | 0 Participants |
| Chloroquine | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 AE | 10 Participants |
| Chloroquine | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 severe or life-threatening AE | 2 Participants |
| Chloroquine | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 treatment-related AE | 9 Participants |
| Chloroquine | Number of Participants With Adverse Events (AEs) | Nr subj. with≥1 AE leading to drug discontinuation | 0 Participants |
| Chloroquine | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 SAE | 0 Participants |
| Chloroquine | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 AE leading to death | 0 Participants |
| Chloroquine | Number of Participants With Adverse Events (AEs) | Nr subj. with ≥1 treatment-related SAE | 0 Participants |
Secondary
Parasite Clearance Time (PCT)
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 period)
Population: Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication 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, did not have major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pyronaridine - Artesunate | Parasite Clearance Time (PCT) | 32.0 hours |
| Chloroquine | Parasite Clearance Time (PCT) | 63.9 hours |
Secondary
Percentage of Patients Who Had Cleared Fever on Days 1, 2, and 3
Fever clearance is defined as at least 2 consecutive normal body temperature measurements (\<37.5 C axillary/tympanic or \<38.0 C oral/rectal) obtained within an interval of 7 to 25 hours postdosing
Time frame: Days 1, 2, and 3
Population: Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication 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, did not have major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pyronaridine - Artesunate | Percentage of Patients Who Had Cleared Fever on Days 1, 2, and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 76.9 percentage of participants |
| Pyronaridine - Artesunate | Percentage of Patients Who Had Cleared Fever on Days 1, 2, and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 92.3 percentage of participants |
| Pyronaridine - Artesunate | Percentage of Patients Who Had Cleared Fever on Days 1, 2, and 3 | Clearance rate (%) at Day 3 (72h after first dose) | 100.0 percentage of participants |
| Chloroquine | Percentage of Patients Who Had Cleared Fever on Days 1, 2, and 3 | Clearance rate (%) at Day 1 (24h after first dose) | 41.7 percentage of participants |
| Chloroquine | Percentage of Patients Who Had Cleared Fever on Days 1, 2, and 3 | Clearance rate (%) at Day 2 (48h after first dose) | 91.7 percentage of participants |
| Chloroquine | Percentage of Patients Who Had Cleared Fever on Days 1, 2, and 3 | Clearance rate (%) at Day 3 (72h after first dose) | 100.0 percentage of participants |
Secondary
Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3
Parasite clearance is defined as at least 2 consecutive negative smears for asexual parasites obtained within an interval of 7 to 25 hours post-dosing
Time frame: Days 1, 2, and 3
Population: Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication 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, did not have major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pyronaridine - Artesunate | Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3 | Day 1 (24h after first dose) | 30.8 percentage of participants |
| Pyronaridine - Artesunate | Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3 | Day 2 (48h after first dose) | 92.3 percentage of participants |
| Pyronaridine - Artesunate | Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3 | Day 3 (72h after first dose) | 100.0 percentage of participants |
| Chloroquine | Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3 | Day 1 (24h after first dose) | 0.0 percentage of participants |
| Chloroquine | Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3 | Day 2 (48h after first dose) | 26.7 percentage of participants |
| Chloroquine | Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3 | Day 3 (72h after first dose) | 60.0 percentage of participants |
Other Pre-specified
Crude Cure Rate on Day 42
Proportion of subjects with crude cure rate at Day 42, defined as absence of parasitaemia on Day 42, irrespective of body temperature without previously meeting any of the criteria of treatment failure
Time frame: Day 42
Population: Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication 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, did not have major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pyronaridine - Artesunate | Crude Cure Rate on Day 42 | 100 percentage of subjects |
| Chloroquine | Crude Cure Rate on Day 42 | 100 percentage of subjects |