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| Name | Class |
|---|---|
| Shin Poong Pharmaceuticals | INDUSTRY |
| Institute of Tropical Medicine, University of Tuebingen | OTHER |
The purpose of this study is to evaluate three dose levels of a combination tablet and a fixed dose granule formulation of pyronaridine and artesunate (PA) for the treatment of acute uncomplicated falciparum malaria in children.
This is a Phase II, open-label, sequential-group, dose-escalation, single-centre study to study pharmacokinetics, bioavailability comparison of tablets vs. granules, and safety/tolerability of PA in paediatric patients with acute symptomatic uncomplicated P. falciparum malaria. The study population will include 60 patients, comprising male and female children recruited from a single study site located in the endemic region of Gabon.
Patients will be assigned sequentially to 1 of 4 treatment groups (15 per group): Group A (Tablets) PA (48 mg + 16 mg), Group B (Tablets) PA (72 mg + 24 mg), Group C (Tablets) PA (96 mg + 32 mg), Group D (Granules) PA (60 mg + 20 mg). Oral tablets will be taken once daily for 3 consecutive days (Days 0, 1 and 2). The dose given to each patient depends on the dosing cohort group and the patient's body weight.
Each patient will attend the study site for screening and baseline procedures, as well as receipt of the first dose of study drug on Day 0 (Visit 1, baseline). Patients will be hospitalised for the first 72 hours and remain near the study site for the entire duration of the study. The patients will return to the study site for all scheduled follow-up visits until discharge on Day 42.
The primary efficacy end point for the study is the incidence of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A (Tablets) | Experimental | Pyronaridine artesunate 6:2 mg/kg. The tablet strength is 48:16 mg oral PA, with the number of tablets depending on body weight. |
|
| Group B (Tablets) | Experimental | Pyronaridine artesunate 9:3 mg/kg. The tablet strength is 72:24 mg oral PA, with the number of tablets depending on body weight. |
|
| Group C (Tablets) | Experimental | Pyronaridine artesunate 12:4 mg/kg. The tablet strength is 96:32 mg oral PA, with the number of tablets depending on body weight. |
|
| Group D (Granules) | Experimental | Pyronaridine artesunate 9:3 mg/kg. The sachet of granules strength is 60:20 mg PA, with the number of sachets depending on body weight, and is administered as a suspension with water. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pyronaridine-Artesunate | Drug | Once a day for 3 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Patients With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 28 | Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 28 days, without previously meeting any of the criteria for early treatment failure, late clinical failure, or late parasitological failure. | Day 28 |
| Measure | Description | Time Frame |
|---|---|---|
| Parasite Clearance Time | The time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of parasites for 2 consecutive negative readings taken between 8 and 24 hours apart. | Day 3 |
| Treatment Success or Failure |
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Inclusion Criteria:
Patients presenting with symptoms of acute uncomplicated falciparum malaria with the following inclusion criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Ramharter, MD | Albert Schweitzer Hospital, Lambaréné, Gabon | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Medical Research Unit, Albert Schweitzer Hospital | Lambaréné | Gabon |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8531545 | Background | Ringwald P, Bickii J, Basco L. Randomised trial of pyronaridine versus chloroquine for acute uncomplicated falciparum malaria in Africa. Lancet. 1996 Jan 6;347(8993):24-8. doi: 10.1016/s0140-6736(96)91558-5. | |
| 38418982 | Derived | Ramharter M, Djimde AA, Borghini-Fuhrer I, Miller R, Shin J, Aspinall A, Richardson N, Wibberg M, Fleckenstein L, Arbe-Barnes S, Duparc S. Safety and efficacy of pyronaridine-artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study. Malar J. 2024 Feb 28;23(1):61. doi: 10.1186/s12936-024-04885-3. |
| Label | URL |
|---|---|
| Shin Poong Pharmaceuticals | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Group A (Tablets) | Pyronaridine artesunate 6:2 mg/kg. Number of PA tablets (48 mg + 16 mg) administered based on posology. 3-day course of once-daily dosing. |
| FG001 | Group B (Tablets) | Pyronaridine artesunate 9:3 mg/kg. Number of PA tablets (72 mg + 24 mg) administered based on posology. 3-day course of once-daily dosing. |
| FG002 | Group C (Tablets) | Pyronaridine artesunate 12:4 mg/kg. Number of PA tablets (96 mg + 32 mg) administered based on posology. 3-day course of once-daily dosing. |
| FG003 | Group D (Granules) | Pyronaridine artesunate 9:3 mg/kg. Number of PA sachets containing granules (60 mg + 20 mg) administered based on posology. Sachet is administered as a suspension with water. 3-day course of once-daily dosing. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety population: all subjects who received at least 1 dose of study drug. Males/Females between ages of 2 and 14 years, with body weight between 10 and 40kg.
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| ID | Title | Description |
|---|---|---|
| BG000 | Group A (Tablets) | Pyronaridine artesunate 6:2 mg/kg |
| BG001 | Group B (Tablets) | Pyronaridine artesunate 9:3 mg/kg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Patients With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 28 | Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 28 days, without previously meeting any of the criteria for early treatment failure, late clinical failure, or late parasitological failure. | Per protocol population: all patients who received a full course of study treatment, had a known status of the primary efficacy variable, and did not have major protocol violations. | Posted | Count of Participants | Participants | Day 28 |
|
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
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Group A (Tablets) | Pyronaridine artesunate 6:2 mg/kg | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Plasmodium falciparum infection | Infections and infestations | MedDRA | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stephan Duparc, MD | Medicines for Malaria Venture | +41 22 555 0300 | duparcs@mmv.org |
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| ID | Term |
|---|---|
| D008288 | Malaria |
| ID | Term |
|---|---|
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D000096724 | Mosquito-Borne Diseases |
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| ID | Term |
|---|---|
| C000712628 | pyronaridine tetraphosphate, artesunate drug combination |
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|
Treatment success for the ACPR analysis is defined as the clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 28 days, without previously meeting any of the criteria for early treatment failure, late clinical failure, or late parasitological failure. Early and late failures are classified according to the WHO Protocol 2005. |
| Day 28 |
| Fever Clearance Time | The time from first dosing to the first normal reading with fever clearance, defined as 2 consecutive assessments without fever (<37.5°C) taken between 8 and 24 hours apart. NB: Time to fever clearance was only summarised for subjects who had fever at baseline or within the first 24 hours after the start of study treatment. Since only 12 subjects in total had fever during this time, the time to fever clearance estimates are not very meaningful. | Day 3 |
| Number of Patients With PCR-corrected ACPR on Day 14 | Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 14 days. | Day 14 |
| Number of Patients With Parasite Clearance at Day 1, 2 and 3 | Zero presence of parasites for 2 consecutive negative readings taken between 8 and 24 hours apart. | Days 1, 2, 3 |
| Number of Subjects With P. Falciparum Gametocytes During the Trial | The number of gametocytes per μl at Days 0, 3, 7, 14, 21, 28, 35, and 42 summarised from blood slides taken on the respective days. P. falciparum gametocytes are responsible for transmission from host to vector. | Day 42 |
| Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Patient without fever for 2 consecutive readings taken between 8 and 24 hours apart. NB: Percentage of fever clearance was only summarised for subjects who had fever at baseline or within the first 24 hours after the start of study treatment. Since only 12 subjects in total had fever during this time, the time to fever clearance estimates are not very meaningful. | Days 1, 2, 3 |
| Crude ACPR on Day 14, 28 and 42 | The proportion of patients with crude (non-PCR corrected) ACPR. | Days 14, 28, 42 |
| Number of Patients With PCR-corrected ACPR on Day 42 | Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 42 days. | Day 42 |
| 26666916 | Derived | Ayyoub A, Methaneethorn J, Ramharter M, Djimde AA, Tekete M, Duparc S, Borghini-Fuhrer I, Shin JS, Fleckenstein L. Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients. Antimicrob Agents Chemother. 2015 Dec 14;60(3):1450-8. doi: 10.1128/AAC.02004-15. |
| 23433102 | Derived | Duparc S, Borghini-Fuhrer I, Craft CJ, Arbe-Barnes S, Miller RM, Shin CS, Fleckenstein L. Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials. Malar J. 2013 Feb 21;12:70. doi: 10.1186/1475-2875-12-70. |
| 18694333 | Derived | Ramharter M, Kurth F, Schreier AC, Nemeth J, Glasenapp Iv, Belard S, Schlie M, Kammer J, Koumba PK, Cisse B, Mordmuller B, Lell B, Issifou S, Oeuvray C, Fleckenstein L, Kremsner PG. Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon. J Infect Dis. 2008 Sep 15;198(6):911-9. doi: 10.1086/591096. |
| Withdrawal by Subject |
|
| Lost to Follow-up |
|
| Protocol Violation |
|
| Not treated |
|
| BG002 |
| Group C (Tablets) |
Pyronaridine artesunate 12:4 mg/kg |
| BG003 | Group D (Granules) | Pyronaridine artesunate 9:3 mg/kg |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Height | Mean | Standard Deviation | cm |
|
| Weight | Mean | Standard Deviation | kg |
|
Pyronaridine artesunate 9:3 mg/kg |
| OG002 | Group C (Tablets) | Pyronaridine artesunate 12:4 mg/kg |
| OG003 | Group D (Granules) | Pyronaridine artesunate 9:3 mg/kg |
|
|
| Secondary | Parasite Clearance Time | The time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of parasites for 2 consecutive negative readings taken between 8 and 24 hours apart. | Per protocol population: all patients who received a full course of study treatment, had a known status of the primary efficacy variable, and did not have major protocol violations. | Posted | Median | 95% Confidence Interval | hours | Day 3 |
|
|
|
| Secondary | Treatment Success or Failure | Treatment success for the ACPR analysis is defined as the clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 28 days, without previously meeting any of the criteria for early treatment failure, late clinical failure, or late parasitological failure. Early and late failures are classified according to the WHO Protocol 2005. | Per protocol population: all patients who received a full course of study treatment, had a known status of the primary efficacy variable, and did not have major protocol violations. | Posted | Count of Participants | Participants | Day 28 |
|
|
|
| Secondary | Fever Clearance Time | The time from first dosing to the first normal reading with fever clearance, defined as 2 consecutive assessments without fever (<37.5°C) taken between 8 and 24 hours apart. NB: Time to fever clearance was only summarised for subjects who had fever at baseline or within the first 24 hours after the start of study treatment. Since only 12 subjects in total had fever during this time, the time to fever clearance estimates are not very meaningful. | Only patients with a fever at baseline or within 24 hours were taken into account. | Posted | Median | 95% Confidence Interval | hours | Day 3 |
|
|
|
| Secondary | Number of Patients With PCR-corrected ACPR on Day 14 | Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 14 days. | Per protocol population: all patients who received a full course of study treatment, had a known status of the primary efficacy variable, and did not have major protocol violations. | Posted | Count of Participants | Participants | Day 14 |
|
|
|
| Secondary | Number of Patients With Parasite Clearance at Day 1, 2 and 3 | Zero presence of parasites for 2 consecutive negative readings taken between 8 and 24 hours apart. | Per protocol population: all patients who received a full course of study treatment, had a known status of the primary efficacy variable, and did not have major protocol violations. | Posted | Count of Participants | Participants | Days 1, 2, 3 |
|
|
|
| Secondary | Number of Subjects With P. Falciparum Gametocytes During the Trial | The number of gametocytes per μl at Days 0, 3, 7, 14, 21, 28, 35, and 42 summarised from blood slides taken on the respective days. P. falciparum gametocytes are responsible for transmission from host to vector. | Per protocol population: all patients who received a full course of study treatment, had a known status of the primary efficacy variable, and did not have major protocol violations. | Posted | Count of Participants | Participants | Day 42 |
|
|
|
| Secondary | Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Patient without fever for 2 consecutive readings taken between 8 and 24 hours apart. NB: Percentage of fever clearance was only summarised for subjects who had fever at baseline or within the first 24 hours after the start of study treatment. Since only 12 subjects in total had fever during this time, the time to fever clearance estimates are not very meaningful. | Only patients with a fever at baseline or within 24 hours were taken into account. | Posted | Count of Participants | Participants | Days 1, 2, 3 |
|
|
|
| Secondary | Crude ACPR on Day 14, 28 and 42 | The proportion of patients with crude (non-PCR corrected) ACPR. | Per protocol population: all patients who received a full course of study treatment, had a known status of the primary efficacy variable, and did not have major protocol violations. | Posted | Count of Participants | Participants | Days 14, 28, 42 |
|
|
|
| Secondary | Number of Patients With PCR-corrected ACPR on Day 42 | Clearance of asexual parasitaemia within 7 days of initiation of study medication without recrudescence within 42 days. | Per protocol population: all patients who received a full course of study treatment, had a known status of the primary efficacy variable, and did not have major protocol violations. | Posted | Count of Participants | Participants | Day 42 |
|
|
|
| 14 |
| 2 |
| 14 |
| 13 |
| 14 |
| EG001 | Group B (Tablets) | Pyronaridine artesunate 9:3 mg/kg | 0 | 15 | 0 | 15 | 11 | 15 |
| EG002 | Group C (Tablets) | Pyronaridine artesunate 12:4 mg/kg | 0 | 15 | 0 | 15 | 13 | 15 |
| EG003 | Group D (Granules) | Pyronaridine artesunate 9:3 mg/kg | 0 | 15 | 0 | 15 | 12 | 15 |
| Pyrexia | General disorders | MedDRA | Systematic Assessment |
|
| Paronychia | Infections and infestations | MedDRA | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Ascariasis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Malaria | Infections and infestations | MedDRA | Systematic Assessment |
|
| Acarodermatitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Abscess | Infections and infestations | MedDRA | Systematic Assessment |
|
| Fungal skin infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Giardiasis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Respiratory tract infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Schistosomiasis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Splenomegaly | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Hepatomegaly | Hepatobiliary disorders | MedDRA | Systematic Assessment |
|
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| D000079426 |
| Vector Borne Diseases |
| Treatment failure |
|
| Clearance by >24 - 48 hours (Day 2) |
|
| Clearance by >48 - 72 hours (Day 3) |
|
| Clearance by >72 hours (Day 3 onwards) |
|
| No clearance achieved |
|
| >0-24 hours |
|
| >24-48 hours |
|
| >48-72 hours |
|
| >72 hours - Day 7 |
|
| >Day 7 - Day 28 |
|
| >Day 28 - Day 42 |
|
| >Day 42 |
|
| Clearance by >24 - 48 hours |
|
| Clearance by >48 - 72 hours |
|
| No clearance achieved |
|
|
| Day 28 |
|
|
| Day 42 |
|
|