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| Name | Class |
|---|---|
| Shin Poong Pharmaceuticals | INDUSTRY |
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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pyronaridine - artesunate | Experimental | Oral pyronaridine artesunate (180:60mg tablets) once a day for 3 consecutive days (Day 0, 1, and 2). Posology based on body weight ranges. |
|
| Mefloquine plus artesunate | Active Comparator | Mefloquine (250mg tablets) plus artesunate (100mg tablets) once a day for 3 consecutive days (Day 0, 1, and 2). Posology based on body weight ranges. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pyronaridine - artesunate | Drug | once a day for 3 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Day 28 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Day 14 |
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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:
Written informed consent provided by patient and/or parent/guardian/spouse.
Ability to swallow oral medication.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Isabelle Borghini-Fuhrer, PhD | Medicines for Malaria Venture | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| RAOTAP2/Centre Muraz | Bobo-Dioulasso | Houet Province | 01 BP390 | Burkina Faso | ||
| Pailin Referral Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22475593 | Result | Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, Penali LK, Valecha N, Tien NT, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L; Pyronaridine-Artesunate Study Team. Pyronaridine-artesunate versus mefloquine plus artesunate for malaria. N Engl J Med. 2012 Apr 5;366(14):1298-309. doi: 10.1056/NEJMoa1007125. | |
| 26666916 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Pyronaridine - Artesunate | Pyronaridine - artesunate (180:60mg) once a day for 3 days. Posology was based on body weight ranges. |
| FG001 | Mefloquine Plus Artesunate | Mefloquine (250mg) plus artesunate (100mg) once a day for 3 days. Posology was based on body weight ranges. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Mefloquine plus artesunate | Drug | once a day for 3 days |
|
| 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 |
| Days 14 and 28 |
| 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. | 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). |
| 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. | 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. |
| 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. | Days 1, 2 and 3 |
| 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. | Days 1, 2 and 3 |
| 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 | 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 |
| Pailin |
| Pailin |
| Cambodia |
| Institut Pasteur | Abidjan | Côte d’Ivoire |
| Wentlock District Hospital | Mangalore | India |
| Bagamoyo Research and Training Centre of Ifakara Health Institute | Bagamoyo | Tanzania |
| MaeLamad District Hospital | Mae Ramat | Changwat Tak | Thailand |
| MaeSod General Hospital | Mae Sot | Changwat Tak | Thailand |
| NIMPE | Hanoi | Commune Xy | Vietnam |
| Choray Hospital, Dak O | Ho Chi Minh City | Vietnam |
| 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. |
| COMPLETED |
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| NOT COMPLETED |
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Safety population, consisted of all randomized subjects who received any amount of study medication.
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| ID | Title | Description |
|---|---|---|
| BG000 | Pyronaridine - Artesunate | Pyronaridine - artesunate (180:60mg) once a day for 3 days. Posology was based on body weight ranges. |
| BG001 | Mefloquine Plus Artesunate | Mefloquine (250mg) plus artesunate (100mg) once a day for 3 days. Posology was based on body weight ranges. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Age, Continuous | Median | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| 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 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. | 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. | Posted | Number | 95% Confidence Interval | percentage of subjects | Day 28 |
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| 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 | 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. | Posted | Mean | 95% Confidence Interval | percentage of subjects | Day 14 |
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| 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 | 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. | Posted | Number | 95% Confidence Interval | percentage of subjects | Days 14 and 28 |
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| 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. | 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. | Posted | Median | 95% Confidence Interval | hours | 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). |
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| 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. | 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. | Posted | Median | 95% Confidence Interval | hours | 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. |
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| 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. | 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. | Posted | Number | 95% Confidence Interval | percentage of subjects | Days 1, 2 and 3 |
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| 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. | 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. | Posted | Number | 95% Confidence Interval | percentage of subjects | Days 1, 2 and 3 |
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| 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 | The safety population consisted of all randomised subjects who received any amount of study medication; subjects were analysed as treated. | Posted | Count of Participants | Participants | 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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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
An AE was defined as any unfavorable and unintended sign, symptom, syndrome, or illness that developed or worsened during the period of observation in the clinical study.
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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 | Pyronaridine - Artesunate | Pyronaridine artesunate (180:60mg) Pyronaridine artesunate: once a day for 3 days | 0 | 848 | 6 | 848 | 389 | 848 |
| EG001 | Mefloquine Plus Artesunate | Mefloquine (250mg) plus artesunate (100mg) Mefloquine plus artesunate: once a day for 3 days | 0 | 423 | 3 | 423 | 190 | 423 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cholera | Infections and infestations | MedDRA (10.1) | Systematic Assessment | Cholera Inaba |
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| Anaemia haemolytic autoimmune | Blood and lymphatic system disorders | MedDRA (10.1) | Systematic Assessment | Transient auto immune hemolytic anemia |
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| Pyelonephritis acute | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
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| Wound infection | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
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| Pneumonia | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
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| Abortion complete | Pregnancy, puerperium and perinatal conditions | MedDRA (10.1) | Systematic Assessment |
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| Depression | Psychiatric disorders | MedDRA (10.1) | Systematic Assessment |
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| Grand mal convulsion | Nervous system disorders | MedDRA (10.1) | Systematic Assessment | Tonic clonic seizure. Treatment-related SAE. |
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| Convulsion | Nervous system disorders | MedDRA (10.1) | Systematic Assessment | Seizure. Treatment related SAE. |
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| Cerebral malaria | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (10.1) | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (10.1) | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (10.1) | Systematic Assessment |
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| Anorexia | Metabolism and nutrition disorders | MedDRA (10.1) | Systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | MedDRA (10.1) | Systematic Assessment |
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| Basophilia | Blood and lymphatic system disorders | MedDRA (10.1) | Systematic Assessment |
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| Eosinophilia | Blood and lymphatic system disorders | MedDRA (10.1) | Systematic Assessment |
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| Vertigo | Ear and labyrinth disorders | MedDRA (10.1) | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
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| Fatigue | General disorders | MedDRA (10.1) | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA (10.1) | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA (10.1) | Systematic Assessment |
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| Alanine aminotransferase increased | Investigations | MedDRA (10.1) | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA (10.1) | Systematic Assessment |
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| Blood creatinine phosphokinase increased | Investigations | MedDRA (10.1) | Systematic Assessment |
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| Electrocardiogram QT prolonged | Investigations | MedDRA (10.1) | Systematic Assessment |
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| Eosinophil count increased | Investigations | MedDRA (10.1) | Systematic Assessment |
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| Haemoglobin decreased | Investigations | MedDRA (10.1) | Systematic Assessment |
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| Platelet count increased | Investigations | MedDRA (10.1) | Systematic Assessment |
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| Transaminases increased | Investigations | MedDRA (10.1) | Systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA (10.1) | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (10.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stephan Duparc, MD | Medicines for Malaria Venture | +41 22 555 0300 | duparcs@mmv.org |
| ID | Term |
|---|---|
| D016778 | Malaria, Falciparum |
| D008288 | Malaria |
| ID | Term |
|---|---|
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D000096724 | Mosquito-Borne Diseases |
| D000079426 | Vector Borne Diseases |
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| ID | Term |
|---|---|
| C000712628 | pyronaridine tetraphosphate, artesunate drug combination |
| D015767 | Mefloquine |
| D000077332 | Artesunate |
| ID | Term |
|---|---|
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D037621 | Artemisinins |
| D017382 | Reactive Oxygen Species |
| D005609 | Free Radicals |
| D007287 | Inorganic Chemicals |
| D009930 | Organic Chemicals |
| D012717 | Sesquiterpenes |
| D013729 | Terpenes |
| D006838 | Hydrocarbons |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Burkina Faso |
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| Cambodia |
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| Tanzania |
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| Côte D'Ivoire |
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| Thailand |
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| India |
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| Non-Inferiority or Equivalence (legacy) |
The primary efficacy analysis tested the non-inferiority of the PA group compared to the comparator group with regard to the PCR-corrected ACPR response rate at Day 28 using the 2-sided 95% confidence interval (CI) (Newcombe-Wilson score method without continuity correction). Non-inferiority of PA to MQ + AS was concluded if the lower limit of the CI for the difference was >-5%. |
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| Participants |
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| Participants |
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