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| Name | Class |
|---|---|
| Shin Poong Pharmaceuticals | INDUSTRY |
The primary objective of this phase III study is to compare the efficacy and safety of the fixed combination of pyronaridine artesunate (Pyramax®, PA) with that of Coartem® (artemether lumefantrine, AL) in children and adults with uncomplicated P falciparum malaria in Africa and South East Asia.
This is a multi-centre, comparative, randomised, (double-blind, double-dummy), parallel-group, non-inferiority study comparing the efficacy and safety of the fixed combination of PA with that of AL in the treatment of acute, uncomplicated P. falciparum malaria. The study population will include 1269 patients, comprising male and female children (≥20 kg body weight) and adults recruited from study sites in Africa and South East Asia.
Patients will be randomised to receive either oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Days 0, 1, and 2) or AL twice a day plus PA-placebo (once a day) for 3 consecutive days (Days 0, 1, and 2) in a 2:1 ratio. The dose range of PA covered by this regimen is 7.2:2.4 mg/kg to 13.8:4.6 mg/kg, respectively, which has been shown to be effective and safe in Phase I and II studies. Posology will be based on body weight ranges for both the PA and AL regimens.
Patients will be confined to the study facility for ≥4 days (Days 0, 1, 2, and 3) and remain near the study site for ≥7 days, or once fever and parasite clearance has been confirmed for ≥24 hours - whichever occurs later.
The primary efficacy end point for the study is the proportion of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. Scheduled follow-up visits will continue until completion of the study at Day 42. In the case of adverse events reported and unresolved at Day 42, patients will be followed up for a further 30 days, or until resolution of the event.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PA group | Experimental | Pyronaridine artesunate (PA) |
|
| AL group | Active Comparator | Arthemether lumefantrine (AL) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pyronaridine artesunate | Drug | Oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Day 0, 1, and 2) |
|
| Measure | Description | Time Frame |
|---|---|---|
| PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on Day 28 | Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28, defined as absence of parasitaemia on Day 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure. | Day 28 |
| Measure | Description | Time Frame |
|---|---|---|
| PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 14 | Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 14, defined as absence of parasitaemia on Day 14 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure. | Day 14 |
Not provided
Inclusion Criteria:
Male or female patients between the age of 3 and 60 years, inclusive.
Body weight between 20 kg and 90 kg with no clinical evidence of severe malnutrition.
Presence of acute uncomplicated P. falciparum mono-infection confirmed by:
Written informed consent, in accordance with local practice, provided by patient and/or parent/guardian/spouse.
Ability to swallow oral medication.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Claude Oeuvray, PhD | Medicines for Malaria Venture | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa | Kinshasa | Democratic Republic of the Congo | ||||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20417857 | Result | Tshefu AK, Gaye O, Kayentao K, Thompson R, Bhatt KM, Sesay SS, Bustos DG, Tjitra E, Bedu-Addo G, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L; Pyronaridine-artesunate Study Team. Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial. Lancet. 2010 Apr 24;375(9724):1457-67. doi: 10.1016/S0140-6736(10)60322-4. | |
| 35726133 |
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| ID | Title | Description |
|---|---|---|
| FG000 | PA Group | Pyronaridine artesunate (PA) Pyronaridine artesunate: Oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Day 0, 1, and 2) |
| FG001 | AL Group |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Coartem® (artemether lumefantrine) | Drug | AL (20:120mg tablets) twice a day plus PA-placebo (once a day) for 3 consecutive days (Day 0, 1, and 2) |
|
|
| Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28 | Percentage of subjects with adequate clinical and parasitological response (ACPR) on Day 28, without correction by PCR, defined as absence of parasitaemia on Day 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure. | Day 14 and 28 |
| Parasite Clearance Time | Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart. | Days 0, 3, 7, 14, 21, 28, 35, and 42 (or on any other day if the subject spontaneously returned) |
| Fever Clearance Time | Fever clearance time is defined as the time from first dosing to first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart | Day 0 and every 8 hours over ≥72 hours following first study drug administration or temperature normalization for ≥2 readings between 7 and 25 hours apart, then at each visit and as clinically indicated |
| Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Fever clearance time is defined as the time from first dosing to first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart. | Days 1, 2, 3 |
| Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 | Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance was defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart. | Days 1, 2, 3 |
| Adverse Events and Clinically Significant Laboratory Results | Incidence 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 |
| Komfo Anoykye Teaching Hospital |
| Kumasi |
| Ghana |
| RSUD TC Hillers | Maumere | East Nusa Tenggara | 86113 | Indonesia |
| Jayapura General Hospital (RSUD) DOK II | Jayapura | Special Region of Papua | Indonesia |
| Siaya District Hospital, Medical Superintendent's office | Siaya | Kenya |
| Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie | Bamako | Mali |
| Instituto Nacional de Saude, Ministero de Saude | Maputo | Mozambique |
| Puerto Princesa General Hospital | Puerto Princesa City | Philippines |
| Service de Parasitologie, Faculté de Médecine, Université Cheikh Anta Diop | Dakar | Dakar Fann | Senegal |
| Farafenni Field Station, c/o: MRC Laboratories | Fajara | The Gambia |
| Derived |
| Pryce J, Taylor M, Fox T, Hine P. Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev. 2022 Jun 21;6(6):CD006404. doi: 10.1002/14651858.CD006404.pub4. |
| 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. |
Arthemether lumefantrine (AL)
Coartem® (artemether lumefantrine): AL twice a day plus PA-placebo (once a day) for 3 consecutive days (Day 0, 1, and 2)
| COMPLETED |
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| NOT COMPLETED |
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Intent-to-treat (ITT) population, defined as all randomized subjects who received any amount of study medication. Subjects were analyzed as randomized.
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| ID | Title | Description |
|---|---|---|
| BG000 | PA Group | Pyronaridine artesunate (PA) Pyronaridine artesunate: Oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Day 0, 1, and 2) |
| BG001 | AL Group | Arthemether lumefantrine (AL) Coartem® (artemether lumefantrine): AL twice a day plus PA-placebo (once a day) for 3 consecutive days (Day 0, 1, and 2) |
| 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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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on Day 28 | Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28, defined as absence of parasitaemia on Day 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure. | Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations. | Posted | Number | 95% Confidence Interval | percentage of subjects | Day 28 |
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| Secondary | PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 14 | Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 14, defined as absence of parasitaemia on Day 14 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure. | Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations. | Posted | Number | 95% Confidence Interval | percentage of subjects | Day 14 |
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| Secondary | Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28 | Percentage of subjects with adequate clinical and parasitological response (ACPR) on Day 28, without correction by PCR, defined as absence of parasitaemia on Day 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure. | Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations. | Posted | Number | 95% Confidence Interval | percentage of subjects | Day 14 and 28 |
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| Secondary | Parasite Clearance Time | Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart. | Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations. | Posted | Median | 95% Confidence Interval | hours | Days 0, 3, 7, 14, 21, 28, 35, and 42 (or on any other day if the subject spontaneously returned) |
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| Secondary | Fever Clearance Time | Fever clearance time is defined as the time from first dosing to first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart | Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations. | Posted | Median | 95% Confidence Interval | hours | Day 0 and every 8 hours over ≥72 hours following first study drug administration or temperature normalization for ≥2 readings between 7 and 25 hours apart, then at each visit and as clinically indicated |
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| Secondary | Percentage of Patients With Fever Clearance at Day 1, 2 and 3 | Fever clearance time is defined as the time from first dosing to first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart. | Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations. | Posted | Number | 95% Confidence Interval | percentage of subjects | Days 1, 2, 3 |
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| Secondary | Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 | Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance was defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart. | Efficacy evaluable population subjects completed a full course of study medication; has a known primary efficacy endpoint at D28; did not miss a dose due to vomiting (except at D0); did not use a concomitant medication (except acetaminophen); did not have a concomitant disease which may have interfered with the classification of the treatment outcome; and did not have major protocol deviations. | Posted | Number | 95% Confidence Interval | percentage of subjects | Days 1, 2, 3 |
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| Secondary | Adverse Events and Clinically Significant Laboratory Results | Incidence of adverse events and of clinically significant laboratory results, ECG, vital signs or physical examination abnormalities. | The safety population consists of all randomized subjects who received any amount of study medication; subjects were analyzed 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 | PA Group | Pyronaridine artesunate (PA) Pyronaridine artesunate: Oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Day 0, 1, and 2) | 0 | 849 | 3 | 849 | 506 | 849 |
| EG001 | AL Group | Arthemether lumefantrine (AL) Coartem® (artemether lumefantrine): AL twice a day plus PA-placebo (once a day) for 3 consecutive days (Day 0, 1, and 2) | 0 | 423 | 2 | 423 | 239 | 423 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Parotitis | Infections and infestations | Systematic Assessment |
| ||
| Typhoid fever | Infections and infestations | Systematic Assessment |
| ||
| Urinary tract infection | Infections and infestations | Systematic Assessment |
| ||
| Cerebral malaria | Infections and infestations | Systematic Assessment |
| ||
| Immunosuppression | Immune system disorders | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Eosinophilia | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Lymphocytosis | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
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| Bradycardia | Cardiac disorders | Systematic Assessment |
| ||
| Vertigo | Ear and labyrinth disorders | Systematic Assessment |
| ||
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
| ||
| Abdominal pain upper | Gastrointestinal disorders | Systematic Assessment |
| ||
| Diarrhoea | Gastrointestinal disorders | Systematic Assessment |
| ||
| Dyspepsia | Gastrointestinal disorders | Systematic Assessment |
| ||
| Nausea | Gastrointestinal disorders | Systematic Assessment |
| ||
| Toothache | Gastrointestinal disorders | Systematic Assessment |
| ||
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
| ||
| Influenza like illness | General disorders | Systematic Assessment |
| ||
| Pyrexia | General disorders | Systematic Assessment |
| ||
| Helminthic infection | Infections and infestations | Systematic Assessment |
| ||
| Influenza | Infections and infestations | Systematic Assessment |
| ||
| Nasopharyngitis | Infections and infestations | Systematic Assessment |
| ||
| Oral herpes | Infections and infestations | Systematic Assessment |
| ||
| Respiratory tract infection | Infections and infestations | Systematic Assessment |
| ||
| Rhinitis | Infections and infestations | Systematic Assessment |
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| Upper respiratoty tract infection | Infections and infestations | Systematic Assessment |
| ||
| Urinary tract infection | Infections and infestations | Systematic Assessment |
| ||
| Alanine aminotransferase increased | Investigations | Systematic Assessment |
| ||
| Aspartate aminotransferase increased | Investigations | Systematic Assessment |
| ||
| Platelet count increased | Investigations | Systematic Assessment |
| ||
| Anorexia | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Haematuria | Renal and urinary disorders | Systematic Assessment |
| ||
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stephan Duparc, MD, Chief Medical Officer | Medicines for Malaria Venture (MMV) | +41 22 555 0300 | 351 | duparcs@mmv.org |
| ID | Term |
|---|---|
| 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 |
| D000077611 | Artemether, Lumefantrine Drug Combination |
| ID | Term |
|---|---|
| D000077549 | Artemether |
| D037621 | Artemisinins |
| D017382 | Reactive Oxygen Species |
| D005609 | Free Radicals |
| D007287 | Inorganic Chemicals |
| D009930 | Organic Chemicals |
| D000078102 | Lumefantrine |
| D005449 | Fluorenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D012717 | Sesquiterpenes |
| D013729 | Terpenes |
| D011083 | Polycyclic Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
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| Male |
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| Asian/Oriental |
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| Gambia |
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| Mali |
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| Senegal |
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| Philippines |
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| Congo, The Democratic Republic of the |
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| Ghana |
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| Kenya |
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| Indonesia |
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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) and a 5% non-inferiority margin. Non-inferiority was demonstrated if the lower limit of the CI for the difference >-5%. |
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