Safety and Efficacy of Pyronaridine Artesunate Vs Chloroquine in Children and Adult Patients With Acute Vivax Malaria

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase III Randomised, Double-blind, Double-dummy, Comparative Study to Assess the Safety and Efficacy of Pyronaridine Artesunate (180:60 mg) Versus Chloroquine (155 mg) in Children and Adult Patients in Korea With Acute P. Vivax Malaria

Conditions
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Malaria

Intervention / Treatment
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* Drug: Pyronaridine - artesunate
* Drug: Chloroquine


Participation Criteria
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Eligibility Criteria
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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. vivax mono-infection confirmed by: 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, Positive microscopy of P. vivax with parasite density ≥250/ μL of blood (including at least 50% of asexual parasites). 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. Ability to swallow oral medication. Ability and willingness to participate based on information given to patient or parent or guardian and access to health facility. Exclusion Criteria: Presence of a mixed Plasmodium infection. Presence of other clinical condition requiring hospitalization. Presence of significant anaemia, as defined by Hb <8 g/dL. 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). Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, chloroquine or artesunate or other artemisinins. Known history of hypersensitivity, allergic or adverse reactions to chloroquine, primaquine and related agents. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab). Known seropositive HIV antibody. Have received any antimalarial treatment in the preceding 2 weeks, as determined by history and, whenever feasible, by screening test. Have received antibacterial with known antimalarial activity in the preceding 2 weeks. Have received any investigational drug within the past 4 weeks. Liver function tests (AST/ALT levels) >2.5 times the upper limit of normal range. Known significant renal impairment as indicated by serum creatinine levels of >1.4 mg/dL. 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. Previous participation in the present clinical trial with pyronaridine artesunate.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pyronaridine - artesunate<br>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. | Drug: Pyronaridine - artesunate<br>* Oral pyronaridine artesunate (180:60 mg tablets), plus chloroquine-placebo once a day for 3 consecutive days.<br>* Other names: Pyramax;|
| Active Comparator: Chloroquine<br>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. | Drug: Chloroquine<br>* Oral chloroquine (155 mg tablets), plus pyronaridine artesunate-placebo, once a day for 3 consecutive days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Day 28 | 
| 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 | 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) | 
| 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 | 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) | 
| 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 | Days 1, 2, and 3 | 
| 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 | Days 1, 2, and 3 | 
| 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 | Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Artemisinin-based combination therapy (ACT), Pyramax, Pyronaridine artesunate, Chloroquine, Children, Adults, Plasmodium vivax, Republic of Korea