Bioequivalence Trial of Pyronaridine Artesunate To-be-marketed Tablet to the Clinical Trial Reference Tablet

Study Overview
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Brief Summary
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The primary objective of this study is to determine the bioequivalence of the combination of pyronaridine and artesunate (180:60mg) to-be-marketed tablet to the clinical trial reference tablet administered as a single total dose of 720:240 mg in healthy adults. The secondary objective is to assess the safety of the two formulations.

Detailed Description
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This is a phase I, randomized, single dose, two-way cross-over study of two tablet formulations of the combination of pyronaridine and artesunate (180:60 mg). The study will include 42 healthy participants, comprising male and female adults. Participants will be randomized to receive either reference tablet formulation or to-be-marketed formulation first and then will be crossed over to receive the opposite Intervention. The study will consist of two single dose treatments of 720:240 mg tablets, separated by a washout period of 43 days. Participants will go to the clinic the evening before dosing (dosing days were Day 0 for period 1 and Day 43 for period 2) under fasting condition and remain in the hospital for 24 hours after receiving dosing. Participants will stay in the hospital for 24 hours after their arrival at the clinic. They will return to the clinic at Day 2, 3, 5, 7, 14, 21, 28, 35 and 42 on an ambulatory basis. At Day 43, the dosing for the second sequence will start and a similar schedule of visits will be followed. Each participant will be followed-up for an additional 42 days after the start of the second study period, until the final visit (Day 85). The total duration of participation is 85 days plus a maximum of 2 weeks screening period.

Official Title
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Phase I, Randomized, Single Dose, Bioequivalence Trial of Pyronaridine Artesunate To-be-marketed Tablet to the Clinical Trial Reference Tablet

Conditions
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Malaria

Intervention / Treatment
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* Drug: pyronaridine artesunate clinical trial reference tablets
* Drug: pyronaridine artesunate to-be-marketed tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between the ages of 18 and 45 years with a body weight between 55 and 75 kg and a body mass index using Quetelet's Index - weight (kg)/height2 (m2) between 18-28 Signed and dated written informed consent form before undergoing any study related activities, including discontinuation of any prohibited medications Medically normal subjects with no significant abnormal findings at the screening physical examination as evaluated by the clinical investigator Normal (or abnormal and clinically insignificant) laboratory values at screening Female subjects of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who was post-menopausal (i.e., one year without menses) Female subjects of childbearing potential with a negative urine pregnancy test at screening and who agreed to one of the accepted forms of contraception The ability to understand the requirements of the study and willingness to comply with all study procedures Exclusion Criteria: Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, acute QTc interval greater or equal to 450 mseconds), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other abnormality (including head trauma) Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab) Known seropositive HIV antibody Previous participation in any clinical trial with pyronaridine artesunate Presence or recent history (last two years) of tobacco abuse (≥10 cigarettes/day) Known or suspected alcohol abuse or illicit drug use 10 years before the study start or positive findings on urine drug screen Intake of alcoholic beverages or caffeine-containing food or beverages, such as coffee, tea, chocolate, or cola, 24 h before study drug administration Use of over-the-counter (OTC) medications, including vitamins, analgesics, or antacids, 72 h before the study start Use of prescription medications 14 days before the study start or required chronic use of any prescription medication Use of enzyme-altering agents (e.g., barbiturates, phenothiazines, cimetidine, etc.) 30 days before the study start Plasma donation 3 months before the study start Blood donation of 500 mL or more 3 months before the study start Participation in an investigational drug study 3 months before randomization

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clinical Trial Reference Tablets first, then To-Be-Marketed Tablets<br>Participants first received clinical trial reference 720:240 mg tablets on Day 0. After a washout period of 43 days, they then received to-be-marketed 720:240 mg tablets on Day 43, with a follow-up period of 42 days. | Drug: pyronaridine artesunate clinical trial reference tablets<br>* Single total oral dose of 720:240 mg (4 tablets of 180:60 mg)<br>* Other names: PA;Drug: pyronaridine artesunate to-be-marketed tablets<br>* Single total oral dose of 720:240 mg (4 tablets of 180:60 mg)<br>* Other names: PA;|
| Experimental: To-Be-Marketed Tablets first, then Clinical Trial Reference Tablets<br>Participants first received to-be-marketed 720:240 mg tablets on Day 0. After a washout period of 43 days, they then received clinical trial reference 720:240 mg tablets on Day 43, with a follow-up period of 42 days. | Drug: pyronaridine artesunate clinical trial reference tablets<br>* Single total oral dose of 720:240 mg (4 tablets of 180:60 mg)<br>* Other names: PA;Drug: pyronaridine artesunate to-be-marketed tablets<br>* Single total oral dose of 720:240 mg (4 tablets of 180:60 mg)<br>* Other names: PA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pyronaridine Pharmacokinetics: Tmax, Half-life | Tmax: time to maximum concentration Half-life: computed as ln (2)/kel | Sampling performed at predose at 0 h and at, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12, 24, 48, 72 h and on Day 5, 7, 14, 21, 28, 35, 42 for each period | 
| Pyronaridine (PP), Artesunate (AS), Dihydroartemisinin (DHA) Pharmacokinetics: Cmax | Cmax: maximum peak observed concentration | PP sampling performed at predose at at 0 h and at, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12, 24, 48, 72 h and on Day 5, 7, 14, 21, 28, 35, 42 for each period AS, DHA sampling performed at predose at 0 h and at 0.25, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12 h for each period | 
| Artesunate (AS) and Dihydroartemisinin (DHA) Pharmacokinetics: Tmax, Half-life | Tmax: time to maximum concentration Half-life: computed as ln (2)/kel | Sampling performed at predose at 0 h and at 0.25, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12 h for each period | 
| Pyronaridine Pharmacokinetics: AUC0-last, AUC0-∞ | AUC0-last: Area under the concentration-time curve from time 0 (0 h) through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was drawn AUC0-∞: Area under the concentration-time curve from time 0 (0 h) to infinity, computed using the linear trapezoidal rule as AUClast + CLQCT / Kel | Sampling performed at predose at 0 h and at, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12, 24, 48, 72 h and on Day 5, 7, 14, 21, 28, 35, 42 for each period | 
| Artesunate (AS) and Dihydroartemisinin (DHA): AUC0-last, AUC0-∞ | AUC0-last: Area under the concentration-time curve from time 0 (0 h) through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was drawn AUC0-∞: Area under the concentration-time curve from time 0 (0 h) to infinity, computed using the linear trapezoidal rule as AUClast + CLQCT / Kel | Sampling performed at predose at 0 h and at 0.25, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12 h for each period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, anti-malarial, pyronaridine, pyronaridine artesunate (Pyramax), artemisinin based combination therapy (ACT)