Clinical trial NCT01868438: Relative Bioavailability of Pyronaridine-artesunate in Tablet and Granule Formulations in Healthy Volunteers
Official title: Phase 1, Open-label, Cross-over Study to Investigate the Relative Bioavailability of Pyramax (Pyronaridine-artesunate) in Tablet and Granule Formulations, in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malaria
Keywords: Pyronaridine artesunate tablet
Pyronaridine artesunate granules
Pyramax tablet
Pyramax granules
Bioavailability
artemisinin based combination therapy (ACT)
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
Collaborators: name: Shin Poong Pharmaceutical Co. Ltd.
First posted: 2013-06-04
Enrollment: 60
Sex: ALL
Minimum age (years): 20
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to compare the bioavailability of two formulations (tablets and granules for dispersion) of the antimalarial drug pyronaridine-artesunate \[3:1\] (Pyramax, PA) in healthy adults. The secondary objective is to compare the safety of the two PA formulations and liver function test changes following the first and second administrations.

Detailed description: This is a Phase I, single centre, open-label, randomised, two-way cross-over study in healthy volunteers to compare the bioavailability of two formulations of pyronaridine-artesunate, in tablet and in granule formulation. The study population will include 60 healthy volunteers, comprising male and female adults aged 20 to 45 years inclusive.

The volunteers will be randomised equally on Day -1 to one of two sequences: Sequence 1 (tablets in Period 1, granules in Period 2), or Sequence 2 (granules in Period 1, tablets in Period 2). The periods will be separated by a 60-day wash-out period. Each of the two pyronaridine-artesunate formulations will be administered as a single dose of either 180:60 mg pyronaridine-artesunate tablets (3 tablets) or 60:20 mg pyronaridine-artesunate granules (9 sachets). The total dose of each formulation administered is 540:180 mg pyronaridine-artesunate.

The study duration from the first study drug administration (Day 1) through to the last follow-up will be approximately 103 days. Screening is to be performed within 28 days before Day 1. Adverse events will be monitored throughout the study (and to resolution if necessary) to assess the general safety and tolerability of the treatments.

Eligibility criteria: Inclusion Criteria:

* Healthy male and/or female subjects between the ages of 20 and 45 years, inclusive. (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests)
* Weight between 50 kg and 80 kg and Body Mass Index (BMI) calculated using Quetelet's Index - weight(kg)/height (m2) between 18.5 to 27 kg/m2;
* An informed consent document signed and dated by the subject (prior to screening and any study activities, including discontinuation of any prohibited medications)
* Strictly normal values of alanine aminotransferase(ALT), aspartate aminotransferase (AST), and bilirubin, and normal or abnormal but clinically insignificant results of the other blood and urine laboratory parameters at screening.
* Female subjects of non-childbearing potential \[i.e., physiologically incapable of becoming pregnant, including any female who was post-menopausal (i.e., one year without menses) or who has undergone sterilization (via hysterectomy or bilateral tubal ligation)\]
* Female subjects of childbearing potential with a negative urine pregnancy test at screening, and a negative pregnancy blood test on admission, and who :

  * agree to double barrier method of contraception for 4 weeks before first study drug administration and throughout the entire study follow up period, or
  * whose partner has undergone vasectomy and has been negative for sperm for at least 6 months
* Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

* Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, acute corrected QT interval (QTc) greater or equal to 450 milliseconds), 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)
* Seropositive HIV antibody, seropositive syphilis \[Syphilis reagin test (+)\]
* Previous exposure to pyronaridine-artesunate (Pyramax)
* Present or recent history (last two years) of tobacco abuse (≥10 cigarettes/day)
* Known or suspected alcohol abuse or illicit drug use up to 5 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, 48 hours before study drug administration
* Intake of grapefruit, Seville oranges or products containing these from 72 hours before the start of study drug administration
* Gilbert's disease
* Use of over-the-counter (OTC) medications, including vitamins, analgesics, antipyretics or antacids within 7 days before study drug administration
* Use of prescription medications within 14 days before the start of study drug administration or required chronic use of any prescription medication
* Use of enzyme-altering agents (e.g. barbiturates, phenothiazines, cimetidine, etc.) within 30 days before the start of study drug administration
* Plasma donation within 60 days before the start of study drug administration
* Blood donation of 500 mL or more within 60 days before the start of study drug administration
* Participation AND having had drug administration in any other clinical study within the 60 days before start of study drug administration

Primary outcomes:
measure: Area Under the Concentration-time Curve From Hour 0 to the Last Sampling Point (AUC 0-t) for Pyronaridine and Dihydroartemisinin (DHA)
timeFrame: First intervention: Day 1 pre-dose to Day 43 visit (D1, 2, 3, 4, 6, 8, 15, 22, 29, 36, 43) ; second intervention: Day 61 pre-dose to Day 103 visit (D61, 62, 63, 64, 66, 68, 75, 82, 89, 96, 103)
Secondary outcomes:
measure: Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA
timeFrame: First intervention: Day 1 pre-dose to Day 43 visit (D1, 2, 3, 4, 6, 8, 15, 22, 29, 36, 43) ; second intervention: Day 61 pre-dose to Day 103 visit (D61, 62, 63, 64, 66, 68, 75, 82, 89, 96, 103)
measure: Safety Evaluation - Summary of Adverse Events
timeFrame: End of study (Day 103)
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Dept. of Clinical Pharmacology and Therapeutics, Asan Medical Center, Univ. of Ulsan
Study officials:
References: