A Two-Part Study to Assess the Effects of Ritonavir on PRN1008 Pharmacokinetics, and the Effect of PRN1008 on QTc Interval Compared to Placebo and Moxifloxacin in Healthy Participants
A Two-Part Study to Assess the Effects of Ritonavir on PRN1008 Pharmacokinetics, and the Effects of PRN1008 on QTc Interval Compared to Placebo and Moxifloxacin in Healthy Participants
Principia Biopharma, Inc.
40 participants
Jun 27, 2018
Interventional
Conditions
Summary
This will be a two part, single-center, randomized, crossover study to investigate the impact of ritonavir co-administration on PRN1008 pharmacokinetics, and to assess the effect of therapeutic and supratherapeutic concentrations of PRN1008 on the QT interval. Participants may enroll in Part A or Part B; participants may not enroll in both Parts. Participants will be screened for this study within 28 day before dosing. Total length of participation in the study for study participants is; Part A, 46 days and Part B 53 days, from study screening through study completion.
Eligibility
Inclusion Criteria5
- Healthy adult male or non-pregnant, non-lactating females, 18 to 55 years of age (inclusive) at the time of screening
- Body mass index (BMI) greater than or equal to 18 and less than or equal to 30 (kg/m2) (inclusive) and a minimum body weight of 45 kg
- Able to participate and comply with all study procedures and restrictions, and willing to provide written informed consent to participate in the study
- A female subject of childbearing potential with a negative pregnancy test must agree for the duration of active treatment to use an effective means of contraception (hormonal contraception methods that inhibits ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, condoms or sexual abstinence). Unless surgically sterile, postmenopausal females should have menopause confirmed by FSH testing.
- Negative urine drug and alcohol breath testing at screening and at each period check-in (Day -1). Screening drug/alcohol testing may be repeated once if deemed appropriate by the site Investigator
Exclusion Criteria21
- Use of any prescription or over-the-counter (OTC) medications, including herbal products and supplements, within the 14 days prior to Day -1 or 5 half-lives, whichever is longer. Use of hormonal contraception and less than or equal to 2 g paracetamol per day is allowed prior to and during the study.
- Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV)
- Use of more than two tobacco/nicotine-containing products per month within 6 months prior to the first study drug administration
- History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration
- Regular alcohol consumption greater than 14 units per week (1 unit equals ½ pint beer, 25 mL of 40 percent spirit, or a 125 mL glass of wine)
- History of any significant (as determined by the Investigator) drug-related allergic reactions such as anaphylaxis, Stevens-Johnson syndrome, urticaria, or multiple drug allergies
- Blood donation or significant blood loss within 30 days prior to screening
- Plasma donation within 14 days prior to the first study drug administration
- Participation in another clinical trial of a drug or device whereby the last investigational drug/device administration is within 30 days prior to the first study drug administration or 5 half-lives, whichever is longer
- Surgery within the past three months prior to the first study drug administration determined by the PI to be clinically relevant
- Personal or family history of prolonged QT syndrome or family history of sudden death
- QTcF greater than 450 msec (males) or greater than 470 msec (females) or less than 300 msec at screening or baseline (Day -1), unless deemed clinically insignificant by the Investigator
- Evidence of atrial fibrillation, atrial flutter, complete bundle branch or heart block, Wolff-Parkinson-White Syndrome, or cardiac pacemaker at screening or baseline visit
- Seated or semi-supine resting systolic blood pressure (SBP) greater than 150 or less than 90 mm Hg, or diastolic blood pressure (DBP) greater than 100 or less than 40 mm Hg
- Hypersensitivity or history of idiosyncratic reaction to any components or excipients of the investigational formulation, or to ritonavir or moxifloxacin.
- Active infection
- Participant is febrile, temperature greater than 37.5°C (assessed at Screening and at Baseline [Day -1])
- Any acute illness within 30 days prior to Day 1 unless deemed clinically insignificant by the Investigator and discussed with the Sponsor
- Failure to satisfy the Investigator of fitness to participate for any other reason
- History or presence of any other medical condition that makes the participant unsuitable for the study in the opinion of the Investigator
- Use of live vaccine product within 30 days of Day 1, or anticipated need for live vaccine during the study
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Interventions
This will be a single center, two-part (Parts A & B) study in healthy adult participants. Participants will be screened for participation within 28 days before dosing. Participants may be enrolled in Part A or Part B of the study; participants may not be enrolled in both Parts. Part A is randomized, open-label, three-period, complete crossover study with a 7-day washout between treatment periods. All participants will complete 3 treatment periods in Part A of the study, and will be randomized to receive one of the following treatments in each period: • Treatment 1: single dose of 100 mg PRN1008 tablet under fasting conditions • Treatment 2: single dose of 100 mg PRN1008 plus 100 mg oral ritonavir oral tablet under fasting conditions, with a second dose of 100mg ritonavir tablet only 12 hours after the first dose • Treatment 3: single dose of 1200 mg (4 x 300 mg tablet) PRN1008 tablet under fasting conditions There are 6 possible sequences in which the listed treatments for Part A will be administered. Part A participants will be admitted to the study unit one day (Day -1) before dosing in each Period. On Day 1 Periods, 1, 2, and 3, following an overnight fast, participants will be randomized to receive Treatment 1, 2, or 3. Following dosing, blood samples for pharmacokinetic (PK) analysis of PRN1008 will be collected over a period of 24 hours. In each period, participants will be admitted to the study unit on Day -1 and remain in the study unit to Day 2. Participants will be discharged on Day 2, then return to the study unit on Day 6 (Day -1, Period 2) for follow-up safety assessments and check-in for the next dosing period. Following discharge of Period 3, participants will complete a follow-up visit approximately 7 days (± 1 day) after the last dose of study drug. Part B is a randomized, single-dose, placebo-controlled, 4 period, complete crossover study with a 7-day washout between treatment periods. All participants will complete 4 treatment periods in Part B of the study, and will be randomized to receive one of the following single-dose treatments in each period: • Treatment 1 (Therapeutic dose): 400 mg (1 x 100 mg tablet and 1 x 300 mg tablet) PRN1008 under fasting conditions • Treatment 2 (Supratherapeutic dose): Either 1200 mg (4 x 300 mg tablet) PRN1008 or (TBD) mg PRN1008 with 100 mg ritonavir oral tablet. The supratherapeutic regimen will be determined following review of Part A data. If dosed with ritonavir, a second dose of 100mg ritonavir tablet will be administered 12 hours after the morning dose. Based on emerging data from Part A, the second dose of 100mg ritonavir in Treatment 2 may be omitted as needed. • Treatment 3: PRN1008 Placebo under fasting conditions • Treatment 4: Moxifloxacin 400 mg tablet (positive control) under fasting conditions There are 12 possible sequences in which the listed treatments will be administered. Participants in Part B will be screened for participation in the study within 28 days before dosing. Participants will be admitted to the study unit two days (Day -2) before dosing in Period 1. Following confirmation of study eligibility on Day -1, participants will be randomized to treatment order and baseline pre-treatment ECGs will be collected via Holter monitor for 24 hours. On Day 1 of each period, following an overnight fast, participants will receive Treatment 1, 2, 3, or 4, and blood samples for PK analysis of PRN1008 will be collected over a period of 24 hours. In each subsequent period, participants will be admitted to the study unit on Day -1 and remain in the study unit to Day 2. Participants will be discharged on Day 2, then return to the study unit on Day 6 (Day -1, Period 2) for follow-up safety assessments and check-in for the next dosing period. Following discharge of Period 4, participants will complete a follow-up visit approximately 7 days (± 1 day) after the last dose of study drug.
Locations(1)
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ACTRN12618001036202