Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001036202
Ethics application status
Approved
Date submitted
7/06/2018
Date registered
21/06/2018
Date last updated
27/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
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
Scientific title
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
Secondary ID [1] 295113 0
PRN1008-014
Universal Trial Number (UTN)
U1111-1215-2945
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pemphigus 308191 0
Immune Thrombocytopenic Purpura 308192 0
Condition category
Condition code
Skin 307222 307222 0 0
Dermatological conditions
Inflammatory and Immune System 307223 307223 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 301447 0
Treatment: Drugs
Comparator / control treatment
Moxifloxacin is an antimicrobial drug which, when given as a single 400 mg dose, is commonly used as a positive control in thorough QT studies.
Control group
Placebo

Outcomes
Primary outcome [1] 306195 0
Part A: Blood samples will be collected to determine the plasma pharmacokinetics of PRN1008 following each treatment, The primary pharmacokinetic study parameters are AUC0-8, AUClast, Cmax, Tmax, and half-life of PRN1008 administered alone or with ritonavir. Geometric mean ratios and 90% confidence intervals will be calculated. Other pharmacokinetic parameters will be regarded as secondary variables.
Timepoint [1] 306195 0
Pre-dose (prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after PRN1008 dosing.
Primary outcome [2] 306196 0
Part B: Continuous ECGs will be collected prior to dosing in Part B (Day -1), and before and after each treatment. The primary outcome measure for the cardiovascular ECG assessment is the placebo-corrected change-from-baseline QTcF (change in QTcF). In case a substantial heart rate effect is observed on-treatment (peak mean change in HR > 10 bpm), other QT corrections will be explored.
Timepoint [2] 306196 0
-1.0, -0.75, and -0.5 hours pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 16, and 24 hours post-dose.
Secondary outcome [1] 347814 0
Change-from-baseline heart rate (HR), as assessed by Holter ECG data.
Timepoint [1] 347814 0
-1.0, -0.75, and -0.5 hours pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 16, and 24 hours post-dose
Secondary outcome [2] 348278 0
Changes in PR and QRS (change in HR, QTcF, QTcI, PR and QRS), as assessed by Holter ECG data.
Timepoint [2] 348278 0
-1.0, -0.75, and -0.5 hours pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 16, and 24 hours post-dose
Secondary outcome [3] 348279 0
Placebo-corrected HR, QTc with correction methods not selected as primary in case a substantial heart rate effect is observed as assessed by Holter ECG data.
Timepoint [3] 348279 0
-1.0, -0.75, and -0.5 hours pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 16, and 24 hours post-dose
Secondary outcome [4] 348391 0
Changes in QTcF, QTcS and QTcI if a substantial heart rate effect is observed, as assessed by Holter ECG data.
Timepoint [4] 348391 0
-1.0, -0.75, and -0.5 hours pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 16, and 24 hours post-dose

Eligibility
Key inclusion criteria
- 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
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- 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
- Resting HR less than 40 beats per minute (bpm) or greater than 90 bpm at screening or baseline (Day -1) (the heart rate recorded from vital sign assessment will be utilized for this exclusion criteria)
- 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])
19. 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
27/06/2018
Actual
27/06/2018
Date of last participant enrolment
Anticipated
30/09/2018
Actual
Date of last data collection
Anticipated
1/11/2018
Actual
Sample size
Target
40
Accrual to date
12
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11203 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 23065 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 299692 0
Commercial sector/Industry
Name [1] 299692 0
Principia Biopharma, Inc.
Country [1] 299692 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Principia Biopharma, Inc.
Address
400 East Jamie Court
Suite 302
South San Francisco, CA 94080
Country
United States of America
Secondary sponsor category [1] 299034 0
Commercial sector/Industry
Name [1] 299034 0
Clinical Network Services Pty Ltd
Address [1] 299034 0
Level 4
88 Jepson Street
Toowong
QLD, 4066
Country [1] 299034 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300595 0
Bellberry Human Research Ethics Committee G (EC00458)
Ethics committee address [1] 300595 0
Ethics committee country [1] 300595 0
Australia
Date submitted for ethics approval [1] 300595 0
01/05/2018
Approval date [1] 300595 0
04/06/2018
Ethics approval number [1] 300595 0
2018-05-309

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84158 0
Dr Jason Lickliter
Address 84158 0
Nucleus Network Limited
Level 5 Burnet Tower, AMREP Precinct, 89 Commercial Road, Melbourne, VIC 3004
Country 84158 0
Australia
Phone 84158 0
+61 3 8593 9860
Fax 84158 0
Email 84158 0
[email protected]
Contact person for public queries
Name 84159 0
Jason Lickliter
Address 84159 0
Nucleus Network Limited
Level 5 Burnet Tower, AMREP Precinct, 89 Commercial Road, Melbourne, VIC 3004
Country 84159 0
Australia
Phone 84159 0
+61 3 8593 9860
Fax 84159 0
Email 84159 0
[email protected]
Contact person for scientific queries
Name 84160 0
Jason Lickliter
Address 84160 0
Nucleus Network Limited
Level 5, Burnet Institute, AMREP Precinct, 89 Commercial Road
Prahran, Melbourne, VIC 3004
Country 84160 0
Australia
Phone 84160 0
+61 03 8593 9860
Fax 84160 0
Email 84160 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects.2022https://dx.doi.org/10.1111/cts.13271
N.B. These documents automatically identified may not have been verified by the study sponsor.