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Trial registered on ANZCTR


Registration number
ACTRN12618000650291
Ethics application status
Approved
Date submitted
20/04/2018
Date registered
24/04/2018
Date last updated
1/02/2019
Date data sharing statement initially provided
1/02/2019
Date results information initially provided
1/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Double-Blind, Placebo-Controlled, Randomized Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Multiple-Ascending Doses of PRAX-114 in Healthy Subjects
Scientific title
A Phase 1, Double-Blind, Placebo-Controlled, Randomized Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Multiple-Ascending Doses of PRAX-114 in Healthy Subjects
Secondary ID [1] 294664 0
Nil Known
Universal Trial Number (UTN)
U1111-1212-5216
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 307520 0
Condition category
Condition code
Neurological 306596 306596 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will be performed in healthy male and female subjects with administration of multiple oral doses of PRAX-114 or vehicle (placebo) in suspension for 14 days in a sequential ascending manner. Subjects will be fasted overnight (no food or drink except water) for at least 8 hours prior to dosing.

Up to 48 healthy male and female subjects will be enrolled. Within each cohort, the subjects will be randomized in a 3:1 ratio with 9 subjects in the active group and 3 subjects in the placebo group.

Eligible subjects will be assigned to 1 of 4 cohorts and will receive 1 or 2 daily doses of study treatment for 14 days with doses ranging from 15 mg to 60 mg daily.
Cohort 1: 15 mg once a day
Cohort 2: 30 mg once a day
Cohort 3: 60 mg once a day
Cohort 4: 30 mg two times per day

These multiple dose cohorts will be followed by a single-dose, two treatment
(fed vs. fasting), two-period, two-sequence crossover evaluation of food effects at 30mg (once fasted once fed).

Adherence to the intervention will be monitored by direct observation by study personnel at the clinical trials site.
Intervention code [1] 300963 0
Treatment: Drugs
Comparator / control treatment
Placebo (vehicle) oral suspension, same as PRAX-114 suspension but without active ingredient
Control group
Placebo

Outcomes
Primary outcome [1] 305594 0
Safety and tolerability, including the assessment of physical examinations, ECGs, vital signs, clinical laboratory results, and adverse events
Timepoint [1] 305594 0
Cohort 1-4:
- A complete physical examination (PE) will be performed at Screening, Day -1 and Day 17 and on early termination (ET).
- Standard 12-lead ECGs will be performed at the following time points: Day -1; Day 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, h, Day 2 - 14: predose, Day 15 and ET.
- Vital signs (including oral temperature, respiratory rate, supine blood pressure, and pulse rate) will be obtained as follows: Screening; Day -1; Day 1 at pre-dose, 0.25, 1, 2, 3, 4, 6, 8, and 12 hrs post dose; Days 2 through 13 at 2 hours post dose, Day 14 at pre-dose, 2, 4, 6, 8, 12, 24 hrs post dose, and ET.
- Continuous 24 h 16-channel EEG will be recorded on Days -1, 1 and 14
- Clinical laboratory evaluations (include complete blood count (CBC), clinical chemistry, coagulation studies, and urinalysis) will be conducted on at Screening and Days -1, 2, 7, 15, 17 and ET
- Adverse events (AE) and concomitant medications will be recorded throughout the study period.

Food effect cohort:
- A complete physical examination (PE) will be performed at Screening, Day -1 and Day 8 and on early termination (ET).
- Standard 12-lead ECGs will be performed at the following time points: Screening, Day -1; Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, and 12 hrs post dose); Day 2; Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, and 12 hrs post dose); Day 6; Day 8; Day 11; and ET.
- Vital signs (including oral temperature, respiratory rate, supine blood pressure, and pulse rate) will be obtained as follows: Screening; Day -1; Day 1 and Day 5 (pre-dose, 0.25, 1, 2, 3, 4, 6, 8, and 12 hrs post dose); Days 2, 3, 4, 6, 7, 8, 11, and ET.
- Clinical laboratory evaluations (include complete blood count (CBC), clinical chemistry, coagulation studies, and urinalysis) will be conducted at Screening, Days -1, 2, 5, 8, 11 and ET.
- Adverse events (AE) and concomitant medications will be recorded throughout the study period.
Primary outcome [2] 305595 0
To evaluate the pharmacokinetic (PK) profile of oral PRAX-114 following multiple ascending doses
The following PK parameters will be assessed from plasma concentration-time data:
• Cmax, maximum observed concentration
• Tmax, time to Cmax
• AUC0-t, area under the plasma concentration-time curve from time 0 to last measurable concentration
• AUC0-8, area under the concentration-time curve from time 0 extrapolated to infinity
• T1/2, apparent terminal elimination half-life
• CL/F, oral clearance
• Vz/F, apparent volume of distribution following extravascular administration
• Tlag, time elapsed from time 0 to the last time of sample below quantitative limit
Timepoint [2] 305595 0
Serial blood samples will be collected relative to the dosing of PRAX-114 at the following time points:
Cohort 1-4
- Day 1: predose (0 hours), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours post-dose
- Days 2 to 6: predose
- Day 14: predose (0 hours), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (Day 15), 36, 48 (Day 16), and 72 (Day 18) hours post-dose.

Urine will be collected/pooled at the following collection windows: Day -1 6 hours and at Day 15: (0 to 6 hours), (6 to 12 hours), (12 to 24 hours), and (24-48 hours) to determine IP concentrations in urine.

Food Effect Cohort
- Day 1 and 5: predose (0 hours), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose
Secondary outcome [1] 345849 0
To characterize and identify, if possible, major metabolites of PRAX-114 in plasma.
Human metabolites are currently not known. The existence or absence of circulating human metabolites in plasma will be determined in this study.
Timepoint [1] 345849 0
For measurement of possible circulating plasma metabolites, remaining plasma samples collected for PK analysis on day 14 will be pooled. Plasma samples that will be pooled for metabolite analysis are collected on Day 14 at: 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 hours.
Secondary outcome [2] 345922 0
Exploratory endpoint: To characterize and identify, if possible, major metabolites of PRAX-114 in urine.
Timepoint [2] 345922 0
For measurement of metabolites in urine, day 15 urine samples will be used: Day 15 (pooled samples): (0 to 6 hours), (6 to 12 hours), (12 to 24 hours), and (24-48 hours)

Eligibility
Key inclusion criteria
A participant must meet the following criteria at Screening (Days -28 to -2) to be eligible to participate in this study:
1. The subject must be a female of nonchildbearing potential or male and between the ages of 18 and 55 years, inclusive. Documentation of hysterectomy, bilateral tubal ligation, or postmenopausal status must be available for female subjects.
2. Weight of at least 50 kg with body mass index (BMI) between 18 and 30 kg/m2 (inclusive)
3. Male subjects with female partners of childbearing potential must be using 2 acceptable methods of contraception, including at least one barrier method, from the day of first dose of study drug to at least 90 days after the last dose of study drug. Periodic abstinence and withdrawal are not acceptable methods of contraception
4. Willing to avoid consumption of grapefruit, grapefruit juice and Seville oranges within 2 weeks prior to first dose of study drug until discharge from the clinic
5. The subject must be willing to sign an informed consent document indicating that he/she understands the purpose of the study and the procedures that are required for the study and that he/she is willing to participate in the study.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
A participant who meets any of the following criteria at Screening (unless otherwise specified) will be excluded from this study:
1. Ongoing or history of any medical or surgical condition that, in the judgment of the Investigator, might jeopardize the subject’s safety or interfere with the absorption, distribution, metabolism or excretion of the study drug
2. Any abnormal electrocardiographic (ECG) findings at Screening judged to be clinically significant by the Investigator
3. Any abnormal laboratory value or physical examination findings at Screening that is judged by the Investigator as clinically significant
4. Hemoglobin less than 12 g/dL
5. Serology test positive for HIV, or hepatitis B or C at Screening
6. Positive drug test for ethanol, barbiturates, cocaine, methamphetamines, Methadone, benzodiazepines, phencyclidine, tetrahydrocannabinols, methylenedioxymethamphetamine, opiates, or amphetamines at Screening and clinic Check-in
7. Smokers and/or Positive urine cotinine test at Screening and Check-in
8. Use of systemic prescription medications or over-the-counter (OTC) medication, including multivitamins, and dietary and herbal supplements within 2 weeks or 5 times the terminal half-lives of the medication prior to first dose of study drug, whichever is longer and for the duration of the study
9. Use of any experimental or investigational drug or device within 30 days prior to first dose of study drug or 5 half-lives of the drug, whichever is longer
10. Donation or loss of great than or equal to 400 mL blood within 8 weeks and/or donation of plasma within 7 days prior to initial dosing of study drug
11. History of drug or alcohol abuse within 12 months prior to initial dosing of study drug. Abuse is defined as consumption of greater than 2 standard drinks per day (14 standard drinks per week)
12. Psychosocial or addictive disorders that would interfere with subject’s ability to give informed consent or could compromise compliance with the protocol

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)
Random treatment assignments are held by a third party who would be contacted in the event of a request for unblinding.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using a randomization table generated by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
NA
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Approximately 48 healthy subjects will be enrolled into the study to ensure 7 evaluable subjects per cohort with up to 4 cohorts. In the food effect cohort, up to 10 subjects will be enrolled to ensure inclusion of at least 8 subjects in the cohort. As the primary objectives of this study are to describe, for the first time in humans, the safety and tolerability of multiple ascending doses of oral PRAX-114 in healthy subjects, no statistical significance tests are planned. Consequently, the sample size for this study was not selected on the basis of statistical power calculations.
Descriptive statistics will include mean, SD, Minimum, maximum, percent coefficient of variation (%CV), and geometric mean will be presented by dose group for the clinical outcomes and the plasma concentration of PRAX-114 at each scheduled sample time point.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10765 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 22493 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 299277 0
Commercial sector/Industry
Name [1] 299277 0
Praxis Precision Medicines Australia Pty Ltd
Address [1] 299277 0
Tower Two Collins Square, Level 36
727 Collins Street
Docklands Vic 3008
Country [1] 299277 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Praxis Precision Medicines Australia Pty Ltd
Address
Tower Two Collins Square, Level 36
727 Collins Street
Docklands Vic 3008
Country
Australia
Secondary sponsor category [1] 298547 0
None
Name [1] 298547 0
Address [1] 298547 0
Country [1] 298547 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300189 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 300189 0
89 Commercial Road, Melbourne
VIC 3004
Ethics committee country [1] 300189 0
Australia
Date submitted for ethics approval [1] 300189 0
23/04/2018
Approval date [1] 300189 0
04/06/2018
Ethics approval number [1] 300189 0
217/18

Summary
Brief summary
The study is a phase 1, double-blind, placebo-controlled, randomized study to evaluate the safety, tolerability, and pharmacokinetics of multiple-ascending doses of PRAX-114 in healthy subjects. In addition, potential metabolites of PRAX-114 will also be evaluated.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82850 0
Dr Ben Snyder
Address 82850 0
Nucleus Network Limited
Level 5 Burnet Institute. AMREP Precinct
89 Commercial Road, Melbourne
VIC 3004
Country 82850 0
Australia
Phone 82850 0
+61 3 9076 8960
Fax 82850 0
Email 82850 0
b.snyder@nucleusnetwork.com.au
Contact person for public queries
Name 82851 0
Dr Bernard Ravina
Address 82851 0
Praxis Precision Medicines, One Broadway, Cambridge, MA 02142
Country 82851 0
United States of America
Phone 82851 0
+1 617 300 8500
Fax 82851 0
Email 82851 0
clinicaltrials@praxismedicines.com
Contact person for scientific queries
Name 82852 0
Dr Kiran Reddy
Address 82852 0
Praxis Precision Medicines, One Broadway, Cambridge, MA 02142
Country 82852 0
United States of America
Phone 82852 0
+1 617 949 2220
Fax 82852 0
Email 82852 0
kiran@praxismedicines.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No plan to share individual participant data.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary