Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000102572p
Ethics application status
Submitted, not yet approved
Date submitted
8/01/2024
Date registered
6/02/2024
Date last updated
6/02/2024
Date data sharing statement initially provided
6/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
An Open-label, Randomised, Crossover Study to Assess Fasted Versus Fed Bioavailability of Radiprodil in Healthy Adults
Scientific title
An Open-label, Randomised, 3-period, 6-sequence Crossover Study to Assess the Relative Bioavailability of Radiprodil Under Fasted and Fed Conditions in Healthy Adult Subjects
Secondary ID [1] 311145 0
RAD-GRIN-501
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
glutamate receptor ionotropic N-methyl-D-aspartate (GRIN) related disorder - neurodevelopmental syndromes 332312 0
Condition category
Condition code
Neurological 329020 329020 0 0
Other neurological disorders
Human Genetics and Inherited Disorders 329370 329370 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open-label, randomised, 3-period, 6-sequence crossover study to determine the relative bioavailability of two formulations (10% and 30%) of radiprodil under fasted conditions and the effect of food on the bioavailability of the 30% formulation in healthy adult participants. Approximately 18 healthy adult male and female participants will be enrolled and randomised to 1 of 6 treatment sequences in equal proportion: ABC, ACB, BAC, BCA, CAB, or CBA.

• Treatment B: Single oral dose of 45 mg radiprodil (30%) under fasted conditions. Day -1 participants will fast overnight for at least 10 hours prior to the administration of radiprodil in on Day 1. Participants will continue to fast for an additional 4 hours after administration of IP.

• Treatment C: Single oral dose of 45 mg radiprodil (30%) under fed conditions. Following an overnight fast of at least 10 hours, participants will eat a high fat, high calorie breakfast to be consumed prior to administration of radiprodil 30 minutes after the start of the meal and consisting of:
1. Two eggs fried in butter
2. Two rashers of bacon
3. Two slices of toast with 16 g butter per slice
4. 125 g of hash browns
5. 240 mL of full cream milk

There will be at least a 96-hour washout period between doses.

Adherence to and administration of study treatment will be conducted by delegated study site personnel.
Intervention code [1] 327589 0
Treatment: Drugs
Comparator / control treatment
Treatment A: A single oral dose of 45 mg radiprodil (10%) under fasted conditions.

Day -1 participants will fast overnight for at least 10 hours prior to the administration of radiprodil on Day 1. Participants will continue to fast for an additional 4 hours after administration of investigational product (IP) .
Control group
Active

Outcomes
Primary outcome [1] 336817 0
To determine the effect of food on the pharmacokinetics (PK) parameters of radiprodil (30% formulation) after administration of an oral single dose (fasted)
Timepoint [1] 336817 0
Blood plasma samples collected for Period 1 pre-dose Day 1 - 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72hrs post-dose, Period 2 pre-dose Day 1 - 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72hrs post-dose.
Primary outcome [2] 336818 0
To determine the effect of food on the pharmacokinetics (PK) parameters of radiprodil (30% formulation) after administration of an oral single dose (fed)
Timepoint [2] 336818 0
Blood plasma samples collected for Period 3 pre-dose Day 1 - 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96 hrs post-dose.
Primary outcome [3] 336819 0
To determine the relative bioavailability of radiprodil after oral administration of two formulations (10% and 30%) under fasted conditions
Timepoint [3] 336819 0
Blood plasma samples collected for Period 1 pre-dose Day 1 - 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72hrs post-dose, Period 2 pre-dose Day 1 - 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72hrs post-dose.
Secondary outcome [1] 429748 0
To determine the safety and tolerability of radiprodil after administration of an oral single dose (fasted)
Timepoint [1] 429748 0
Adverse Events: The severity of any adverse events experienced during the study will be categorized by the Investigator as 'Mild,' 'Moderate,' or 'Severe.' These events will be continuously monitored and assessed as soon as they are reported or observed. The review of these events will occur daily, starting from the Screening phase and continuing throughout the study, using safety assessments, observations, and reports from participants.

Vital signs - Blood pressure and heart rate is measured using sphygmomanometer respiratory rate by manual breath count, temperature by thermometer. Measured at Screening and Day -1 with BP and HR assessed pre-dose Day 1 - 1, 3, 6 hrs post-dose, then Day 2, Day 3 and Day 4 post-dose.

Electrocardiogram (ECG) - 12-lead ECG recordings will be obtained in triplicate at screening, Day -1, Single recordings will be obtained from pre-dose Day 1 - 1, 3 and 4 hrs post-dose.

Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) - blood and urine samples will be collected from Screening, Day -1, Period 1 - within 2 hrs pre-dose Day 1 and Day 4 post-dose. Period 2 - Day 4 post-dose.
Secondary outcome [2] 429749 0
To determine the safety and tolerability of radiprodil after administration of an oral single dose (fed)
Timepoint [2] 429749 0
Adverse Events: The severity of any adverse events experienced during the study will be categorized by the Investigator as 'Mild,' 'Moderate,' or 'Severe.' These events will be continuously monitored and assessed as soon as they are reported or observed. The review of these events will occur daily, starting from the Screening phase and continuing throughout the study, using safety assessments, observations, and reports from participants.

Vital signs - Blood pressure and heart rate is measured using sphygmomanometer respiratory rate by manual breath count, temperature by thermometer. Assessed pre-dose Day 1 - 1, 3, 6 hrs post-dose, with BP and HR assessed Day 2, Day 3 and Day 4 post-dose.

Electrocardiogram (ECG) - 12-lead ECG single recordings will be obtained from pre-dose Day 1 - 1, 3 and 4 hrs post-dose.

Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) - blood and urine samples will be collected Day 5 post-dose (Early Termination).

Eligibility
Key inclusion criteria
1. Healthy males and females between 18 and 55 years of age, inclusive, at Screening.
2. Body mass index (BMI) between 18 and 32 kg/m2 (inclusive) and weighs at least 50 kg at Screening.
3. Healthy in the opinion of the Investigator, based upon medical history, physical examination (including 12-lead ECG, and clinical laboratory assessments without any clinically significant findings, as deemed by the Investigator) at Screening and prior to dosing on admission or pre dose as applicable.
4. Female participants must be non-lactating and of non-child-bearing potential (i.e., surgically sterilized by hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at least 6 weeks before Screening) or postmenopausal (defined as no menses for 12 months without an alternative medical cause and a follicle stimulating hormone [FSH] result per local laboratory guidelines; luteinizing hormone [LH] testing may be done if FSH results are inconclusive), or, if of child-bearing potential:
a. Must have a negative pregnancy test at Screening and a negative pregnancy test on
Day -1, prior to dose administration.
b. Must agree not to donate ova or attempt to become pregnant from the time of signing
consent until at least 90 days after the last dose of radiprodil.
c. If not exclusively in a same-sex relationship, must agree to use adequate contraception
(which is defined as use of a condom by the male partner combined with use of a highly
effective method of contraception) from one month prior to Screening until at least 90 days after the last dose of radiprodil.
5. Male participants, if not surgically sterilized, must:
a. Agree not to donate sperm from the time of signing consent until at least 90 days after
the last dose of IP.
b. If engaging in sexual intercourse with a female partner who could become pregnant,
must agree to use adequate contraception (defined as use of a condom plus a highly
effective method of contraception) from the time of signing consent until at least 90 days after the last dose of IP.
c. If engaging in sexual intercourse with a female partner who is not of child-bearing potential or a same-sex partner, must agree to use a condom from the time of signing consent until at least 90 days after the last dose of IP
6. Ability to provide signed informed consent and to understand and comply with the requirements of the study including dietary requirements and requirement to stay confined on site for the duration of the study.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of hypersensitivity to radiprodil or any components of the formulations.
2. History of any medical condition that, in the opinion of the Investigator, would pose an additional risk to the participant by their participation in the study.
3. Females who are pregnant, breastfeeding, or have a positive pregnancy test at Screening or on Study Day -1.
4. History or presence of significant (in the opinion of the Investigator) cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, urologic, neurological, malignancy, psychiatric disease, or brain surgery or injury.
5. Any surgical or medical condition that, in the opinion of the Investigator, could interfere with the absorption, distribution, metabolism, or excretion of the drug.
6. History of any clinically significant allergic conditions (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, asymptomatic seasonal allergies at time of dosing on Day 1).
7. History of illicit drug abuse or alcohol abuse use within 2 years of Screening.
8. History of suicide attempts or deliberate self-harm, or a score of 4 or 5 on ideation or any suicidal behaviour on the Columbia-Suicide Severity Rating Scale (C-SSRS).
9. Routine consumption of more than 2 units of alcoholic beverages per day or more than 14 units per week (A unit of alcohol is equivalent to 1 can of beer, 1 glass of wine, or the equivalent of 1 alcoholic drink).
10. Routine consumption of an average of more than five (5) 240 mL servings of coffee or other caffeinated beverages per day.
11. A positive test result for amphetamines, barbiturates, benzodiazepines, cocaine metabolites, opiates, methylenedioxymethamphetamine, cotinine, or alcohol at Screening or Day 1.
12. Use of marijuana (including prescribed marijuana) within 30 days of Day -1.
13. Use of tobacco-containing products and nicotine or nicotine containing products in the 2 months prior to Day 1.
14. Use of any investigational product and prescription drug (with the exception of birth control medication) within 30 days of Day -1 or within 5 half lives whichever is longer.
15. Use of any over-the-counter (OTC) medication including herbal products (e.g., St John’s wort) within the 14 days or 5 half-lives prior to dosing, whichever is longer, and through the completion of all study procedures. Up to 2 grams per day of acetaminophen will be allowed at the discretion of the Investigator.
16. Any vaccine within 7 days of Day -1.
17. Donation of blood or blood products within 30 days of Day -1.
18. Acute illness within 14 days of study Day 1.
19. Positive serologic findings for HBsAg, HCV Ab, and/or HIV Ab at Screening.
20. Surgery within the past 90 days prior to Day 1 as determined by the Investigator to be clinically relevant.
21. Blood pressure was less than 90/40 mmHg or greater than 140/90 mmHg at Screening.
22. Heart rate (HR) < 40 or > 100 beats/minute after at least 5 minutes rest in supine, semi-supine, or seated position (whichever is site standard)
23. Any clinically significant ECG abnormality at Screening (as deemed by the Investigator).
24. QTcF interval > 450 msec for male and >470 msec for female (the average value for the triplicate ECG at Screening and Day -1), or history of prolonged QT syndrome.
25. Dosed in another clinical trial within 28 days prior to radiprodil dosing.
26. Consumption of the following prior to dosing period:
a. Alcohol 48 hours prior to dosing
b. Grapefruit (or pomelo or star fruit), Seville oranges, Seville orange marmalade, or other products containing these fruits within 10 days prior to dosing
c. Xanthine-containing products (e.g., tea, coffee) within 24 hours prior to dosing
27. Poor venous access.

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Study participants who sign an informed consent form (ICF) at Screening will receive a unique sequential number (i.e., a Screening number). A sequential ‘on study’ number will be assigned to each eligible participant. The allocation to treatment sequence will be handled manually via a printed randomization schedule.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis
For this study, no prospective calculations of statistical power have been made. The sample size has been selected to provide information on food effect, PK parameters, safety, and tolerability, following single doses of radiprodil, and it is deemed sufficient to meet the study objectives.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/03/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
18
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 25934 0
Nucleus Network - Melbourne
Recruitment hospital [2] 25969 0
Nucleus Network - Geelong
Recruitment postcode(s) [1] 41768 0
3004 - Melbourne
Recruitment postcode(s) [2] 41811 0
3220 - Geelong

Funding & Sponsors
Funding source category [1] 315400 0
Commercial sector/Industry
Name [1] 315400 0
GRIN Therapeutics, Inc.
Country [1] 315400 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
GRIN Therapeutics, Inc.
Address
230 Park Avenue, Suite 2830 New York, NY, United States
Country
United States of America
Secondary sponsor category [1] 317463 0
Commercial sector/Industry
Name [1] 317463 0
Avance Clinical Pty Ltd
Address [1] 317463 0
213 Glynburn Road, Firle, South Australia, 5070
Country [1] 317463 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 314318 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [1] 314318 0
123 Glen Osmond Road, Eastwood, South Australia, 5063
Ethics committee country [1] 314318 0
Australia
Date submitted for ethics approval [1] 314318 0
20/12/2023
Approval date [1] 314318 0
Ethics approval number [1] 314318 0

Summary
Brief summary
This is a open-label, randomized, 3-period, 6-sequence crossover study to determine the relative bioavailability of two formulations (10% and 30%) of radiprodil under fasted and fed conditions in healthy adult participants. Radiprodil may be indicated for use in patients with GRIN related disorders, but a trial of the drug in healthy volunteers is needed before trials in patients with GRIN related disorders can proceed.

Who is it for?
You may be eligible for this study if you are aged 18 to 55 years and are in good general health without a clinically significant medical history.

Study details:
All healthy volunteer participants who choose to enrol in this study will receive a single dose of radiprodil over 3 separate periods under fasted and fed conditions. All participants will have their vital signs checked (heart rate, blood pressure, temperature, etc), and will provide blood and urine samples for testing.
The data generated in this study will inform the design of future clinical studies and to select the dose(s) for future studies in patients with GRIN related disorders.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131166 0
Dr Ofer Michael Gonen
Address 131166 0
Nucleus Network, Level 5, Burnet Tower, 89 Commercial Rd, Melbourne, Victoria, 3004
Country 131166 0
Australia
Phone 131166 0
+61 0385939800
Fax 131166 0
Email 131166 0
o.gonen@nucleusnetwork.com.au
Contact person for public queries
Name 131167 0
Dr Ofer Michael Gonen
Address 131167 0
Nucleus Network, Level 5, Burnet Tower, 89 Commercial Rd, Melbourne, Victoria, 3004
Country 131167 0
Australia
Phone 131167 0
+61 0385939800
Fax 131167 0
Email 131167 0
o.gonen@nucleusnetwork.com.au
Contact person for scientific queries
Name 131168 0
Dr Ofer Michael Gonen
Address 131168 0
Nucleus Network, Level 5, Burnet Tower, 89 Commercial Rd, Melbourne, Victoria, 3004
Country 131168 0
Australia
Phone 131168 0
+61 0385939800
Fax 131168 0
Email 131168 0
o.gonen@nucleusnetwork.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
No additional documents have been identified.