Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000878572
Ethics application status
Approved
Date submitted
13/06/2024
Date registered
18/07/2024
Date last updated
13/10/2024
Date data sharing statement initially provided
18/07/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Study to Evaluate the Effect of Multiple Doses of Rabeprazole on the Pharmacokinetics of a Single Dose of Radiprodil in Healthy Adult Participants
Scientific title
A Phase 1, Fixed Sequence, Open-Label Study to Evaluate the Effect of Multiple Doses of Rabeprazole on the Pharmacokinetics of a Single Dose of Radiprodil in Healthy Adult Participants
Secondary ID [1] 312290 0
RAD-GRIN-502
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malformations of Cortical Development 334021 0
Condition category
Condition code
Neurological 330693 330693 0 0
Other neurological disorders
Human Genetics and Inherited Disorders 330699 330699 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase 1, fixed sequence, open-label study to evaluate the effect of multiple oral doses of rabeprazole (20 mg once daily) on the pharmacokinetics (PK) of a single dose (45 mg) of radiprodil in healthy adult participants. Rabeprazole administration may have the potential to impact solubility and absorption of radiprodil.

Approximately 18 subjects will be enrolled in the study. The study will consist of multiple periods: a screening period (Day -28 to -2), radiprodil period (Day -1 to 5), a rabeprazole run-in period (Day 5 to 9), a combined rabeprazole and radiprodil period (Day 9 to 13). Participants will be discharged on Day 13 (end of study).

Following the 28-day screening period, participants will be admitted into the Clinical Research Unit (CRU) on Day -1. On Day 1 a single oral dose of radiprodil (45 mg suspension) will be administered to participants with approximately 240 mL of room temperature water, after at least a 10-hour fast. Participants will remain fasted for at least 4 hours after dosing. Water will be permitted except for the 1hr period prior to and the 1hr period following radiprodil administration. On Day 5 participants will receive oral rabeprazole (20mg tablet) once daily for 4 days (Days 5, 6, 7 and 8). The rabeprazole dose will be administered with approximately 240 mL of room temperature water, after an overnight fast of at least 8 hours and 30 minutes before breakfast.
On the morning of Day 9, after at least an 8-hour fast, participants will receive a single oral dose of rabeprazole (20 mg tablet) with approximately 240 mL of room temperature water, followed 2 hours later by a single oral dose of radiprodil (45 mg suspension) administered with 240 mL water. The radiprodil dose is to be administered at the same time (± 30 min) as for the Day 1 dose. Participants will remain fasted after the rabeprazole dose and for at least 4 hours after receiving radiprodil. Water will be permitted, except for the period between rabeprazole dose administration until 1hr post-radiprodil administration. Participants will be discharged from the CRU on the morning of Day 13.

Adherence to and administration of study treatment will be conducted by delegated study site personnel.
Intervention code [1] 328758 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 338453 0
To assess the effect of oral rabeprazole 20 mg on the plasma PK profile of a single oral dose of radiprodil
Timepoint [1] 338453 0
Blood samples for plasma PK will be collected at the following timepoints:
Day 1 pre-dose (within 15 min prior to radiprodil dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 75 and 96hrs post-dose, Day 9 pre-dose (within 15 min prior to radiprodil dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96hrs post-dose.
Secondary outcome [1] 435983 0
To assess the safety and tolerability of a single oral dose of radiprodil co administered with oral rabeprazole 20 mg
Timepoint [1] 435983 0
Adverse events: The severity of any adverse events experienced during the study will be categorised 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, Day 1 and Day 9 pre-dose (within 60 minutes prior to dosing with radiprodil) and post-dose at 1, 3, 4 and 6hrs post-dose, then Day 5, 6, 7 and 8 pre-dose (within 60 minutes prior to dosing with rabeprazole), once daily on Day 2, 3, 4, 10, 11 and 12, and post-dose on Day 13 (end of treatment).

Electrocardiogram (ECG): 12-lead ECG recordings will be obtained in triplicate at Screening and Day -1, single recordings will be obtained pre-dose (within 60 minutes prior to radiprodil dose) on Day 1 and 9 and at 1, 3 and 4hrs post-dose, on Day 5 pre-dose (within 60 minutes prior to rabeprazole dose) and once on Day 13 (end of treatment).

Clinical Laboratory Evaluations (haematology, serum chemistry, coagulation and urinalysis): blood and urine samples will be obtained at Screening, Day -1, Day 5, Day 9 and Day 13 (end of treatment)
Secondary outcome [2] 435984 0
To assess the effect of oral rabeprazole 20 mg on the plasma PK profile of radiprodil metabolites following a single oral dose of radiprodil
Timepoint [2] 435984 0
Blood samples for metabolite PK will be collected at the following timepoints:
Day 1 pre-dose (within 15 min prior to radiprodil dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 75 and 96hrs post-dose, Day 9 pre-dose (within 15 min prior to radiprodil dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 96hrs post-dose.

Eligibility
Key inclusion criteria
Volunteers will be included in the study only if they satisfy all the following criteria:
1. Must have given written informed consent before any study-related activities are performed and must be able to understand the full nature and purpose of the study, including possible risks and adverse effects.
2. Adult males and females, 18 to 55 years of age (inclusive) at screening.
3. Body mass index (BMI) greater than or equal to 18.0 and less than or equal to 32.0 kg/m2, with a body weight greater than 50 kg at screening.
4. Medically healthy (in the opinion of the PI or delegate), as determined by pre-study medical history, and without clinically significant abnormalities including the following:
a. Physical examination without any clinically relevant findings;
b. Systolic blood pressure in the range of 90 to 140 mmHg and diastolic blood pressure in the range of 40 to 90 mmHg after resting for 5 minutes in a supine or semi-supine position.
c. Pulse rate in the range of 40 to 100 bpm after 5 minutes resting in a supine or semi-supine position.
d. Body temperature (tympanic), between 35.5°C and 37.5°C.
e. Electrocardiogram without clinically significant abnormalities including QT interval corrected for Fredericia (QTcF) <450 msec for male participants and <470 msec for female participants.
f. No clinically significant findings in serum chemistry, hematology, coagulation, and urinalysis tests.
5. Female volunteers:
a. Must be of non-child-bearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the screening visit or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with postmenopausal status, per local laboratory guidelines), or
b. If of child-bearing potential, must:
i. Have a negative pregnancy test at the screening visit and on admission to the study site on Day-1.
ii. Agree not to attempt to become pregnant or donate ova from signing the consent form until at least 90 days after the last dose of study drug.
iii. Agree to use adequate contraception (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 study drug, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle.
6. Male volunteers, if not surgically sterilised, must:
a. Agree not to donate sperm from signing the consent form until at least 90 days after the last dose of study drug.
b. If engaging in sexual intercourse with a female partner who could become pregnant, agree to use adequate contraception (defined as use of a condom combined with use of a highly effective method of contraception) from signing the consent form until at least 90 days after the last dose of study drug.
c. If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, agree to use a condom from signing the consent form until at least 90 days after the last dose of study drug.
7. Have suitable venous access for blood sampling.
8. Willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Volunteers will be excluded from the study if they meet any of the following criteria:
1. Known hypersensitivity to the study drug or any of the study drug ingredients, or hypersensitivity to proton pump inhibitors.
2. 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).
3. History of anaphylaxis or other significant allergy (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, asymptomatic seasonal allergies at time of dosing on Day 1) which, in the opinion of the PI (or delegate), would interfere with the volunteer’s ability to participate in the study.
4. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, psychiatric, or neurological disease/disorder, including any acute illness, determined by the PI (or delegate) to be clinically relevant.
5. History of surgery within 3 months prior to Day 1 as determined by the PI to be clinically relevant, or surgery planned during the study.
6. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma).
7. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia.
8. Presence or having sequelae of gastrointestinal, liver (including Gilbert’s syndrome), kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
9. Liver function test results elevated greater than 1.5-fold above the ULN for gamma glutamyl transferase (GGT), bilirubin (total, conjugated and unconjugated), ALP, AST or alanine aminotransferase (ALT). Volunteers with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the PI (or delegate), if the levels are unaccompanied by clinical signs and are determined to be normal variants.
10. Estimated creatinine clearance (CrCl) < 60 mL/min using the Cockcroft-Gault formula or serum creatinine greater than 1.5-fold above the ULN.
11. A history of or positive test results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit.
12. Positive drugs of abuse test, cotinine test or alcohol breath test results at the screening visit and/or on admission to the study site on Day 1.
13. Regular consumption of more than 10 standard alcoholic drinks/week and/or more than 4 standard alcoholic drinks on any one day, where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc/Vol], 100 mL wine [12% Alc/Vol], or 30 mL spirit [40% Alc/Vol]).
14. Routine consumption of an average of more than five (5) 240 mL servings of coffee or other caffeinated beverages per day.
15. Use of marijuana (including prescribed marijuana) within 30 days of Day -1.
16. Use of tobacco-containing products and nicotine or nicotine containing products in the 2 months prior to Day 1.
17. Females who are breastfeeding or planning to breastfeed.
18. Unable to swallow oral medication.
19. Use of any prescription or over-the-counter medication (including herbal products, diet aids, vitamins, and hormone supplements) within 14 days or 5 half-lives of the medication (whichever is longer) prior to the first dose of study drug, except use of contraceptives. Up to 2 grams per day of acetaminophen will be allowed at the discretion of the Investigator.
20. Acute illness within 14 days of study Day 1.
21. Use of any vaccinations within 7 days prior to screening.
22. Donation of blood or plasma within 30 days prior to first dose of study drug, or loss of whole blood of more than 500 mL within 30 days prior to first dose of study drug, or receipt of a blood transfusion within 1 year of the first dose of study drug.
23. Dosed in another clinical trial within 28 days prior to radiprodil dosing.
24. 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, poppy seeds 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.
25. Any other condition or prior therapy that in the opinion of the PI (or delegate) would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
29/07/2024
Actual
26/08/2024
Date of last participant enrolment
Anticipated
Actual
22/09/2024
Date of last data collection
Anticipated
Actual
5/10/2024
Sample size
Target
18
Accrual to date
Final
18
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26648 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 42688 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 316679 0
Commercial sector/Industry
Name [1] 316679 0
GRIN Therapeutics, Inc.
Country [1] 316679 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
GRIN Therapeutics, Inc.
Address
Country
United States of America
Secondary sponsor category [1] 318868 0
Commercial sector/Industry
Name [1] 318868 0
Avance Clinical Pty Ltd
Address [1] 318868 0
Country [1] 318868 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315457 0
Bellberry Human Research Ethics Committee A
Ethics committee address [1] 315457 0
Ethics committee country [1] 315457 0
Australia
Date submitted for ethics approval [1] 315457 0
12/06/2024
Approval date [1] 315457 0
11/07/2024
Ethics approval number [1] 315457 0

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

Contacts
Principal investigator
Name 134762 0
Dr Ofer Gonen
Address 134762 0
Nucleus Network Melbourne, Level 5, Burnet Tower, 89 Commercial Rd, Melbourne, Victoria, 3004
Country 134762 0
Australia
Phone 134762 0
+61 3 8593 9801
Fax 134762 0
Email 134762 0
[email protected]
Contact person for public queries
Name 134763 0
Dr Ofer Gonen
Address 134763 0
Nucleus Network Melbourne, Level 5, Burnet Tower, 89 Commercial Rd, Melbourne, Victoria, 3004
Country 134763 0
Australia
Phone 134763 0
+61 1800 243 733
Fax 134763 0
Email 134763 0
[email protected]
Contact person for scientific queries
Name 134764 0
Dr Ofer Gonen
Address 134764 0
Nucleus Network Melbourne, Level 5, Burnet Tower, 89 Commercial Rd, Melbourne, Victoria, 3004
Country 134764 0
Australia
Phone 134764 0
+61 1800 243 733
Fax 134764 0
Email 134764 0
[email protected]

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.