Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000460707
Ethics application status
Approved
Date submitted
18/12/2021
Date registered
23/03/2022
Date last updated
23/03/2022
Date data sharing statement initially provided
23/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study in Healthy Males and Females to Test How Different Doses of OPC-224333 are Tolerated (Arm 1)
Scientific title
A Phase 1, Randomized, Double-blind, Placebo-controlled Trial to Assess
the Tolerability, Safety, and Pharmacokinetics of Single Ascending Oral Tablet Doses of
OPC-224333 in Healthy Male and Female Subjects (Arm 1)
Secondary ID [1] 305927 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 324520 0
Condition category
Condition code
Neurological 321990 321990 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
OPC-224333

Participants are planned to be dosed in 9 ascending dose groups, with 8 participants in each group. There will be 9 ascending doses of Investigational Medicinal Product (IMP) (1 dose per each of the 9 groups; 8 participants in each group [6 active and 2 placebo]). There is a single dose on Day 1 of Treatment.

Dose groups 1, 2, 3, 4, 5, 6, 7, 8, and 9 correspond to planned doses of 3, 10, 30, 100, 200, 400, 600, 800,and 1000 mg, respectively.

However, the planned doses and escalation scheme may be modified, including dose reductions or repeating a dose, based on available Pharmacokinetic (PK) and safety information.

Doses will be given using the least number of tablets as possible. Treatment will be administered following an overnight (at least 10 hours) fast and participants will continue to fast for at least 4 hours after dosing.

In case the maximum tolerated dose (MTD) is determined in less than 9 dosing cohorts, lower doses may be explored.

In each cohort, a sentinel group consisting of 2 healthy participants (1 active:1 placebo) will be dosed first. The remaining participants in the cohort will be dosed at least 48 hours after dosing in the sentinel group.

All oral doses of IMP will be administered with 240 mL of still water. Water may be increased by up to 240mL more for higher doses.
Except with water given with the dose, water will be restricted beginning 1 hour prior to dosing.
Intervention code [1] 322918 0
Treatment: Drugs
Comparator / control treatment
Placebo comparator (tablets to match OPC-224333).
OPC-224333 0-mg (placebo) tablets are composed of lactose monohydrate, microcrystalline cellulose, magnesium stearate, hypromellose, talc, titanium dioxide, and ferric oxide red.
Control group
Placebo

Outcomes
Primary outcome [1] 329740 0
Safety of OPC-224333 assessed in accordance with a 3-point grading system (Mild, Moderate and Severe) based upon participant self-report and investigators regularly assessing participants. As this is a first in human study, the safety and efficacy of OPC-224333 in humans has not been established.
Timepoint [1] 329740 0
Collected at Screening Visit, Check in at the hospital/clinic (Day -1), Treatment Period (Days 1, 2, 3, 4, 5, 6, 7), Discharge (Day 8/Early Termination (ET)), and Follow Up at 30 days post dose.
Primary outcome [2] 330538 0
Safety assessed by collecting vital sign measurements (including blood pressure, pulse rate, respiratory rate, and temperature) and compared with the toxicity grading scale to identify vital sign measurements of potential clinical relevance. Blood pressure will be collected by sphygmomanometer, temperature by infrared thermometer, Pulse by palpation, respiratory rate by sound and count.
Timepoint [2] 330538 0
Collected at Screening Visit, Check in at the hospital/clinic (Day -1), Treatment Period (Days 1, 2, 3, 4, 5, 6, 7) and Discharge (Day 8/ET)
Primary outcome [3] 330539 0
Safety assessed by 12-Lead Safety Electrocardiograms (ECGs) to measure heart rate (HR), time interval between the start of the P wave and the start of the QRS complex (PR interval), Q-wave, R-wave, S-wave (QRS) duration, Q-wave and T-wave (QT) intervals, and corrected QT interval (QTc). The toxicity grading scale will be used for identifying ECGs of potential clinical relevance.
Timepoint [3] 330539 0
Will be performed at Screening Visit and in each dosing period within 24 hours predose (on Day -1), on Day 1: predose and at 2 and 8 hours postdose; Day 2: 24 hours postdose; and at discharge (Day 8/ET): 168 hours postdose.
Secondary outcome [1] 403638 0
Primary outcome: Safety and tolerability assessed by clinical laboratory tests including Haematology, Serum Chemistry and Urinalysis. The toxicity grading scale will be used for identifying laboratory values of potential clinical relevance.
Timepoint [1] 403638 0
Collected at Screening Visit, Check in (Day -1), Treatment Period (Day 1, 2, 4), Discharge (Day 8/ET).
Secondary outcome [2] 403639 0
Primary Outcome: Safety assessed by completing neurological examinations, which includes an evaluation of mental status, cranial nerves, motor system, reflexes, sensory system, coordination, and station and gait.
A targeted neurological examination will focus on participant-driven issues based on
investigator judgment (eg, the investigator enquires if the subject has any complaints,
pains, or disturbances and this would lead to further evaluation of the problematic area)
and can be completed at any time per investigator discretion. Any neurological examination findings that are considered by the investigator to be clinically significant are to be recorded as AEs. Each evaluation listed will be assessed as a composite outcome.
Timepoint [2] 403639 0
Performed at Screening Visit, Check-in (Day -1), and Discharge (Day 8/ET).
Secondary outcome [3] 406573 0
Primary Outcome: Safety assessed by physical examinations, including weight (measured by digital scales), as well as an assessment of the head, eyes, ears, nose, and throat; thorax; abdomen; urogenital; skin and mucosae; and extremities. Each evaluation listed will be assessed as a composite outcome. Any physical examination findings that are considered by the investigator to be clinically significant are to be recorded as AEs.
Timepoint [3] 406573 0
Performed at Screening Visit, Check-in (Day -1), and Discharge (Day 8/ET).
Secondary outcome [4] 406575 0
Primary Outcome: Suicidality assessed using the C-SSRS questionnaire.
Timepoint [4] 406575 0
Collected at Screening Visit, Check in (Day -1), Treatment Period (Day 2, 4), Discharge (Day 8/ET)
Secondary outcome [5] 406576 0
Efficacy assessed by ECG parameters using 12-lead Holter ECG monitoring
Timepoint [5] 406576 0
Performed on Day 1: 3 predose time points (-0.75, -0.5, and -0.25 hours) and at 1, 2, 3, 4, 6, and 12 hours postdose; and on Day 2: 24 hours postdose.
Secondary outcome [6] 406581 0
Primary Outcome: Pharmacokinetics (PK) samples assessed using power model:

ln (maximum [peak] plasma concentration of the drug [Cmax], or area under the concentration-time curve to the last observable concentration at time t[AUCt], or area under the concentration-time curve from time zero to infinity [AUC8]) = a + ß ln (dose)
where a is the intercept and ß is the slope parameter.
Timepoint [6] 406581 0
Treatment Period (Day 1, 2, 3, 4, 5, 6, 7) and Discharge (Day 8/ET).

Blood samples for PK analysis will be collected at predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 (ET) hours postdose.

Eligibility
Key inclusion criteria
Participants are required to meet the following inclusion criteria when assessed:
1) Male and nonchildbearing potential (NCBP) female participants between 18 and 55 years of age, inclusive.
2) Body mass index (BMI) between 19.0 to 32.0 kg/m2 (inclusive).
3) In good health as determined by:
a) Medical history
b) Physical examination
c) Neurological examination
d) Electrocardiogram (ECG)
e) Serum/urine biochemistry, hematology, and serology tests.
4) Ability to provide written, informed consent prior to initiation of any trial-related procedures, and ability, in the opinion of the principal investigator, to comply with all the requirements of the trial.
5) Female participants who are surgically sterile (ie, have undergone bilateral oophorectomy or hysterectomy) or who have been postmenopausal for at least 12 consecutive months. This will be confirmed with follicle-stimulating hormone (FSH) assessment.
6) Male participants must agree to remain abstinent or to practice double-barrier forms
of birth control and refrain from sperm donation from trial screening through 90 days from the last dose of the IMP.
7) Participants who are nonsmokers (with an acceptable cotinine test), nontobacco
users, and nonvapers.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants will be excluded if they meet any of the following exclusion criteria when
assessed:
1) Clinically significant abnormality in past medical history or at the screening physical examination (including but not limited to clinical laboratory tests), that in the investigator’s or sponsor’s opinion may place the subject at risk or interfere with outcome variables including absorption, distribution, metabolism, and excretion of the IMP. This includes, but is not limited to, history of or concurrent cardiac, hepatic (liver function tests > 1.5 × upper limit of normal [ULN] at screening/baseline), renal (estimated glomerular filtration rate per chronic kidney disease epidemiology formula <60 mL/min), neurologic, endocrine,
gastrointestinal, respiratory, hematologic, and immunologic disease.
2) History of drug and/or alcohol abuse within 2 years prior to screening.
3) History of or current hepatitis or acquired immunodeficiency syndrome or carriers
of hepatitis B surface antigen (HBsAg), hepatitis C antibodies (anti-HCV), and/or human immunodeficiency virus (HIV) antibodies. Exceptions are permitted for subjects with a prior history of infection with hepatitis A who have fully recovered and are experiencing no liver sequelae, or with hepatitis C who have been adequately treated to be considered cured with no liver sequelae.
4) History of any medically significant allergy.
5) A positive urine or breath alcohol test and/or a positive urine drug screen for substance of abuse at screening or upon check-in to the trial site.
6) Subject having taken an investigational drug within 30 days preceding screening or a biological investigational drug within 30 days or 5 half-lives (whichever is longer) preceding screening,
7) Any history of significant bleeding or hemorrhagic tendencies.
8) Any history of difficulty in donating blood.
9) Donation of blood or plasma within 30 days prior to dosing.
10) Subjects without a permanent physical residence.
11) Consumption of alcohol and/or food and beverages containing methylxanthines (caffeinated coffee, caffeinated tea, caffeinated soda, and chocolate), pomelo, grapefruit, grapefruit juice, Seville oranges, or Seville orange juice within 3 days prior to dosing.
12) Use of prescription drugs, over-the-counter drugs, herbal medication, or vitamin
supplements within 14 days or 5 half-lives, whichever is longer, prior to dosing and antibiotics within 30 days prior to dosing. The sponsor may allow exceptions only if the medication’s administration is deemed unlikely to impact the pharmacokinetic (PK) results.
13) Exposure to any substances known to stimulate hepatic microsomal enzymes
within 30 days prior to screening (eg, occupational exposure to pesticides, organic solvents).
14) Use of tobacco products or daily exposure to second-hand smoke within 2 months
prior to screening, which result in urine cotinine concentrations > 500 ng/mL, or serum cotinine concentrations > 20 ng/mL at screening or at check-in to the trial site.
15) Uncontrolled hypertension, defined as supine systolic blood pressure = greater than or equal to 140 mmHg and/or supine diastolic blood pressure = greater than or equal to 90 mmHg at screening or check-in, or symptomatic hypotension or orthostatic hypotension, which is defined as a decrease of = greater than or equal to 20 mmHg in systolic blood pressure and/or a decrease of = greater than or equal to 10 mmHg in diastolic blood pressure after at least 3 minutes of standing compared with the previous supine blood pressure, at screening or check-in.
16) Supine heart rate (HR), after resting for at least 3 minutes, outside the range of 45 to 100 beats per minute. The sponsor may allow exceptions if the results are not considered to be clinically significant; however, this will need to be approved by the medical monitor. Note: If the first HR measurement is abnormal, it can be repeated at the investigator’s discretion, in which case a third (confirmatory) measurement may also be required.
17) Clinically relevant changes on ECG such as atrioventricular block (ie, PR > 220 msec), prolongation of the QRS complex over 120 msec, or a QT interval corrected for heart rate using Fridericia’s formula (QTcF) = greater than or equal to 450 msec in males or = greater than or equal to 470 msec in females.
18) Sexually active males or females of childbearing potential (FOCBP), or their partners, who do not agree to practice 2 different approved methods of birth control or remain fully abstinent (periodic abstinence or withdrawal are not acceptable methods of contraception) during the trial and for 90 days after the last dose of IMP. If employing birth control, 2 of the following methods must be used: vasectomy, tubal ligation, nonhormonal intrauterine device, condom or occlusive cap (vaginal diaphragm or cervical/vault cap).
19) History of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial.
20) Any subject who, in the opinion of the investigator, should not participate in the trial.

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)
Participants will be randomly assigned to treatment with IMP (on Day 1 and after eligibility is confirmed) and blinded to the identity of the IMP. In order to avoid bias in the evaluation of safety parameters, the investigator and clinic personnel (with the exception of the Pharmacy personnel preparing the doses) will be blinded to the identity of the IMP that is given to each subject. Numbered containers will conceal allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
The people analysing the results/data
Intervention assignment
Other
Other design features
Arm 1 is a randomized, double-blind, placebo-controlled, single-center trial to assess the tolerability, safety, and pharmacokinetic (PK) of single ascending oral doses of OPC-224333.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Safety variables to be analysed include Adverse Events, clinical laboratory tests, vital sign measurements, ECGs, the C-SSRS, and physical and neurological examination results. Changes from baseline in safety variables will be summarized using descriptive statistics; baseline will be the predose value at the start of the treatment period. Summaries will be based upon all available subject data. No inferential statistical analyses will be performed.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
25/03/2022
Actual
Date of last participant enrolment
Anticipated
16/12/2022
Actual
Date of last data collection
Anticipated
16/01/2023
Actual
Sample size
Target
72
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 21239 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 36111 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 310270 0
Commercial sector/Industry
Name [1] 310270 0
Otsuka Pharmaceutical Development & Commercialization, Inc
Country [1] 310270 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Otsuka Pharmaceutical Development & Commercialization, Inc
Address
2440 Research Boulevard, Rockville, Maryland, MD 20850, USA
Country
United States of America
Secondary sponsor category [1] 311374 0
None
Name [1] 311374 0
Address [1] 311374 0
Country [1] 311374 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309941 0
Bellberry Human Research Ethics Committee G
Ethics committee address [1] 309941 0
123 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [1] 309941 0
Australia
Date submitted for ethics approval [1] 309941 0
01/12/2021
Approval date [1] 309941 0
11/01/2022
Ethics approval number [1] 309941 0

Summary
Brief summary
Otsuka Pharmaceutical Development & Commercialization, Inc (OPDC) is studying an investigational drug called OPC-224333. This drug is not available for sale in any country. OPC-224333 is being studied as a possible treatment for epileptic diseases including drug-resistant and rare epilepsies such as Dravet, Lennox-Gastaut, West, and Doose syndrome. Epilepsy is a condition that causes people to have repeated seizures. Seizures are caused by abnormal electrical activity in the brain. Seizures can make you have convulsions, pass out, shaking movements in just one arm or in a part of your face, suddenly stop responding and stare for a few seconds, or behave strangely. Epilepsy can start at any age.
You are invited to take part in this research study. The reason for this study is to find out potential benefits and safety of OPC-224333.

About 72 participants will be in the study and the study is being done at one research site, CMAX Clinical Research Pty Ltd, in Australia.

We are looking for a total of 72 healthy male or non-childbearing potential female participants between the ages of 18 and 55 years (inclusive) who have a body mass index between 19-32 kg/m2 (inclusive).

The study will involve:

• A screening visit (2 – 3 hours), within 28 days of the study starting
• 8 night in-house stay (Day -1 to Day 8)
• Follow-up phone call 30 days after your last dose (approximately 15 minutes)


Expected study duration for Arm 1 is up to approximately 59 days.
Trial website
Trial related presentations / publications
Public notes
The last dose of severe acute respiratory syndrome coronavirus (SARS-CoV-2) (also known as coronavirus disease 2019 [COVID-19]) vaccine, which must be taken at least 7 days prior to screening.

Contacts
Principal investigator
Name 115922 0
Prof Guy Lawrence Ludbrook
Address 115922 0
CMAX Clinical Research Pty Ltd.
Level 5,
21 North Terrace
Adelaide
South Australia 5000
Country 115922 0
Australia
Phone 115922 0
+61 8 7088 7900
Fax 115922 0
+61 8 7088 7999
Email 115922 0
guy.ludbrook@sa.gov.au
Contact person for public queries
Name 115923 0
Prof Guy Lawrence Ludbrook
Address 115923 0
CMAX Clinical Research Pty Ltd.
Level 5,
21 North Terrace
Adelaide
South Australia 5000
Country 115923 0
Australia
Phone 115923 0
+61 8 7088 7900
Fax 115923 0
+61 8 7088 7999
Email 115923 0
guy.ludbrook@sa.gov.au
Contact person for scientific queries
Name 115924 0
Prof Guy Lawrence Ludbrook
Address 115924 0
CMAX Clinical Research Pty Ltd.
Level 5,
21 North Terrace
Adelaide
South Australia 5000
Country 115924 0
Australia
Phone 115924 0
+61 8 7088 7900
Fax 115924 0
+61 8 7088 7999
Email 115924 0
guy.ludbrook@sa.gov.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.