Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000214538
Ethics application status
Approved
Date submitted
29/01/2024
Date registered
4/03/2024
Date last updated
20/03/2024
Date data sharing statement initially provided
4/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
An ascending, single and multiple dose(s), double-blind, randomized, placebo controlled study assessing the safety, tolerability, and pharmacokinetics of ov329 in healthy male and female participants
Scientific title
:An ascending, single and multiple dose(s), double-blind, randomized, placebo controlled study assessing the safety, tolerability, and pharmacokinetics of ov329 in healthy male and female participants
Secondary ID [1] 311347 0
OV329-22-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
rare seizure disorders 332607 0
Condition category
Condition code
Neurological 329307 329307 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
OV329 is a novel chemical compound identified as a potent GABA-AT inhibitor. Its therapeutic component comprises a gamma-amino butyric acid analog zwitterion, with the active pharmaceutical ingredient supplied as a hydrochloride salt.

Study OV329-22-001 is a Phase 1, multi-center, randomized, double-blind, parallel, placebo-controlled, two-part study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of OV329.

This study is divided into sequential Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) segments. The SAD portion (Part A) precedes the MAD portion (Part B), with the latter initiated following a comprehensive review of all data from Part A. It is worth noting that Part B may commence before the completion of all planned cohorts in Part A. Prior to the onset of Part B, an amendment will be submitted to support the proposed dosing regimens, safety evaluations, and PK/PD assessments, if deemed necessary.

Both Part A and Part B will enroll healthy adult males and non-pregnant or non-breastfeeding females. Each segment will comprise of multiple dosing cohorts, each defined by a specific dose. The Dose Review Committee (DRC) will assess safety, tolerability, PK, and Magnetic Resonance Spectroscopy (MRS) data for each cohort to determine subsequent dosing levels, particularly for Part B based on Day 30 data, which includes ophthalmologic assessments.

Within each cohort of Part A and Part B, a sentinel group comprising two participants (one receiving active treatment and one receiving placebo) will be randomized and dosed ahead of the remaining participants. These individuals will undergo close monitoring for 48 hours post-dose during the in-unit phase of Part A (Day 3) and for 13 days (312 hours) during the inpatient and outpatient follow-up period up to Day 14 of Part B. All safety data will be reviewed by the Principal Investigator who will determine if it is safe to proceed with the rest of the cohort. Then, the remaining 6 participants will be dosed and the safety assessment of these 6 participants will proceed as planned.

For SAD cohorts conducted in the United States, doses were administered at 1mg, 2mg, and 3mg per participant per cohort, using oral capsules as the mode of administration. Adherence to the intervention will be monitored through supervised dosing and the return of unused drug tablets, if applicable, in all SAD cohorts.

Participants involved in SAD cohorts will not be eligible for inclusion in MAD cohorts, ensuring unique enrollment across both segments. In the MAD dose cohort, OV329 will be orally administered once daily for 7 consecutive days.
Intervention code [1] 327792 0
Treatment: Drugs
Comparator / control treatment
Placebo is a matching oral capsule for each dosing strength
Part A: single administration of oral capsule in fasting conditions
Part B: repeated administration for 7 days, given once daily as oral capsule, in fasting conditions
OV329 Capsule placebo is comprised of only D-mannitol in a hydroxypropyl methylcellulose capsule shell. The placebo matches the active drug product in appearance and in weight.
Control group
Placebo

Outcomes
Primary outcome [1] 337131 0
To assess the safety and tolerability of single (Part A) oral doses of OV329 in healthy male and female participants
Timepoint [1] 337131 0
Part A: Single Ascending Dose
Screening period: Day-28 to Day-2
Treatment period: single administration on Day 1
Follow-up period: Day 1 to Day 7
Primary outcome [2] 337407 0
To assess the safety and tolerability of single (Part B) oral doses of OV329 in healthy male and female participants
Timepoint [2] 337407 0
Screening period: from Day -28 to Day-2
Treatment period: repeated once daily administration for 7 days
Follow-up period: from Day 7 to Day 30 +/- 5 days
Secondary outcome [1] 430808 0
To characterize the PK of OV329 in healthy male and female participants after single (Part A)
Timepoint [1] 430808 0
Single Dose Plasma PK (Day 1):
Day 7 Plasma PK: OV329 plasma PK profile, including Cmax, tmax, AUC0-24, AUClast, AUCinf, t1/2, accumulation ratio (RA) AUC0-24,
Secondary outcome [2] 431749 0
To characterize the PK of OV329 in healthy male and female participants after single (Part B)
Timepoint [2] 431749 0
Accumulation ratio (RA) AUC0-24, RA Cmax (Part B)
Urine PK: OV329 PK as data allow after single dose (Day 1, Part B) and on Day 7 (Part B)

Eligibility
Key inclusion criteria
Participants are eligible to be included in the study only if they meet all the following criteria and none of the exclusion criteria:
1. Participant must give written informed consent prior to participation in the study.
2. Participant agrees not to post any of the participant's personal or medical data or information related to the study on any website, message board(s), online groups, or social media website (e.g. Facebook, Instagram, Twitter etc.) until notified that the study is completed.
3. Participant must be willing and able to comply with the study procedures (including diet) and visit schedules and must be able to follow verbal and written instructions.
4. Male and female participants aged 18 to 55 years at the time of informed consent.
5. Weighs at least 50 kg and body mass index (BMI) greater than or equal to 18.0 and less than 35.0 kg/m2 at screening.
6. Continuous nonsmoker who has not used nicotine containing products (including vaping) for at least 1 month prior to the first dosing and throughout the study, based on participant self-reporting.
7. Resting supine systolic blood pressure 90 to 145 mmHg (inclusive) and diastolic blood pressure no higher than 90 mmHg at Screening and Day -1 (to be taken after about 10 minutes in supine position).
8. A 12-lead ECG with no clinically significant abnormalities as deemed by the investigator and Fredericia corrected QT interval (QTcF) interval less than or equal to 450 milliseconds at Screening and Day -1 (to be taken after about 10 minutes in supine position).
9. Resting supine pulse rate between 45 and 100 beats per minute at Screening and Day -1.
10. Normal physical examination and laboratory investigations within the normal reference range, or if outside of the reference ranges, deemed not clinically significant in the opinion of the investigator. In the event the investigator deems a Grade 2 value at screening to be not clinically significant, the investigator will obtain approval for inclusion of participant from medical monitor and Sponsor (Clinical Lead) at Screening. Out-of-range labs (not within reference ranges) at Day -1 are exclusionary if deemed clinically significant by the investigator or designee; exceptions include lab results for Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma glutamyl transferase (GGT) and Alkaline phosphatase (ALP), which would be exclusionary at Screening and Day -1 if greater than 1.5x +/- upper limit of normal (ULN) of reference ranges regardless of clinical significance.
11. Willing to abstain from illicit drugs, alcohol, and nicotine products/tobacco use during study participation.
12. Participant must be willing to stay within the clinical research unit for the duration of the in-patient study period and return for all additional study visits as specified by the protocol.
13. Female participants who are sexually active with the opposite sex and of childbearing potential (defined as first menarche through post-menopause or permanent sterilization) must agree to use a highly effective method of birth control from time of screening and for 1 month following the last dose of study drug combined with the use of a condom by the male partner.
Highly effective contraceptive methods are as follows and must be in use for at least 90 consecutive days before drug administration:
- Intrauterine device
- Intrauterine hormone-releasing system
- Bilateral tubal occlusion
- Intravaginal or transdermal hormonal contraception
- Injectable or implantable contraceptive systems, including progestogen-only hormonal contraception associated with inhibition of ovulation
- Vasectomized or same sex partner
- Abstinence (see note below)
NOTE: Double barrier is not considered highly effective per Clinical Trials Facilitation and Coordination Group contraceptive guidance. Oral contraceptives alone (without a highly effective contraceptive listed above) is not permissible. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of this clinical trial and the preferred and usual lifestyle of the subject.
14. Female participants not of childbearing potential due to surgical sterilization (at least six weeks after hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) confirmed by medical history, or menopause.
Menopausal women include women with either:
- Spontaneous amenorrhea for at least 12 months without an alternative medical cause
OR
- Spontaneous amenorrhea for six to 12 months and a follicle-stimulating hormone level greater than 40 mIU/mL
15. Male participants (post-pubertal unless permanently sterilized by bilateral orchidectomy) must agree to use male contraception (condom) combined with the use of a highly effective method of contraception by the female partner and/or male abstinence from time of screening and for 90 days following the last dose of study drug (t half life estimated to be less than one day based on preliminary data after SAD)
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 from study enrollment if they meet any of the following criteria:
1. Any past or current history of an ophthalmologic condition that is congenital, infectious, genetic or acquired, that required medication, surgery or ongoing care, including: reduced visual acuity, reduced visual field, cataract, glaucoma, elevated intraocular pressure, uveitis, vitritis, optic neuritis, optic atrophy, optic nerve edema, papilledema, neuroretinitis, any inflammatory optic nerve or retinal condition (e.g., Multiple Evanescent White Dot Syndrome [MEWDS], Familial Exudative Vitreoretinopathy [FEVR], Acute Zonal Occult Outer Retinopathy [AZOOR]), any inflammatory or autoimmune condition of the orbit (e.g. thyroid eye disease, idiopathic orbital inflammatory syndrome, Rosai-Dorfman, IgG4, etc), retinal detachment, retinal edema, retinal or optic nerve hemorrhage, maculopathy, diabetic retinopathy, retinal artery or vein occlusion, retinal degeneration, congenital retinal abnormality, glaucoma, corneal laceration or trauma, choroidal neovascularization, age related macular degeneration, pathologic myopia, and optic nerve or retinal coloboma.
Of note, the following ophthalmologic conditions if resolved >6 months ago (i.e., prior to Screening) are permitted: conjunctivitis (viral, bacterial or allergic) and chalazion. Reduced visual acuity secondary to refractive error that is corrected to normal with glasses/contacts is permitted.
2. Contraindications to magnetic resonance imaging (MRI) scanning, including but not limited to the presence of metallic surgical hardware, cardiac pacemaker, stents, mechanical heart valves, artificial limbs, brain stimulator devices, implanted drug pumps, cochlear implants, ocular implants or known metal fragments in eyes, exposure to shrapnel or metal filings, magnetic dental implants, or permanent retainer; history of clinically significant claustrophobia; participant had obtained a new tattoo within 30 days before first scan.
3. History or presence of gastritis, gastrointestinal tract disorder, gastric bypass surgery, or hepatic disorder or other clinical condition which, in the opinion of the Investigator or designee, may affect the absorption, distribution, metabolism, or elimination of study drug. And also, recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation, within 2 weeks prior to first dosing.
4. Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee).
5. History or presence of alcohol or drug abuse within the past 2 years prior to screening visit as determined by the Investigator (or designee). .
6. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds, including but not limited to vigabatrin.
7. Risk of suicide according to the Investigator’s clinical judgment (e.g., per Columbia Suicide Severity Rating Scale (C-SSRS)) or has made a suicide attempt in the previous year prior to Screening visit.
8. Unable to refrain from or anticipate the use of:
a. Any (oral and non-oral) systemic drug, including prescription and nonprescription medications, herbal remedies, or vitamin supplements within 14 days prior to the first dosing and throughout the study, including the follow-up period. After the first dose of study drug, acetaminophen (up to 2 g per 24 hours) may be administered at the discretion of the Investigator or designee.
b. Alcohol, caffeinated and dietary products such as grapefruit, Seville orange etc.
c. Any product, remedy, supplement, or medication containing cannabidiol (CBD), Tetrahydrocannabinol (THC) or related compounds within 30 days prior to the first dosing and throughout the study, including the follow-up period.
9. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 30 days prior to the first dosing and throughout the study.
10. Participation in another clinical study within 30 days prior to the first dosing. The 30-day window will be derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of the current study. If the previous investigational product has a long half-life, three months or five half-lives (whichever is longer) should have passed; participation in a clinical trial involving an investigational product or nonapproved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
11. Receipt of vaccination (inclusive of influenza and SARS COV2) within 14 days of dosing (Day 1).
12. If male, the participant intends to donate sperm during the course of this study or for 90 days following the last dose of study drug.
13. If female, the participant is pregnant or intending to become pregnant before participating in this study, during the study, and within 1 month after last dose of the study drug; or intending to donate ova during such time period; or lactating.
14. Ovid employees or Investigator site personnel where the study is being conducted and/or their immediate family.
Note: immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
15. Individuals who, in the opinion of the Investigator or designee, should not participate in this 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)
A randomization schedule will be provided from the unblinded biostatistician to the unblinded pharmacy staff in a password-protected file, which will be used solely by the unblinded pharmacy staff for treatment assignment. Based on the randomization schedule, the unblinded pharmacy staff will prepare code-break envelopes containing the treatment assignment information. If needed for intentional unblinding for safety reasons, the code-break envelope will be used in the event of an emergency if the pharmacy staff is not available.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment is randomized 1 to 1 (OV329 : placebo) in the sentinel group, and 5 to 1 (OV329 : placebo) in the rest of the cohort.
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
Not yet recruiting
Date of first participant enrolment
Anticipated
31/03/2024
Actual
Date of last participant enrolment
Anticipated
31/10/2024
Actual
Date of last data collection
Anticipated
30/11/2024
Actual
Sample size
Target
56
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 315603 0
Commercial sector/Industry
Name [1] 315603 0
Ovid Therapeutics Australia Pty Ltd
Country [1] 315603 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Ovid Therapeutics Australia Pty Ltd
Address
c/o Intertrust Australia Pty Ltd Suite 2 Level 25 100 Miller Street
Country
Australia
Secondary sponsor category [1] 317695 0
None
Name [1] 317695 0
Address [1] 317695 0
Country [1] 317695 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314491 0
Alfred Health HREC
Ethics committee address [1] 314491 0
55 Commerical Rd, Melbourne VIC 3004
Ethics committee country [1] 314491 0
Australia
Date submitted for ethics approval [1] 314491 0
10/01/2024
Approval date [1] 314491 0
01/03/2024
Ethics approval number [1] 314491 0

Summary
Brief summary
OV329 [(S)-3-amino-4-(difluoromethylene) cyclopent-1-ene-1-carboxylic acid hydrochloride salt] is a gamma aminobutyric acid (GABA) aminotransferase (GABA-AT) inhibitor that is being developed as an antiseizure medication for rare seizure disorders in adults and pediatric patients.
Part A will consist of up to 5 cohorts, comprising 8 participants each. Dosing will be initiated at 1 mg/day. Subsequent cohorts will be dosed as recommended by the Data Review Committee (DRC) based on the safety, tolerability and PK of OV329 from the previous cohort. Target engagement measured by MRS will also be considered in assessing the potential dose escalation as the dose will not be increased by more than 50% relative to the previous cohort if GABA levels are 2-fold increased.
Part B will consist of 2 planned cohorts comprising 8 participants each, using 2 and 3 mg doses of OV329. Dosing will be initiated at 2 mg/day. Subsequent cohorts will be dosed as recommended by the DRC based on the safety, tolerability and PK of OV329 from the previous cohort (based on review of the Day 30 data, including ophthalmological assessments) and not to exceed a Cmax of 27 ng/mL and/or an AUC of 32 ng*h/mL. Participants will be dosed for a total of 7 days.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131774 0
Dr Ofer Gonen
Address 131774 0
Nucleus Network, Level 5, Burnet Tower, 89 Commerical Road, Melbourne, VIC 3004
Country 131774 0
Australia
Phone 131774 0
+61 03 8593 9800
Fax 131774 0
Email 131774 0
o.gonen@nucleusnetwork.com.au
Contact person for public queries
Name 131775 0
Dr Uzma Siddiqui, MD
Address 131775 0
Ovid Therapeutics, 441 9th Avenue, NY, NY 10001
Country 131775 0
United States of America
Phone 131775 0
+1 256 653 7385
Fax 131775 0
Email 131775 0
clinicaltrials@ovidrx.com
Contact person for scientific queries
Name 131776 0
Dr Uzma Siddiqui, MD
Address 131776 0
Ovid Therapeutics, 441 9th Avenue, NY, NY 10001
Country 131776 0
United States of America
Phone 131776 0
+1 256 653 7385
Fax 131776 0
Email 131776 0
clinicaltrials@ovidrx.com

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.