and anxiety disorders Epilepsy spasticity
Conditions
Interventions
ENX-101 formulated as Size 2 capsules each containing 5 mg ENX-101, which will
be supplied to the pharmacy in bulk.
Subjects will be administered ENX-101 orally, once daily, in the morning with
wate
exact dose
dependent on DEC review of Part 1 data
Placebo formulated as Size 2 capsules, which will be supplied to the pharmacy
in bulk.
Subjects will be administered placebo orally, once daily, as
number of
capsules dependent on DEC review of Part 1 data (up to cohort 4)
Sponsors
Engrail Therapeutics, Inc.
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Subjects must meet all the following criteria to be eligible for the study: 1. Healthy male and female volunteers aged 18 to 55 years, inclusive, at Screening 2. Capable of giving written informed consent 3. Willing to give written consent to have data entered into *Verified Clinical Trials* 4. Female subjects a. Of non-childbearing potential, defined as either permanently sterilized (at least 4 months after surgical sterilization including bilateral salpingectomy, tubal ligation, or oophorectomy with or without hysterectomy) or post-menopausal (defined as amenorrhea for 12 consecutive months and documented plasma follicle-stimulating hormone level >40 IU/mL; in the event a subject's menopausal status has been clearly established and yet serum follicle-stimulating hormone levels are not consistent with a post-menopausal status, determination of the subject*s eligibility to be included in the study will be at the Investigator*s discretion following consultation with the Sponsor), and with a negative pregnancy test at Screening and Day *2; OR b. Of childbearing potential and willing to use 2 effective methods of contraception (i.e., established method of contraception + condom) or remain abstinent (where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from Day *2 through 3 months after the last dose of study drug, and with a negative pregnancy test at Screening and Day *2 5. Male subjects who, if fertile (defined as post-pubertal and not permanently sterile by orchidectomy or vasectomy) must be willing to use a condom or remain abstinent (where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from Day *2 through 3 months after the last dose of study drug 6. Body mass index of 18 to 35 kg/m2 at Screening 7. Willing and able to comply with all study requirements including the following: a. Reside in the inpatient unit from Day *2 until discharge on Day 13 b. Refrain from strenuous exercise from Day *4 until Day 13 c. Abstain from grapefruit-, alcohol-, caffeine-, or xanthine-containing products from Day *4 through Day 13 Part 2 Subjects Only 8. Subjects must have sleep pattern of going to bed between 10:00 pm and 12:00 am over the 4 weeks prior to Screening through to Day -2 9. Subjects must have been sleeping at least 6 to 8 hours per night over the 4 weeks prior to Screening through to Day -2
Exclusion criteria
Exclusion criteria: Subjects meeting any of the following exclusion criteria will not be enrolled in the study: 1. Clinically significant abnormality within 2 years of Screening that in the Investigator*s opinion may place the subject at risk or interfere with study outcome variables; this includes, but is not limited to, history of or current cardiac, renal, neurologic, gastrointestinal, pulmonary, endocrinologic, hematologic, or immunologic disease or history of malignancy 2. History of convulsions (other than benign febrile convulsions of childhood) including epilepsy, or personal history of significant cerebral trauma or central nervous system infections (e.g., meningitis) 3. History or evidence of significant ophthalmologic or neurologic condition that would adversely affect the eye movement assessments 4. History or evidence of any medical condition potentially altering the absorption, metabolism, or elimination of drugs; this includes a surgical history of the gastrointestinal tract affecting gastric motility or altering the gastrointestinal tract 5. Any of the following cardiovascular conditions at Screening or Day *2: a. History or evidence of any of the following: i. Myocardial infarction ii. Cardiac valvulopathy iii. Cardiac surgery revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) iv. Unstable angina v. Cerebrovascular accident or stroke or transient ischemic attack vi. Pacemaker vii. Atrial fibrillation, flutter, or non-sustained or sustained ventricular tachycardia viii. Pulmonary arterial hypertension ix. Sick sinus syndrome, second- or third-degree atrioventricular block x. Uncontrolled hypertension xi. Congestive heart failure xii. Family history of sudden death or personal history of long QT syndrome xiii. Hypokalemia xiv. Unexplained syncope or syncope within the last 3 years regardless of etiology b. Electrographically and clinically significant abnormalities, as judged by the Investigator, that might interfere with ECG analysis, including evidence of a previous myocardial infarction, significant left ventricular hypertrophy, flat T waves (particularly in the inferior leads), or more than minor non-specific ST-T*wave changes c. Rhythm other than sinus rhythm d. Mean HR 100 bpm e. Mean systolic blood pressure >140 mm Hg; mean diastolic blood pressure >90 mm Hg f. QTc interval using Fridericia*s formula (QTcF) >450 msec in males or >470 msec in females g. QRS interval *120 msec h. PR interval >200 msec 6. Reports having experienced suicidal ideation (Type 4 or 5 on the C-SSRS) within 30 days prior to Screening, any suicidal behavior within 2 years prior to Screening (any *Yes* answers on Suicidal Behavior section of C-SSRS), and/or the Investigator assesses the subject to be a safety risk to him/herself or others 7. Diagnosis of any sleep disorder (including narcolepsy, central sleep apnea, sleep related hypoventilation, circadian rhythm sleep-wake disorders, substance/medication induced sleep disorder or parasomnias - NREM sleep arousal disorders, nightmare disorder, REM sleep behavior disorder for Part 2) in the last 6 months or current complaints of sleep disturbance or daytime symptoms attributable to unsatisfactory sleep or shift worker whose routine
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The safety and tolerability of ENX-101 will be assessed by the following: - AEs - Vital signs (2-positional blood pressure and HR, respiratory rate, and tympanic body temperature) - 12-lead ECG - 24-hour continuous 12-lead ECG Holter monitoring (Part 1 only) - Clinical laboratory tests (hematology, serum chemistry, urinalysis) - Physical examination - Pregnancy test (where applicable) - C-SSRS - MOAA/S - LSEQ (Part 2 only) - CSD-Core (Part 2 only) | — |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetic Measures: Blood will be collected before and after ENX-101 administration for bioanalytical measurement of plasma levels of ENX-101 and metabolites (ENX-101-M3, triazole aldehyde, triazole alcohol, and triazole acid). The time points for collecting blood and the evaluation parameters are as follows: Part 1 - Day 1: Pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after dosing - Day 2: Pre-dose (24 hours after Day 1 dose) and 1, 2, 4, 6, 8, 10, and 12 hours after dosing - Days 3, 4, 5, 6, 7, and 8: Pre-dose (24 hours after the previous day*s dose) - Day 9: Pre-dose (24 hours after Day 8) and 1, 2, 4, 6, 8, 10, and 12 hours after dosing - Day 10: Pre-dose (24 hours after Day 9) and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after dosing - Days 11, 12, 13: At 24, 36, and 72 hours, respectively, after Day 10 dosing The plasma concentration-time data for ENX-101 and, if possible, its metabolites will be analyzed using non-compartmental methods. The following PK parameters will be evaluated: maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), area under the plasma concentration-time curve from administration to the end of dosing (AUC0-t), AUC from administration to 24 hours after dosing (AUC0 24), AUC extrapolated to infinite time (AUC0-*), plasma concentration half-life (t1/2),terminal rate constant (*z), apparent total clearance of the drug from plasma after oral administration (CL/F), apparent volume of distribution during terminal phase after non-intravenous administration (Vz/F), and metabolite/parent (M/P) ratio. Other parameters may be evaluated. Actual elapsed time from dosing will be used to estimate all subject plasma PK parameters. Part 2 * Day 1: Pre-dose * Day 2: 12, 16, and 20 hours post-dose * Day 3 through Day 10: 12 hours post-dose * Day 11: 12, 16, and 20 hours post-dose Day 12 and Day 13 Pharmacodynamic Measures: PD assessments will be conducted at | — |
Countries
Netherlands
Outcome results
None listed