Epilepsy, spasticity and anxiety disorders Not Applicable
Conditions
Interventions
Administration of up to 50 mg of ENX-101 or a matching placebo.
Sponsors
Engrail Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 4.1. 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 4.2. Of childbearing potential and willing to use two 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: 7.1. Reside in the inpatient unit from Day –2 until discharge on Day 13 7.2. Refrain from strenuous exercise from Day –4 until Day 13 7.3. 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 -29. 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: 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 CNS 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 –1: 5.1. History or evidence of any of the following: 5.1.1. Myocardial infarction 5.1.2. Cardiac valvulopathy 5.1.3. Cardiac surgery revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) 5.1.4. Unstable angina 5.1.5. Cerebrovascular accident or stroke or transient ischemic attack 5.1.6. Pacemaker 5.1.7. Atrial fibrillation, flutter, or nonsustained or sustained ventricular tachycardia 5.1.8. Pulmonary arterial hypertension 5.1.9. Sick sinus syndrome, second- or third-degree atrioventricular block 5.1.10. Uncontrolled hypertension 5.1.11. Congestive heart failure 5.1.12. Family history of sudden death or personal history of long QT syndrome 5.1.13. Hypokalemia 5.1.14. Unexplained syncope or syncope within the last 3?years regardless of etiology 5.2. Electrographically and clinically significant abnormalities, as judged by the Investigator, that might interfere with ECG (electrocardiogram) analysis, including evidence of a previous myocardial infarction, significant left ventricular hypertrophy, flat T waves (particularly in the inferior leads), or more than minor nonspecific STT–wave changes. 5.2.1. Rhythm other than sinus rhythm 5.2.2. Mean HR 100 bpm 5.2.3. Mean systolic blood pressure >140 mmHg; mean diastolic blood pressure >90 mmHg 5.2.4. QTc interval using Fridericia’s formula (QTcF) >450 msec in males or >470 msec in females 5.2.5. QRS interval =120 msec 5.2.6. PR interval >200 msec 6. Reports having experienced suicidal ideation (Type 4 or 5 on the C-SSRS (Colombia-Suicide Severity Rating Scale)) within 30 days prior to Screening, any suicidal behavior within 2 years prior to Screening (any “Yes” answers on the 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 in the last 6 months or as judged significant by the Investigator or daytime symptoms attributable to unsatisfactory sleep or shift
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The safety and tolerability of ENX-101 will be assessed using the following: 1. Adverse events (AEs) recorded throughout the study 2. Physical examination at Screening, Day -2, Day 10, Prior to discharge on Day 13 3. Vital signs* (blood pressure, HR, respiratory rate and tympanic body temperature) at Screening, Day –2, Day –1, Day 1 through Day 10: Pre-dose, 2 and 6 hours after dosing, Day 11 through Day 13 *Vital signs will include two-position blood pressure and heart rate (HR), respiratory rate, and tympanic temperature. Blood pressure and HR will be measured in both the supine and standing positions; measurements will be performed after at least 10 minutes lying down and then at 2 minutes after rising from the supine position to standing 4. Continuous 12-lead ECG holter monitoring on Day –1: timepoints scheduled to approximately match the Day 1 timepoints; Day 1: 60, 45, and 30 minutes pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after dosing; Day 10: 60, 45, and 30 minutes pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours 5. Clinical laboratory tests (hematology, serum chemistry, serum coagulation, urinalysis) at Screening, Day -2, Day 5, Day 10, and Day 13 6. Suicidality (suicidal behavior and suicidal ideation) assessed using the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening, Day 1, Day 2, Day 5, Day 11, Day 13 7. Degree of sedation assessed using the Modified Observer's Alertness/Sedation Scale (MOAA/S) at Day 1: Pre-dose and 2, 4, 6, 8, 10, and 24 hours (Day 2) after dosing; Day 10: Pre-dose and 2, 4, 6, 8, 10, and 24 hours (Day 11) after dosing; Day 12: 48 hours after Day 10 dosing; Day 13: 72 hours after Day 10 dosing | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. The effects of ENX-101 on the following electrocardiogram (ECG) parameters in healthy volunteers: cardiac repolarization (corrected QT interval [QTc]), heart rate (HR), PR and QRS intervals, T-wave morphology, and U-wave presence; measured using 12-lead ECG at Screening, Day -2, Day 1: Pre-dose and 2 and 6 hours after dosing, Day 10: Pre-dose and 2 and 6 hours after dosing, Day 13 2. The PK of ENX-101 and, if possible, ENX-101 metabolites (ENX-101-M3, triazole aldehyde, triazole alcohol, and triazole acid), in plasma of healthy volunteers after the first dose and at plasma steady-state at 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, 48, and 72 hours respectively, after Day 10 dosing 3. The effects of ENX-101 on a battery of pharmacodynamic (PD) measures (NeuroCart®): 3.1. Saccadic reaction time (seconds), saccadic peak velocity (degrees/second) 3.2. Smooth pursuit eye movements (percentage of time the eyes of the participant are in smooth pursuit of the target) (%) 3.3. Adaptive tracking (average performance) (%) 3.4. Body sway (anteroposterior sway) (mm) 3.5. Pupil size 3.6. VAS according to Bond and Lader, to assess mood, alertness and calmness (mm) 3.7. VAS according to Bowdle, to assess external and internal perception Measured at Screening, Day -2 (twice during the day for baseline measurement), Day 2 and Day 9: At 2, 4, 6, 8, 10, and 24 hours (i.e. Day 3 and Day 10) after dosing | — |
Countries
Netherlands
Contacts
Public ContactPauline Nettesheim
Outcome results
None listed