Safety and Pharmacokinetics of Y-4 Tablets in Healthy Subjects

A Randomized, Double-blind, Placebo-controlled, Dose-escalation Phase 1 Study to Assess the Safety and Pharmacokinetics of Y-4 Tablets After Single- and Multiple-dose in Healthy Subjects

Y-4 is a new fixed-dose combination drug product containing two active ingredients of pregabalin and riluzole.

The primary objective is to evaluate the safety and tolerability of Y-4 tablets in Chinese healthy adult subjects after single- and multiple-dose.

The secondary objective is to characterize the pharmacokinetics (PK) of pregabalin and riluzole in Chinese healthy adult subjects after single- and multiple-dose of Y-4 tablets.

This study will be a single-center, randomized, double-blind, placebo-controlled, dose-escalation study in Chinese healthy adult subjects. A total of 36 subjects, 3 cohorts of 12 subjects each (half men and half women), will be enrolled in this study. In each dose cohort, subjects will undergo single and multiple (BID, 11 doses) administration, among them, 10 subjects (half men and half women) will receive Y-4 tablets and 2 subjects (half men and half women) will receive placebo randomly.

After providing written informed consent, subjects will undergo screening for eligibility. Screening for the study will begin 14 days prior to the dosing. Subjects will be admitted to research center in the afternoon of Day-1 prior to the dosing day and fasting for the next 10 hours overnight. In the morning of the following day (Day 1), subjects will be administered the assigned dose of Y-4 tablets or placebo orally, then subjects will be monitored for the following 72 hours. During Day 5 to Day 9, the subjects will be required to be administered twice a day (Q12 h), once in the morning and once in the evening. In the morning of Day 10, subjects will be administered to the last dose. In the morning of Day 13 (approximately 72 hours after the last administration), the safety and tolerance will be evaluated and then subjects will be discharged.

A telephone follow-up/completion visit will be conducted 7 days (±1) post discharge.

Treatment cohorts are planned as following:

Cohort 1: 75 mg/18.75 mg Y-4 tablets (75 mg pregabalin and 18.75 mg riluzole) or placebo tablets (two little Y-4 tablets) Cohort 2: 112.5 mg/28.125 mg Y-4 tablets (112.5 mg pregabalin and 28.125 mg riluzole) or placebo tablets (one large Y-4 tablet) Cohort 3: 150 mg/37.5 mg Y-4 tablets (150 mg pregabalin and 37.5 mg riluzole) or placebo tablets (one large Y-4 tablet and one little Y-4 tablet)

Inclusion Criteria:

1. Healthy adult male and female subjects, 18-45 years of age (including both ends).
2. Body weight ≥ 50 kg for male and ≥ 45 kg for female, body mass index (BMI) within the range of 19 - 28 kg/m2 (including both ends).
3. During the screening period, serum creatinine is within the normal range, or the standard creatinine clearance (CLcr) estimated by Cockcroft-Gault formula is ≥ 80 mL/min (for female subject, according to the calculation result × 0.85）.
4. Subjects who are able to understand and give their signed informed consent before any trial related procedures are performed.

Exclusion Criteria:

1. Subjects who are known to be allergic to pregabalin, riluzole or any excipients of Y-4 tablets (microcrystalline cellulose, Copovidone, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and Opadry amb Ⅱ), have allergic diseases or allergic constitution;
2. Subjects who have special requirements for diet and cannot follow the unified diet;
3. Physical examinations, vital signs, 12-lead electrocardiograms (ECG), chest X-ray (front position), laboratory tests (hematology, serum chemistry, coagulation test, urinalysis, etc.) and other screening tests found abnormalities that the researchers judged to be of clinical significance;
4. Subjects who have experienced angioedema in the past (such as swelling of the face, mouth (tongue, lips, and gums), and neck (pharynx and throat));
5. History of dizziness or vertigo with clinical significance, or disease of inner ear known to cause dizziness or vertigo;
6. QTcF > 450 msec at the screening stage;
7. Diagnosed with insomnia, anxiety disorder, depression, epilepsy, or other serious mental disorders, and principal investigator determines that the subject is not suitable to participate in this trial;
8. Presence or history of hepatic or renal disease or any other condition known to interfere with the absorption, distribution, metabolism or excretion of medicines;
9. Subjects who drink too much tea, coffee and/or caffeine-containing beverages (more than 8 cups, 1 cup = 250 mL) every day within 3 months prior to screening, or disagree that any caffeine-containing beverages are prohibited during the trial;
10. Subjects who have consume any diet (food or beverage) rich in grapefruit, pitaya, mango and cranberry within 14 days prior to screening;
11. Subjects have disease history or current disease that may affect the safety evaluation of the subject or the internal process of the study drug, including the central nervous system, cardiovascular system, digestive system, respiratory system, urinary system, hematological system, immunology, psychiatry, metabolic abnormalities, gastrointestinal surgery (excluding appendicitis surgery), etc. In particular, there is a history of dysphagia or any gastrointestinal disease affecting drug absorption (including frequent nausea or vomiting caused by any cause) and eye diseases;
12. Donation or loss of blood equal to or in excess of 400 mL, or blood transfusion within 3 months prior to screening; or donation or loss of blood equal to or in excess of 200 mL within 1 month prior to screening;
13. Subjects who have taken any drugs known to be strong inhibitors or inducers of cytochrome P450 enzymes within 2 months prior to screening (such as inducers - barbiturates, carbamazepine, phenytoin, glucocorticoids, omeprazole; inhibitors - serotonin reuptake inhibitors (SSRI) antidepressants, cimetidine, diltiazem, macrolides, nitroimidazoles, sedative hypnotics, verapamil, fluoroquinolones, antihistamines); or subjects who have taken any prescription drugs, over-the-counter drugs and Chinese herbal medicine other than the above drugs within 14 days prior to screening;
14. Subjects who have taken central nervous system (CNS) depressants including opioids (pethidine hydrochloride, morphine, dihydromorphine hydrochloride, fentanyl, tramadol, etc), benzodiazepines (diazepam, flurazepam, clonazepam, oxazepam, chlordiazepine and triazolam etc), antiepileptic drugs (carbamazepine, sodium valproate, phenobarbital drugs etc) within 2 months prior to screening;
15. Subject with sleep apnea, or subjects with severe sleep snoring and daytime drowsiness;
16. Subjects with suicidal thoughts and behavior;
17. Subject participated in any other clinical trials within 3 months prior to screening;
18. Current or former drug users, or positive urine screen for drugs of abuse at screening (screening items include: dimethylenedioxyamphetamine, methamphetamine, ketamine, morphine, tetrahydrocannabinoid acid, cocaine);
19. Alcoholics or regular drinkers within 3 months prior to screening, that is, those who drink more than 14 units of alcohol per week (1 unit = 360 mL of beer or 45 mL of alcohol with 40% alcohol content or 150 mL of wine), or whose alcohol breath test results are greater than 0.0 mg/100 mL, or who cannot abstain from alcohol during the trial;
20. Smokers or those who cannot comply with the prohibition of smoking during the trial, or positive for cotinine screening;
21. Subjects who is positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, syphilis antibody or human immunodeficiency virus (HIV) antibody;
22. Male subjects (or their partners) or female subjects have baby plans during the whole trial period and within 3 months after the end of the trial, or subjects are unwilling to take one or more non-drug contraceptive measures (such as complete abstinence, condoms, ligation, etc.) during the trial period;
23. Female subjects who have unprotected intercourse within 14 days prior to screening, or pregnant or lactating women;
24. Subjects with poor compliance or other factors unsuitable for participation in this trial.