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.

Study Overview

• Status: Recruiting
• Conditions: Healthy Adult Male and Female Volunteers
• Intervention / Treatment: Drug: Y-4 tables; Drug: Y-4 placebos

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ya Shu Li, Doctor; Phone Number: +010-59978555; Email: shuyali85@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100000
      • Recruiting
      • Beijing Tiantan Hospital, Capital Medical University Beijing
      • Principal Investigator: Shuya Li
      • Contact: Shuya Li, M.D.; Phone Number: +8613601367028; Email: shuyali85@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Y-4 tables; Each subject will receive a single dose and multiple doses.	Drug: Y-4 tables; Each subject will receive a single dose and multiple doses. During the single dose phase (Day1-Day4), the subjects will be administered with single dose of Y-4 tablets on fasting state in the morning of Day D1. During the multiple dosing phase (Day5-Day13), the subjects will be required to administer with Y-4 tablets continuously for 6 days, BID of Day5-Day9 (once in the morning and once in the evening, Q12h) and QD of Day10, for a total of 11 doses.
Placebo Comparator: Y-4 placebos; Each subject will receive a single dose and multiple doses.	Drug: Y-4 placebos; Each subject will receive a single dose and multiple doses. During the single dose phase (Day1-Day4), the subjects will be administered with single dose of Y-4 placebos on fasting state in the morning of Day D1. During the multiple dosing phase (Day5-Day13), the subjects will be required to administer with Y-4 placebos continuously for 6 days, BID of Day5-Day9 (once in the morning and once in the evening, Q12h) and QD of Day10, for a total of 11 doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
adverse events	An AE is defined as any untoward medical event that occurs after receiving a drug or treatment or any deterioration of a disease or symptom that existed before receiving the investigational product or treatment (excluding the disease studied in this trial) in a subject or a clinical investigation subject, whether or not considered related to the investigational product or treatment. Therefore, an AE can be a discomfort sign (including an abnormal laboratory finding), symptom, or transient disease beyond any indication, whether or not related to the investigational product or treatment. The investigator will name each AE reported during the study by MedDRA PT and evaluate their severity using the criteria of "mild", "moderate" and "severe". The relevance evaluation is divided into 5 grades: 1-certainly related; 2- probably/likely related; 3-possibly related; 4-unlikely related; 5 not related.	From the first day to the 19th± 1st day after the start of administration
Incidence of subject getting abnormal results of laboratory tests after treatment	Record changes from baseline to post-treatment, listing deviations from normal ranges post-treatment. Laboratory tests are composed of hematology, urinalysis, serum chemistry, coagulation test. Normal range is provided by the site.	From the first day to the 19th± 1st day after the start of administration
Incidence of subject getting abnormal results of 12-lead ECG after treatment	Record changes from baseline to post-treatment, listing deviations from normal ranges post-treatment. 12-lead ECG will be analyzed by single RR Heart Rate, aggregate PR Interval, aggregate QRS Duration, aggregate RR Interval, aggregate QT Interval, aggregate QTC Interval. Normal range is provided by the site.	From the first day to the 19th± 1st day after the start of administration
Incidence of subject getting abnormal results of vital signs after treatment.	Record changes from baseline to post-treatment, listing deviations from normal ranges post-treatment. Vital signs(body temperature, respiration, blood pressure, and pulse) will be assessed by according equipment.(electronic sphygmomanometer, thermometer).	From the first day to the 19th± 1st day after the start of administration
Incidence of subject getting abnormal results of physical examinations after treatment.	Record changes from baseline to post-treatment, listing deviations from normal ranges post-treatment. Physical examinations will be conduct by the investigator through observation.	From the first day to the 19th± 1st day after the start of administration
Incidence of subject getting abnormal results of blood oxygen saturation after treatment	Record changes of blood oxygen saturation from baseline to post-treatment, listing deviations from normal ranges post-treatment. Normal range is provided by the site	From the first day to the 19th± 1st day after the start of administration
Incidence of subject getting abnormal results of C-SSSRS scale evaluation after treatment after treatment	Record changes of C-SSSRS scale evaluation from baseline to post-treatment	From the first day to the 19th± 1st day after the start of administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax	peak plasma concentration after single dose	From day 1 to day 4 after the start of administration
AUC0-t	Area under the plasma concentration versus time curve from time 0 to the time of the last quantifiable concentration after single dose	From day 1 to day 4 after the start of administration
AUC0-∞	Area under the plasma concentration-time curve from time 0 to infinity (extrapolated) after single dose	From day 1 to day 4 after the start of administration
Tmax	Time to reach maximum observed plasma concentration after single dose	From day 1 to day 4 after the start of administration
t1/2	Terminal elimination half-life after single dose	From day 1 to day 4 after the start of administration
λz	Terminal-phase elimination rate constant, slope of curves terminal segment at semi-log concentration-time curve calculated by linear regression.	From day 1 to day 4 and from day 8 to day 13 after the start of administration
AUC_%Extrap	The percentage of the AUC0-inf that has been extrapolated. AUC_%Extrap = [(AUC0-∞-AUC0-t)/AUC0-∞] × 100%	From day 1 to day 4 and from day 8 to day 13 after the start of administration
CL/F	Total body clearance after single dose. CL/F = Dose/AUC0-inf	From day 1 to day 4 after the start of administration
Vz/F	apparent volume of distribution after single dose. Vz/F = Dose/AUC0-∞/λz	From day 1 to day 4 after the start of administration
MRT0-t	Mean residence time within the time from time zero to the lowest testing plasma concentration after single dose. MRT0-t = AUMC0-t/AUC0-t	From day 1 to day 4 after the start of administration
MRT0-∞	Mean residence time extrapolated from zero to infinity after single dose. MRT 0-∞ = AUMC 0-∞/AUC 0-∞.	From day 1 to day 4 after the start of administration
Cav, ss	mean plasma concentration at steady state	From day 8 to day 13 after the start of administration
Cmax, ss	Cmax at steady state	From day 8 to day 13 after the start of administration
Cmin, ss	minimal plasma concentration at steady state	From day 8 to day 13 after the start of administration
AUCτ	Area under the concentration-time curve between dosing interval at steady state	From 8 to day 13 after the start of administration
AUC0-t, ss	AUC0-t at steady state	From day 8 to day 13 after the start of administration
AUC0-∞, ss	AUC0-∞ at steady state	From day 8 to day 13 after the start of administration
Tmax, ss	Tmax at steady state	From day 8 to day 13 after the start of administration
t1/2, ss	t1/2 at steady state	From day 8 to day 13 after the start of administration
CLss/F	CL/F at steady state	From day 8 to day 13 after the start of administration
Vz, ss/F	Vz/F at steady state	From day 8 to day 13 after the start of administration
DF	degree of fluctuation of plasma concentration	From day 8 to day 13 after the start of administration

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Collaborators: Neurodawn Pharmaceutical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2025
• Primary Completion (Estimated): May 4, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: April 2, 2025
• First Submitted That Met QC Criteria: April 13, 2025
• First Posted (Actual): April 20, 2025

Study Record Updates

• Last Update Posted (Actual): April 20, 2025
• Last Update Submitted That Met QC Criteria: April 13, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: phase I trial
• Other Study ID Numbers: Y-4-LC-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No