A Study of HS-10353 in Chinese Participants.

A Phase I Randomized, Double-blinded, Placebo-controlled Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetic of HS-10353 in Chinese Adult Subjects

The primary objective of this study is to assess the safety and tolerability of single and multiple oral administered doses of HS-10353 separately in Chinese healthy and major depressive disorder subjects.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: HS-10353; Drug: Placebo

Detailed Description

This is a phase I, randomized, double-blinded, placebo-controlled, both single ascending doses (SAD) study and multiple ascending dose (MAD) clinical trial to assess the safety, tolerability, and pharmacokinetics of HS-10353 tablet(s) separately in Chinese healthy and major depressive disorder (MDD) subjects.

Approximately six sequential dose cohorts will be evaluated in SAD study. Sentinel dosing will be employed for the first SAD cohort to protect the subjects' safety. Escalation to the next dose cohort will be undertaken only after safety and PK data are reviewed by the Safety Review Committee (SRC) and agreement reach that it is safe to increase the dose. Each SAD cohort is dosed at approximately weekly intervals to allow adequate time for collection and review of safety and PK data.

Approximately three sequential dose cohorts will be evaluated in MAD study. The total daily dose for each MAD cohort will be based on information obtained from the SAD study. Each subject will receive only one dose regimen in this study.

Safety data up to Day14 (±1) in SAD and up to Day20 (±1) in MAD will be reviewed prior to the next dose level. The number of Cohorts in SAD and MAD would be adjusted based on the assessment of SRC.

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China
      • West China Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

SAD Inclusion Criteria

1. Healthy male or female subjects between 18 and 45 years old;
2. Body weight more than 50.0kg (male) or 45.0kg (female), body mass index (BMI) within the range of 19.0~26.0kg/m2;
3. Volunteers agree to refrain from smoking, drinking alcohol. Avoid xanthine or caffeine (including chocolate, tea, coffee, cola, etc.) and avoid strenuous exercise;
4. The male volunteers agreed to refrain from donating sperm from the start of the drug until six months after they stopped the study;
5. The female volunteers agreed to avoid ovum donation from the start of the drug until six months after they stopped the study;
6. Pregnancy test results of female volunteers must be negative within 3 days of administration.

SAD Exclusion Criteria

1. Pregnant and breastfeeding female.
2. Volunteers with a history of cardiovascular, respiratory, liver, kidney, digestive tract, mental, neurological, hematological, metabolic and other systemic diseases, who are not suitable to participate in this study as assessed by the investigator.
3. The results of vital signs, physical examination, laboratory examination and 12-lead ECG during screening were abnormal with clinical significance.
4. Hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibody (HCVAb), human immunodeficiency virus antibody (HIVAb) or syphilis antibody is positive
5. Volunteers had a history of drug dependence or abuse.
6. A heavy smoker or smokers who smoked 5 or more cigarettes per day for 3 months prior to screening or tested positive for nicotine during screening.
7. A history of alcohol abuse or a single consumption of more than 14 units of alcohol (1 unit = 285 mL of beer, 25 mL of spirits, 150 mL of wine) in the nearly two weeks prior to screening or a positive breath test for alcohol at screening.
8. Participate in clinical trials of any drug or medical device within 3 months prior to screening.
9. Any medication taken within 2 weeks of administration, including prescription, over-the-counter, and herbal medicines.
10. Diet or dietary treatment or significant change in dietary habits within 30 days prior to administration for whatever reason.
11. Volunteers who have difficulty swallowing solid tablets or capsule.
12. Volunteers with difficulty in blood collection, unable to tolerate multiple venous blood collection and any blood collection contraindications.

MAD Inclusion Criteria

1. Subject has signed an ICF prior to any study-specific procedures being performed.
2. Subject is an ambulatory male or female between 18 and 65 years of age, inclusive.
3. Subject has a diagnosis of MDD that has been present for at least a 4-week period as diagnosed by DSM-5.
4. Subject has a HAM-D17 total score of ≥22 at screening and Day 1 (prior to dosing).
5. Subject is willing to discontinue other antidepressant or anti-anxiety medications （such as benzodiazepines） or antipsychotics during screening and treatment.

MAD Exclusion criteria:

1. Subject has a history of suicide attempt.
2. Subject has a recent history or active clinically significant manifestations of metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to complete or participate in this clinical study.
3. Subject has a history of treatment-resistant depression, defined as persistent depressive symptoms despite treatment with adequate doses of antidepressants from two different classes for an adequate amount of time (ie, at least 4 weeks of treatment).
4. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), or human immunodeficiency virus (HIV) antibody at screening.
5. Subject has active psychosis per Investigator assessment.
6. Subject has a medical history of seizures.
7. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder.
8. Subject has had exposure to another investigational medication or device within 30 days prior to screening.
9. Subject has had administration of psychotropics that have been initiated within 14 days prior to screening and/or are not being taken at a stable dose.
10. Use of any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 within the 14 days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville oranges, or products containing these within 30 days prior to receiving the first dose of study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HS-10353; Capsules；Single dose: only one administration; Multiple doses: continuous administration for 7 days	Drug: HS-10353; Single or multiple dose(s) of HS-10353; Other Names: HS-10353 capsules
Placebo Comparator: Placebo; Capsules；Single dose: only one administration; Multiple doses: continuous administration for 7 days	Drug: Placebo; Single or multiple dose(s) of placebo; Other Names: HS-10353 placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endpoints of the trial：AE，SAE	The incidence, severity, and association of AE, SAE and AE leading to withdrawal from the trial	Baseline to end of follow-up (a maximum of 20 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SAD pharmacokinetic endpoints：Cmax	The maximum plasma concentration (Cmax)	Day1-Day6
SAD pharmacokinetic endpoints：Tmax	Time to Cmax (Tmax)	Day1-Day6
SAD pharmacokinetic endpoints：AUC0-t	The area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t)	Day1-Day6
SAD pharmacokinetic endpoints：AUC0-∞	The area under the plasma concentration-time curve from time zero to infinite time (AUC0-∞)	Day1-Day6
SAD pharmacokinetic endpoints：λz	Terminal rate constant (λz)	Day1-Day6
SAD pharmacokinetic endpoints：t½	Half-life (t½)	Day1-Day6
SAD pharmacokinetic endpoints：CL/F	Apparent clearance following oral administration (CL/F)	Day1-Day6
SAD pharmacokinetic endpoints：Vz/F	Apparent volume of distribution following oral administration (Vz/F)	Day1-Day6
SAD pharmacokinetic endpoints：MRT	Mean residence time (MRT)	Day1-Day6
MAD pharmacokinetic endpoints：Css,max	The maximum steady state drug concentration in plasma during dosing interval (Css,max)	Day1-Day12
MAD pharmacokinetic endpoints：Css,av	Average steady state drug concentration in plasma during dosing interval (Css,av)	Day1-Day12
MAD pharmacokinetic endpoints：Tss,max	Time to Css, max (Tss,max)	Day1-Day12
MAD pharmacokinetic endpoints：AUCss, 0-t	The area under the plasma concentration-time curve from time zero to the time of the last measurable concentration over the dosing interval at steady state (AUCss, 0-t)	Day1-Day12
MAD pharmacokinetic endpoints：DF	Coefficient of fluctuation（DF）	Day1-Day12
MAD pharmacokinetic endpoints：Rac	Accumulation ratio (Rac)	Day1-Day12
MAD pharmacokinetic endpoints：Css,min	The minimum steady state drug concentration in plasma during dosing interval (Css,min)	Day1-Day12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MAD pharmacodynamics endpoints：Ham-D17 response rate	Ham-D17 response rate (score decreased ≥50% from baseline) and (score ≤7)	Day1-Day12

Collaborators and Investigators

• Sponsor: Jiangsu Hansoh Pharmaceutical Co., Ltd.

Publications and helpful links

General Publications

• Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJ, Vos T. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013 Nov 9;382(9904):1575-86. doi: 10.1016/S0140-6736(13)61611-6. Epub 2013 Aug 29.
• Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry. 2011 Apr;16(4):383-406. doi: 10.1038/mp.2010.120. Epub 2010 Nov 16.
• McIntyre RS, Suppes T, Tandon R, Ostacher M. Florida Best Practice Psychotherapeutic Medication Guidelines for Adults With Major Depressive Disorder. J Clin Psychiatry. 2017 Jun;78(6):703-713. doi: 10.4088/JCP.16cs10885.
• Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2009 Jan;19(1):34-40. doi: 10.1016/j.euroneuro.2008.08.009. Epub 2008 Sep 26.
• Mann JJ, Oquendo MA, Watson KT, Boldrini M, Malone KM, Ellis SP, Sullivan G, Cooper TB, Xie S, Currier D. Anxiety in major depression and cerebrospinal fluid free gamma-aminobutyric acid. Depress Anxiety. 2014 Oct;31(10):814-21. doi: 10.1002/da.22278. Epub 2014 May 27.
• Schur RR, Draisma LW, Wijnen JP, Boks MP, Koevoets MG, Joels M, Klomp DW, Kahn RS, Vinkers CH. Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies. Hum Brain Mapp. 2016 Sep;37(9):3337-52. doi: 10.1002/hbm.23244. Epub 2016 May 4.
• Zorumski CF, Paul SM, Izumi Y, Covey DF, Mennerick S. Neurosteroids, stress and depression: potential therapeutic opportunities. Neurosci Biobehav Rev. 2013 Jan;37(1):109-22. doi: 10.1016/j.neubiorev.2012.10.005. Epub 2012 Oct 17.
• Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3239-44. doi: 10.1073/pnas.95.6.3239.
• Fellmeth G, Fazel M, Plugge E. Migration and perinatal mental health in women from low- and middle-income countries: a systematic review and meta-analysis. BJOG. 2017 Apr;124(5):742-752. doi: 10.1111/1471-0528.14184. Epub 2016 Jun 20.
• Osborne LM, Gispen F, Sanyal A, Yenokyan G, Meilman S, Payne JL. Lower allopregnanolone during pregnancy predicts postpartum depression: An exploratory study. Psychoneuroendocrinology. 2017 May;79:116-121. doi: 10.1016/j.psyneuen.2017.02.012. Epub 2017 Feb 16.

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2021
• Primary Completion (Actual): March 11, 2023
• Study Completion (Actual): March 31, 2023

Study Registration Dates

• First Submitted: August 12, 2021
• First Submitted That Met QC Criteria: January 13, 2022
• First Posted (Actual): January 18, 2022

Study Record Updates

• Last Update Posted (Actual): August 3, 2023
• Last Update Submitted That Met QC Criteria: August 1, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: major depressive disorder; Phase I; SAD; MAD; healthy subject
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: HS-10353-101

Drug and device information, study documents

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