Clinical trial NCT05964790: Safety, Tolerability, Pharmacokinetics and Efficacy Study of HS-10380 in Patients With Schizophrenia
Official title: A Phase Ⅰb/Ⅱ, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics and Efficacy of HS-10380 in Chinese Adults With Schizophrenia.
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Schizophrenia
Keywords: Schizophrenia
Psychotropic drug
Antipsychotic agents
Lead sponsor: Jiangsu Hansoh Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2023-07-28
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to evaluate the safety, tolerability, pharmacokinetics and efficacy of HS-10380 relative to placebo for the treatment of participants with schizophrenia.

Detailed description: The trial consists of two parts: dose escalation cohorts and expansion cohorts. The primary aim of the dose escalation cohorts is to evaluate the safety and tolerability of HS-10380 in participants with schizophrenia, and the primary aim of expansion cohorts is to evaluate efficacy of HS-10380 in participants with schizophrenia.

Eligibility criteria: Inclusion Criteria:

* Dose escalation cohorts:

  1. Patients are 18 to 55 years of age, inclusive.
  2. Body mass index (BMI) between 18.5 and 30.0 kg/m2 ,inclusive. Weight ≥ 50 kg for male subjects and ≥ 45 kg for female subjects.
  3. Patient meets DSM-5 criteria for schizophrenia.
  4. Currently not taking antipsychotics. Or on a stable dose of single second-generation antipsychotics (SGA) for at least 2 weeks, limited to either risperidone, olanzapine, quetiapine, aripiprazole, or paliperidone.
  5. PANSS total score ≤ 90. Rating ≤ 4 on hostility and uncooperativeness,
  6. Negative urine pregnancy test (women of childbearing potential only).
  7. Male and female patients must agree to use a highly effective method of birth control during the course of the entire study and for 3 months after the last dose of investigational product.
  8. Written informed consent has been obtained.

Expansion cohorts:

1. Patients are 18 to 65 years of age, inclusive.
2. Patient meets DSM-5 criteria for schizophrenia.
3. No current use of antipsychotics. Or withdrawing from antipsychotics other than clozapine for more than 5 half-lives prior to randomization.
4. PANSS total score ≥70 and ≤120. Rating of at least 4 (moderate) on at least 2 of the following 4 PANSS positive symptoms; P1: delusions; P2: conceptual disorganization; P3: hallucinatory behavior; P6: suspiciousness/persecution.
5. Negative urine pregnancy test (women of childbearing potential only).
6. Male and female patients must agree to use a highly effective method of birth control during the course of the entire study and for 3 months after the last dose of investigational product.
7. Written informed consent has been obtained.

Exclusion Criteria:

* Dose escalation cohorts:

  1. Patients meet DSM-5 criteria for a mental illness other than schizophrenia, and might interfere with the conduct of the study as determined by the investigator.
  2. Current risk of self-harm or violence, including: having any suicidal ideation or suicidal behavior within the last 6 months, as assessed using Columbia-Suicidal Severity Rating Scale (C-SSRS).
  3. Patients who have a clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorder, etc. Medical conditions that are minor or well-controlled may be considered acceptable if the condition does not interfere with the conduct of the study.
  4. Patients who received electroconvulsive therapy (ECT) within 3 months prior to screening.
  5. Received a long-acting antipsychotic within 6 months prior to screening or within the duration of 5 half-lives of the drug.
  6. History of seizure disorder (with the exception of febrile seizure).
  7. History of malignant syndrome.
  8. Any condition that would be expected to affect drug absorption, distribution, metabolism and excretion, including gastrointestinal surgery, urinary tract obstruction or difficulty in urination, etc.
  9. History of severe allergies.
  10. Female patients who are pregnant, puerperal or breastfeeding.
  11. History of drug addiction within 1 year prior to screening.
  12. Patients who has a history of alcohol abuse (defined as more than 14 standard units of alcohol consumption per week, 1 standard unit = 360 mL of beer, 45 mL of distilled spirits or 150 mL of wine) within 6 months prior to screening, or are unable to abstain from alcohol use during the study period.
  13. Patients who smoke ≥10 cigarettes per day within 3 months prior to screening, or are unable to quit smoking during the study period.
  14. Abnormal physical examination results that may interfere with the study.
  15. Abnormal vital signs that may interfere with the study, including: resting heart rate \<60 or \>100 beats per minute, systolic blood pressure \<90mmHg or ≥140mmHg, diastolic blood pressure \<60mmHg or ≥90mmHg.
  16. Abnormal electrocardiogram (ECG) results may interfere with the study, including: QTcF\>450ms for male subjects and \>470ms for female subjects based on Fridericia correction.
  17. Abnormal clinical laboratory test results may interfere with the study, including: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) results \>1.5 × the upper limit of normal (ULN); serum prolactin levels \>5 × ULN or significant clinical symptoms like amenorrhea, gynecomastia, and lactation.
  18. Patients whose results for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), human immunodeficiency virus antibody (HIV-Ab), or syphilis serological reaction (TRUST) is not negative.
  19. Blood donation or blood loss ≥ 200ml within 1 month prior to screening.
  20. Patients requiring concomitant treatment with a moderate or strong cytochrome P450 (CYP) 3A4 inhibitors or CYP3A4 inducers, or a moderate or strong cytochrome CYP2D6 inhibitors or CYP3A4 inducers.
  21. Prior participation in any Interventional clinical trials within 3 months.
  22. Unsuitable for any other reason, as judged by the investigator.

Expansion cohorts:

1. Patients meet DSM-5 criteria for a mental illness other than schizophrenia, and might interfere with the conduct of the study as determined by the investigator.
2. Current risk of self-harm or violence, including: having any suicidal ideation or suicidal behavior within the last 6 months, as assessed using Columbia-Suicidal Severity Rating Scale (C-SSRS).
3. Patients who have a clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorder, etc. Medical conditions that are minor or well-controlled may be considered acceptable if the condition does not interfere with the conduct of the study.
4. Patients who received electroconvulsive therapy (ECT) within 3 months prior to screening.
5. Received a long-acting antipsychotic within 6 months prior to screening or within the duration of 5 half-lives of the drug.
6. History of seizure disorder (with the exception of febrile seizure).
7. History of malignant syndrome.
8. Any condition that would be expected to affect drug absorption, distribution, metabolism and excretion, including gastrointestinal surgery, urinary tract obstruction or difficulty in urination, etc.
9. History of severe allergies.
10. Female patients who are pregnant, puerperal or breastfeeding.
11. History of drug addiction within 1 year prior to screening.
12. Patients who has a history of alcohol abuse (defined as more than 14 standard units of alcohol consumption per week, 1 standard unit = 360 mL of beer, 45 mL of distilled spirits or 150 mL of wine) within 6 months prior to screening, or are unable to abstain from alcohol use during the study period.
13. Abnormal physical examination results that may interfere with the study.
14. Abnormal vital signs that may interfere with the study, including: resting heart rate \<60 or \>100 beats per minute, systolic blood pressure \<90mmHg or ≥140mmHg, diastolic blood pressure \<60mmHg or ≥90mmHg.
15. Abnormal electrocardiogram (ECG) results may interfere with the study, including: QTcF\>450ms for male subjects and \>470ms for female subjects based on Fridericia correction.
16. Abnormal clinical laboratory test results may interfere with the study, including: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) results \> 2 × the upper limit of normal (ULN).
17. Patients whose results for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), human immunodeficiency virus antibody (HIV-Ab), or syphilis serological reaction (TRUST) is not negative.
18. Patients requiring concomitant treatment with a moderate or strong cytochrome P450 (CYP) 3A4 inhibitors or CYP3A4 inducers, or a moderate or strong cytochrome CYP2D6 inhibitors or CYP3A4 inducers.
19. Blood donation or blood loss ≥ 200ml within 1 month prior to screening.
20. Prior participation in any Interventional clinical trials within 3 months.
21. Unsuitable for any other reason, as judged by the investigator.

Primary outcomes:
measure: Dose escalation cohorts: Incidence and severity of adverse events(AE) ，serious AEs and AE leading to withdrawal from treatment.
timeFrame: Baseline to Day 43
measure: Dose escalation cohorts: Changes from baseline in complete blood count (CBC).
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Changes from baseline in urinalysis.
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Changes from baseline in blood biochemistry test.
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Changes from baseline in coagulation function test.
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Changes from baseline in thyroid function test.
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Changes from baseline in serum prolactin.
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Changes from baseline in blood pressure (BP).
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Changes from baseline in pulse rate.
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Changes from baseline in body temperature.
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Change from baseline in body weight
timeFrame: Baseline to Day 29
measure: Dose escalation cohorts: Change from baseline in Electrocardiogram (ECG)
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Change from baseline in Simpson-Angus Scale (SAS)
timeFrame: Baseline to Day 36
measure: Change from baseline in Abnormal Involuntary Movement Scale (AIMS)
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Change from baseline in Barnes Akathisia Rating Scale
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Change from Baseline in Columbia - Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Change from Baseline in Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline to Day 28
measure: Expansion cohorts: Positive and Negative Syndrome Scale (PANSS) Response at Week 4, Defined as a 20% or Greater Improvement from Baseline in PANSS Total Score
timeFrame: Baseline to Day 28
measure: Expansion cohorts: Change from Baseline in Clinical Global Impression-Severity (CGI-S)
timeFrame: Baseline to Day 28
Secondary outcomes:
measure: Dose escalation cohorts: Maximum plasma concentration (Cmax) of first HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Time of the Maximum Concentration (Tmax) of first HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Area under the concentration time curve of intervals (AUC0-τ) of first HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Area under the concentration time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC0-t) of first HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Maximum concentration at steady state (Css, max) of multiple-dose HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Time of the maximum concentration at steady state (Tss, max) of multiple-dose HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Minimum concentration at steady state (Css, min) of multiple-dose HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Area under the concentration-time curve at steady state (AUCss) of multiple-dose HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Apparent clearance at steady state (CLss/F) of multiple-dose HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Apparent volume of distribution at steady state (Vss/F) of multiple-dose HS-10380 administration
timeFrame: Baseline to Day 36
measure: Dose escalation cohorts: Change from Baseline in Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline to Day 28
measure: Dose escalation cohort: Positive and Negative Syndrome Scale (PANSS) Response at Week 4, Defined as a 20% or Greater Improvement from Baseline in PANSS Total Score
timeFrame: Baseline to Day 28
measure: Dose escalation cohorts: Change from Baseline in Clinical Global Impression-Severity (CGI-S)
timeFrame: Baseline to Day 28
measure: Expansion cohorts: Incidence and severity of adverse events(AE) ，serious AEs and AE leading to withdrawal from treatment.
timeFrame: Baseline to Day 43
measure: Expansion cohorts: Changes from baseline in complete blood count (CBC).
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Changes from baseline in urinalysis.
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Changes from baseline in blood biochemistry test.
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Changes from baseline in coagulation function test
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Changes from baseline in hyroid function test
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Changes from baseline in serum prolactin
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Changes from baseline in blood pressure (BP)
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Changes from baseline in pulse rate
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Changes from baseline in body temperature
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Change from baseline in body weight
timeFrame: Baseline to Day 29
measure: Expansion cohorts: Change from baseline in Electrocardiogram (ECG)
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Change from baseline in Simpson-Angus Scale (SAS)
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Change from baseline in Abnormal Involuntary Movement Scale (AIMS)
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Change from baseline in Barnes Akathisia Rating Scale
timeFrame: Baseline to Day 36
measure: Expansion cohorts: Change from Baseline in Columbia - Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline to Day 36
Other outcomes:
Locations:
Study officials:
References: