Clinical trial NCT03392779: Study in Chinese Healthy Adults to Evaluate the Safety, Tolerability and Pharmacokinetics on ZSP1601, and the Effect of Food on ZSP1601 Pharmacokinetics
Official title: A Phase 1 Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ZSP1601 and the Effect of Food on ZSP1601 Pharmacokinetics in Chinese Healthy Subjects.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Nonalcoholic Steatohepatitis (NASH)
Lead sponsor: Guangdong Zhongsheng Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2018-01-08
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the safety, tolerability and pharmacokinetics (PK) of escalating single- and multiple-oral doses of ZSP1601 on fasted condition, and characterize PK of ZSP1601 on an empty stomach (fasted condition) and following a high fat, high calorie meal (fed condition) in a 2-period, 2-sequence manner. The study will be conducted in 3 parts (Ascending single dose, multiple dose and food effect). Participants will receive either ZSP1601 or placebo .

Detailed description: The study is a randomized, double-blind phase 1 trial including 3 parts: single ascending dose(SAD) part,multiple ascending dose(MAD) part and postprandial pharmacokinetics part.The primary aims of the study as below:

Evaluating the safety and tolerance of single and multiple dose of ZSP1601 in healthy volunteers.

Evaluating the fasting and postprandial pharmacokinetic parameters of ZSP1601 in healthy volunteers.

Eligible participants will be admitted to the trial center on Day -1. Subjects will be randomly assigned to either experimental groups or placebo groups, according to a randomisation schedule in a (4:1) ratio (8 in per experimental group). Subjects in SAD will receive 25、50、100、175、275、350 mg once daily respectively.Each dose will be administrated after assurance of safety for the former dose. Subjects in MAD will receive 50 or 100 mg once daily for 14days respectively.The treatment in food effect consists of 2 periods,and subjects will receive 100mg on fasting and postprandial states respectively. There will be a 7-day wash out period between treatment periods.To monitor AEs,record abnormalities (12-lead ECG,Vital signs,Physical examination,Clinical Laboratory),and detect the pharmacokinetics of ZSP1601.

Eligibility criteria: Inclusion Criteria:

* Subjects are required to meet the following criteria in order to be included in the trial:

  1. Signature of a dated Informed Consent Form (ICF) indicating that the subject has been informed of all the relevant aspects(including adverse events) of the trial prior to enrollment.
  2. Subjects must be willing and able to adhere to the visit schedule and protocol requirements and be available to complete the study.
  3. Subjects(including partners)have no gestation plans and must use reliable methods of contraception during the study and until 6 months following the last dose of investigational product.
  4. Males and female subjects between 18-50 years (Both inclusive).
  5. Body weight is no less than 50kg in males and no less than 45kg in females.Body mass index (BMI) 18≤BMI≤28 kg/m2; BMI is determined by the following equation: BMI = weight/height2 (kg/m2).
  6. Physical condition:No significant abnormalities in medical history, including cardiovascular system, liver, kidneys, gastrointestinal system, neural system, respiratory system (eg.asthma,asthma induced by exercise,chronic obstructive pulmonary disease), mental, metabolism, etc.
  7. Subjects in general good health or No significant abnormalities in the opinion of the investigator as determined by vital signs and a physical examination.

Exclusion Criteria:

* Eligible subjects must not meet any of the following exclusion criteria:

  1. The average daily smoking are more than 5 cigarettes within 3 months prior to screening.
  2. Known hypersensitivity and/or allergy to some drugs and food.
  3. Known history of drug or alcohol abuse.(defined as consumption of 14 units of alcohol per week:1 unit=285ml of beer; or the equivalent of 25ml of spirit, or 100ml of wine )
  4. Subjects who donated blood or bleeding profusely(\> 400 mL)in the 3 months preceding study screening.
  5. Dysphagia or any medical history in gastrointestinal that interferes with the absorption of drugs.
  6. History or presence of any disease or condition known to increase the risk of bleeding, eg.acute gastritis, duodenal ulcer, etc.
  7. Frequently suffers from postural hypotension.
  8. History of frequent nausea or vomit causes by any etiology.
  9. Concomitant therapy with any drugs with known hepatic enzyme-inducing or inhibiting agents that may change the activity of CYP3A4 prior to screening or during the study.
  10. Use of any prescription or over-the-counter (OTC) medications, vitamins and herbal or dietary supplements within 14 days prior to screening.
  11. History of having any special food(including dragon fruit,mango,grapefruit,etc.),strenuous exercises,or other factors may interfere with the absorption, distribution, metabolism, or excretion of drug within 14 days prior to screening.
  12. Subjects with recent significant change in diet or exercise .
  13. Participated in another clinical research study and received any investigational products within 3 months prior to dosing.
  14. Inability to consume the food provided in the study ( a high fat, high calorie meal includes two eggs for 100g, bacon 20g, a butter toast for 50g, french fries for 115g, whole milk for 240ml).This requirement only applies to subjects under fed condition.
  15. Presence of clinically significant abnormalities in ECG or QTc\>470ms in males,or QTc\>480ms in females.
  16. Pregnancy or breastfeeding at screening and during the study.All female subjects of childbearing potential must have a negative urine pregnancy test at screening and during the trial.
  17. Any clinically significant abnormality upon physical examination or in the clinical laboratory tests. History or presence of a clinically significant gastrointestinal, renal, hepatic, neurologic, hematic, endocrine, neoplastic, pulmonary, immune, psychiatric or cardiovascular and cerebrovascular disorder(s) (but not limited to above disorders).
  18. Presence of human immunodeficiency virus (HIV), viral hepatitis(including hepatitis C virus (HCV) or hepatitis B virus (HBV) ),treponema pallidum antibodies at screening.
  19. Any acute illness or concomitant medication from screening to first dosing.
  20. Have chocolate, any food or beverage that contains caffeine or xanthine within 24 hours prior to dosing.
  21. Take any product contains alcohol within 24 hours prior to dosing.
  22. Positive for urine drug screening or history of substance abuse for a period of 5 consecutive years before screening.

Primary outcomes:
measure: Number and severity of treatment-emergent adverse events (TEAEs) and Serious Adverse Events(SAE) following oral doses(single,multiple and food effect)of ZSP1601 and placebo.
timeFrame: SAD Group: Up to 4 days, MAD: Up to 17days, FE group: Up to 11 days after first dose
measure: Concomitant Medication
timeFrame: UP to 4, 17, 11 days for SAD, MAD, FE part respectively
measure: Clinical Laboratory Abnormalities(Blood routine test, serum biochemical test, conventional coagulation examinations, urine examination ) post dose of ZSP1601 and placebo.
timeFrame: UP to 4, 17, 11 days for SAD, MAD, FE part respectively
measure: 12-lead ECG Abnormalities following oral dosing of ZSP1601 and placebo.
timeFrame: UP to 4, 17, 11 days for SAD, MAD, FE part respectively
measure: Vital signs Abnormalities following oral dosing of ZSP1601 and placebo.
timeFrame: UP to 4, 17, 11 days for SAD, MAD, FE part respectively
measure: Physical examination Abnormalities following oral dossing of ZSP1601 and placebo.
timeFrame: UP to 4, 17, 11 days for SAD, MAD, FE part respectively
measure: Cardiac color ultrasound(UCG) Abnormalities following multiple oral doses of ZSP1601 and placebo.
timeFrame: Screening, Day17
Secondary outcomes:
measure: AUClast（AUC0-t）of ZSP1601
timeFrame: UP to 2, 16, 9 days for SAD, MAD, FE part respectively
measure: AUCinf（AUC0-∞）of ZSP1601
timeFrame: UP to 2, 16, 9 days for SAD, MAD, FE part respectively
measure: Cmax of ZSP1601
timeFrame: UP to 2, 16, 9 days for SAD, MAD, FE part respectively
measure: Tmax of ZSP1601
timeFrame: UP to 2, 16, 9 days for SAD, MAD, FE part respectively
measure: t1/2z of ZSP1601
timeFrame: UP to 2, 16, 9 days for SAD, MAD, FE part respectively
measure: Single-dose PK Parameter: Ae of ZSP1601
timeFrame: Up to Day 2 post-dose
measure: Single-dose PK Parameter: Fe0-t of ZSP1601
timeFrame: Up to Day 2 post-dose
measure: CL/F of ZSP1601
timeFrame: UP to 2, 16, 9 days for SAD, MAD, FE part respectively
measure: λz of ZSP1601
timeFrame: UP to 2, 16, 9 days for SAD, MAD, FE part respectively
measure: CLr of ZSP1601
timeFrame: UP to 2, 16, 9 days for SAD, MAD, FE part respectively
measure: Multiple-dose plasma PK parameter: Rac of ZSP1601 at steady state
timeFrame: Up to 16days
measure: Multiple-dose plasma PK parameter: DF of ZSP1601 at steady state
timeFrame: Up to 16 days
measure: Multiple-dose plasma PK parameter: Cmin of ZSP1601 at steady state
timeFrame: Up to 16days
Other outcomes:
Locations:
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
Study officials:
affiliation: The First Hospital of Jilin University
name: Yanhua Ding, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhu X, Wu M, Wang H, Li H, Lin J, Peng Y, Hu Y, Li C, Ding Y. Safety, tolerability, and pharmacokinetics of the novel pan-phosphodiesterase inhibitor ZSP1601 in healthy subjects: a double-blinded, placebo-controlled first-in-human single-dose and multiple-dose escalation and food effect study. Expert Opin Investig Drugs. 2021 May;30(5):579-589. doi: 10.1080/13543784.2021.1900822. Epub 2021 Mar 25.