Safety, Pharmacokinetics, and Food Effect of PS1 in Subjects

Study Overview
=================
Brief Summary
-----------------
This is a phase I, double-blind, placebo-controlled, randomized, single- and multiple-ascending dose study to evaluate new study intervention, PS1. PS1 is a potential blood glucose control medication, which is developed by Pharmasaga Co. Ltd. planned for treating type II diabetes mellitus (T2DM). This is a first-in-human study to evaluate the safety, tolerability, pharmacokinetics (PK), food effect and potential efficacy of PS1 in subjects.

Detailed Description
-----------------
This first-in-human Phase I study consists of a single ascending-dose (SAD) portion, a food effect (FE) portion, and a multiple ascending-dose (MAD) portion, aiming to evaluate the safety, tolerability, pharmacokinetics, food effect and potential efficacy of PS1 in healthy subjects. A randomized, double-blinded, placebo-controlled study design will be applied for the SAD portion with three SAD dose cohorts-25 mg (Cohort 1), 50 mg (Cohort 2), and 75 mg (Cohort 3). An eligible subject in this portion will receive a single dose of PS1 or Placebo tablets in a fed condition on Day 1 and be followed for 7 days. In FE portion, only one cohort (Cohort 4) is assigned. The FE cohort (Cohort 4) will use the same study design as the SAD cohorts. An eligible subject in this portion will receive a single dose of 50 mg PS1 or Placebo tablets in a fasted condition on Day 1 and be followed for 7 days. Four cohorts are assigned in the MAD portion: 25 mg/day (Cohort 5 & 7) and 50 mg/day (Cohort 6 & 8) in healthy volunteers and participants respectively. Only the dose level of MAD lower than the maximum tolerated dose (MTD) of SAD portion can be activated (If 50 mg was determined as the MTD of SAD, only cohort 5 & 7 could be activated). An eligible subject will receive PS1 or Placebo tablets once daily in a fed condition for 14 days & 28 days in healthy volunteers and participants respectively and be followed for additional 7 days.

Official Title
-----------------
A Phase I, Double-Blind, Placebo-Controlled, Randomized, Single- and Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Food Effect and Potential Efficacy of PS1 in Subjects

Conditions
-----------------
Type II Diabetes

Intervention / Treatment
-----------------
* Drug: PS1
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Both genders aged 18 to 80 years, inclusive at screening Overtly healthy subject, who is considered to be generally healthy based on medical history, vital signs, laboratory tests, 12-lead EKG, and physical examination, as judged by the investigator With HbA1c value of < 6.5% at Screening Fasting plasma glucose < 110 mg/dL at Screening Body mass index (BMI) between 18.5 and 28.0 kg/m2 Negative test for hepatitis B surface antigen (HBsAg), Anti-HCV antibody, or human immunodeficiency virus (HIV) at screening Is willing to comply with the trial restrictions Able to understand and sign the informed consent form Exclusion Criteria: History of diabetes mellitus Under the systemic treatment of any prescription medication or over-the-counter (OTC) medication within 7 days before Screening Received any vaccination within 14 days before Screening Known hypersensitivity to any of the components of PS1 tablet History of clinically significant hematological, renal, endocrine, pulmonary, respiratory, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, musculoskeletal, immune, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing) within 3 months of Screening that may significantly alter the biomarker panel, require receiving any systemic medications, or interfere with the interpretation of data, as judged by the investigator History of cancer (malignancy) or have ever received any anti-cancer therapy Regular smoker Consumed greater than 3 glasses of alcoholic beverages per day for the past 4 weeks before Screening Received any investigational therapy from another clinical study, performed any major surgeries, or took glucose-lowering medications within the last 12 weeks prior to Screening Received any systemic steroids (inhaled and intranasal steroids are permitted) or other immunosuppressive medications within 4 weeks prior to Screening Have ever received cell therapy or organ transplantation Other conditions not suitable for participating in this study as judged by the investigator Any conditions that forbid the completion of study procedures due to the local regulatory restrictions Female subject of childbearing potential who: Is lactating; or Has a positive pregnancy test result from signing informed consent to the end of the study; or Refuses to adopt at least one form of birth control (refer to Section 5.3) from signing informed consent to the end of the study. Male subject with a female spouse/partner who is of childbearing potential refuses to adopt at least one form of birth control (refer to Section 5.3) from signing informed consent to the end of the study.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD portion - Cohort 1 (25mg)<br>An eligible subject will receive a single dose of 25 mg of PS1 or Placebo tablets in a fed condition on Day 1 and be followed for 7 days. | Drug: PS1<br>* PS1 will be provided as a 120 mg tablet with 25 mg active pharmaceutical ingredient<br>* Other names: PS-001;Drug: Placebo<br>* Placebo<br>|
| Experimental: SAD portion - Cohort 2 (50mg)<br>An eligible subject will receive a single dose of 50 mg of PS1 or Placebo tablets in a fed condition on Day 1 and be followed for 7 days. | Drug: PS1<br>* PS1 will be provided as a 120 mg tablet with 25 mg active pharmaceutical ingredient<br>* Other names: PS-001;Drug: Placebo<br>* Placebo<br>|
| Experimental: SAD portion - Cohort 3 (75mg)<br>An eligible subject will receive a single dose of 75 mg of PS1 or Placebo tablets in a fed condition on Day 1 and be followed for 7 days. | Drug: PS1<br>* PS1 will be provided as a 120 mg tablet with 25 mg active pharmaceutical ingredient<br>* Other names: PS-001;Drug: Placebo<br>* Placebo<br>|
| Experimental: FE portion - Cohort 4 (50mg)<br>An eligible subject will receive a single dose of 50 mg PS1 or Placebo tablets in a fasted condition on Day 1 and be followed for 7 days. | Drug: PS1<br>* PS1 will be provided as a 120 mg tablet with 25 mg active pharmaceutical ingredient<br>* Other names: PS-001;Drug: Placebo<br>* Placebo<br>|
| Experimental: MAD portion - Cohort 5 (25mg)<br>An eligible subject will receive 25 mg PS1 or Placebo tablets once daily in a fed condition for 14 days and be followed for additional 7 days. | Drug: PS1<br>* PS1 will be provided as a 120 mg tablet with 25 mg active pharmaceutical ingredient<br>* Other names: PS-001;Drug: Placebo<br>* Placebo<br>|
| Experimental: MAD portion - Cohort 6 (50mg)<br>An eligible subject will receive 50 mg PS1 or Placebo tablets once daily in a fed condition for 14 days and be followed for additional 7 days. | Drug: PS1<br>* PS1 will be provided as a 120 mg tablet with 25 mg active pharmaceutical ingredient<br>* Other names: PS-001;Drug: Placebo<br>* Placebo<br>|
| Experimental: MAD portion - Cohort 7 (25mg)<br>An eligible subject will receive 25 mg PS1 or Placebo tablets once daily in a fed condition for 28 days and be followed for additional 7 days. | Drug: PS1<br>* PS1 will be provided as a 120 mg tablet with 25 mg active pharmaceutical ingredient<br>* Other names: PS-001;Drug: Placebo<br>* Placebo<br>|
| Experimental: MAD portion - Cohort 8 (50mg)<br>An eligible subject will receive 25 mg PS1 or Placebo tablets once daily in a fed condition for 28 days and be followed for additional 7 days. | Drug: PS1<br>* PS1 will be provided as a 120 mg tablet with 25 mg active pharmaceutical ingredient<br>* Other names: PS-001;Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicity (DLT) during the DLT observation period | DLT is defined as: (1) any adverse event (AE) ≥ Grade 3 (CTCAE v5.0) or (2) Grade 2 AE that does not resolve to grade 1 or less within 72 hours, that occurs in the DLT observation period and is causally related (possibly, probably, or definitely related) to the test article judged by the investigator. | Day 1  Day 8 (SAD cohort); Day 1  Day 36 (MAD cohort) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) and serious adverse events (SAEs) | All adverse events (AEs) will be assessed for severity by the investigator based on NCI-CTCAE v5.0 | SAD, FE: up to 4 weeks; MAD: up to 8 weeks | 
| Number of participants with abnormalities in Vital signs | Number of participants with abnormal systolic/diastolic blood pressure (in mmHg), respiratory rate, pulse rate (in beat per minute, bpm), and body temperature (in ℃) | SAD, FE: Baseline,1 2 weeks; MAD: Baseline,1 6 weeks | 
| Number of participants with abnormalities in Laboratory examinations | Number of participants with abnormal Hematology (hemoglobin, hematocrit, RBC, platelet, WBC, WBC differentials (neutrophils, eosinophils, basophils, lymphocytes, monocytes), MCV, MCH, MCHC), biochemistry (HbA1c, fasting plasma glucose, albumin, alkaline phosphatase, ALT, AST, BUN, creatinine, cholestero1, γ-GT, total protein, total bilirubin, direct bilirubin, triglyceride, amylase, lipase, calcium, sodium, potassium, chloride), and urinalysis (pH, protein, glucose, bilirubin, urobilinogen, ketone body, specific gravity, occult blood, RBC, WBC, creatinine, ratio of albumin/creatinine) results | SAD, FE: Baseline,1 2 weeks; MAD: Baseline,1 6 weeks | 
| Acute kidney injury (AKI) marker - NGAL | Urine samples will be collected for analyzing acute kidney injury (AKI) markers | SAD, FE: Baseline, 1 2 weeks; MAD: Baseline, 1 6 weeks | 
| Acute kidney injury (AKI) marker - KIM-1 | Urine samples will be collected for analyzing acute kidney injury (AKI) markers | SAD, FE: Baseline, 1 2 weeks; MAD: Baseline, 1 6 weeks | 
| Number of participants with abnormalities in 12-lead electrocardiogram (EKG) | Number of participants with abnormal Ventricular rate, PR interval, QRS interval, and QT interval | SAD, FE: Baseline, 1 2 weeks; MAD: Baseline, 1 6 weeks | 
| Number of participants with abnormalities in Physical examination | Number of participants with abnormal Physical examination results, including general appearance, skin, eyes, ears, nose, throat, head and neck (including thyroid), heart, chest and lungs, abdomen, extremities, lymph nodes, musculoskeletal, neurological system, and other body systems | SAD, FE: Baseline, 1 2 weeks; MAD: Baseline, 1 6 weeks | 
| Pharmacokinetics of PS1 - AUC | Area under the serum concentration-time profile | Day 1 and 2 (SAD, FE and MAD portion), Day 28 and 29 (MAD portion only) | 
| Pharmacokinetics of PS1 - Cmax | The peak post-dose concentration | Day 1 and 2 (SAD, FE and MAD portion), Day 28 and 29 (MAD portion only) | 
| Pharmacokinetics of PS1 - Tmax | Time at which Cmax is observed | Day 1 and 2 (SAD, FE and MAD portion), Day 28 and 29 (MAD portion only) | 
| Pharmacokinetics of PS1 - T1/2 | Terminal phase elimination half-life | Day 1 and 2 (SAD, FE and MAD portion), Day 28 and 29 (MAD portion only) | 
| Pharmacokinetics of PS1 - MRT | Mean Residence Time | Day 1 and 2 (SAD and FE portion only) | 
| Pharmacokinetics of PS1 - CL/F | Apparent Clearance | Day 1 and 2 (SAD and FE portion only) |