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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 75
- 试验地点
- 2
- 主要终点
- Incidence of dose-limiting toxicity (DLT) during the DLT observation period
研究概览
简要总结
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.
详细描述
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 for healthy subjects with three SAD dose cohorts-25 mg (Cohort 1), 50 mg (Cohort 2), and 75 mg (Cohort 3). An eligible subject will receive a single dose of PS1 or Placebo tablets (8 subjects in each cohort, 6 PS1 + 2 Placebo) 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 (randomized, double-blinded, placebo-controlled, 6 PS1 + 2 Placebo) as the SAD cohorts. 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.
SAD portion for T2DM patients: An open-labeled study design will be applied for the SAD portion for T2DM patients with two SAD dose cohorts-25 mg (Cohort A) and 50 mg (Cohort B). An eligible T2DM patients will receive a single dose of PS1 tablets (6 subjects in each cohort) in a fed condition on Day 1 and be followed for 14 days. Subjects in this portion will have safety and PK observation but will not be evaluated for DLT.
MAD portion for T2DM patients: After confirming the safety and pharmacokinetics of all SAD cohorts (Cohorts 1, 2, 3, A, and B) and the FE cohort (Cohort 4) by iSMC and approved by the authority, a randomized, double-blinded, placebo-controlled study design will be applied for the MAD portion for T2DM patients with two MAD dose cohorts-25 mg/day (Cohort 7) and 50 mg/day (Cohort 8). An eligible subject will receive PS1 or Placebo (8 subjects in each cohort, in a 6:2 ratio of PS1: Placebo) tablets once daily in a fed condition. The treatment period is 28±1 days. All subjects will be followed for additional 7 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •A subject is eligible for the study if all of the following apply:
- •Both genders aged 18 to 80 years, inclusive at screening
- •Body mass index (BMI) between 18.5 and 40.0 kg/m2
- •Negative test for hepatitis B surface antigen (HBsAg), Anti-HCV antibody, and human immunodeficiency virus (HIV) at screening. Subjects with positive anti-HCV may be enrolled only if they have a negative HCV RNA result during the screening period.
- •Is willing to follow the trial life style instruction and protocol procedure
- •Able to understand and sign the informed consent form
- •Inclusion criteria applied for healthy subjects (Cohorts 1~4)
- •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% and fasting plasma glucose < 110 mg/dL at Screening
- •With estimated glomerular filtration rate (eGFR) > 80 ml/min/1.73m2
- •Inclusion criteria applied for T2DM patients (Cohorts A, B, 7, and 8)
- •Diagnosis of T2DM
- •T2DM treated with diet and exercise alone currently, for at least 2 weeks prior to Screening
- •With HbA1c level between 5.7% to 9.0% or fasting plasma glucose level between 100 mg/dL to 250 mg/dL at Screening
- •With estimated glomerular filtration rate (eGFR) > 60 ml/min /1.73m2
- •Patients taking medications for T2DM comorbidities, i.e., hypertriglyceridemia, hyperlipidemia, and hypertension, should be on a stable dose of their medication for at least 3 months prior to Screening. Any other chronic medications should be on a stable dose for at least 4 weeks prior to Screening.
排除标准
- •Any subject meeting any of the following exclusion criteria will be excluded from study participation.
- •History of Type I diabetes mellitus
- •Under the systemic treatment of any prescription medication or over-the-counter (OTC) medication that may interfere with the safety or PK assessment judged by the investigator within 7 days before Screening
- •Received strong CYP enzyme inhibitor or inducer within 14 days before Screening
- •Received any vaccination within 14 days before Screening
- •Has required insulin therapy within the past 12 weeks
- •Known hypersensitivity to any of the components of PS1 tablet
- •History of major clinically significant hematological, renal, 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-other than T2DM and its comorbidities (i.e., hypertriglyceridemia, hyperlipidemia, and hypertension)
- •History of pancreatitis
- •Serum amylase > 1.5 × Upper Limit of Normal (ULN) or lipase > 1.5 × ULN
- •Clinically significant ECG abnormality at Screening
- •History of cancer (malignancy) or have ever received any anti-cancer therapy
- •Regular smoker Regular smoker is defined as who smokes every day (≥ 1 cigarette/day in average in the past 8 weeks of Screening)
- •Consumed greater than 3 units of alcoholic beverages per day in average for the past 4 weeks before Screening One unit is equivalent to one can of beer (<10% alcohol; about 330 mL), one glass of wine (10~20% alcohol; about 150 mL), or one shot of distilled spirits (>20% alcohol; about 45 mL)
- •Received any investigational therapy from another clinical study or underwent any major surgeries within the last 12 weeks prior to Screening
- •Took glucose-lowering medications within the last 2 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 at Screening; or
- •Refuses abstinence or to adopt at least two forms of highly effective contraception from signing informed consent to the end of the study.
- •Male subject with a female spouse/partner who is of childbearing potential refuses abstinence or to adopt at least two forms of highly effective contraception from signing informed consent to the end of the study.
- •Exclusion criteria applied for healthy subjects (Cohorts 1~4):
- •History of type II diabetes mellitus
- •Exclusion criteria applied for T2DM patients (Cohorts 7 and 8):
- •Triglyceride >300 mg/dL (fasting lipid profile) or cholesterol > 1.5 × ULN (fasting lipid profile)
- •Received beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNI; e.g., Entresto (sacubitril/valsartan)), or renin inhibitors (e.g., Rasilez (aliskiren)) medications within 3 months prior to Screening
研究组 & 干预措施
SAD portion - Cohort 2 (50mg)
An eligible healthy 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.
干预措施: Placebo (Drug)
SAD portion - Cohort 1 (25mg)
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.
干预措施: PS1 (Drug)
SAD portion - Cohort 2 (50mg)
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.
干预措施: PS1 (Drug)
SAD portion - Cohort 1 (25mg)
An eligible healthy subject will receive a single dose of 25 mg of PS1 or Placebo tablet in a fed condition on Day 1 and be followed for 7 days.
干预措施: Placebo (Drug)
SAD portion - Cohort 3 (75mg)
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.
干预措施: PS1 (Drug)
FE portion - Cohort 4 (50mg)
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.
干预措施: PS1 (Drug)
MAD portion - Cohort 5 (25mg)
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.
干预措施: PS1 (Drug)
MAD portion - Cohort 6 (50mg)
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.
干预措施: PS1 (Drug)
MAD portion - Cohort 7 (25mg)
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.
干预措施: PS1 (Drug)
MAD portion - Cohort 8 (50mg)
An eligible subject will receive 50 mg PS1 or Placebo tablets once daily in a fed condition for 28 days and be followed for additional 7 days.
干预措施: PS1 (Drug)
SAD portion - Cohort 3 (75mg)
An eligible healthy 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.
干预措施: Placebo (Drug)
FE portion - Cohort 4 (50mg)
An eligible healthy 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.
干预措施: Placebo (Drug)
MAD portion - Cohort 7 (25mg)
An eligible subject will receive 25 mg PS1 or Placebo tablet once daily in a fed condition for 28±1 days and be followed for additional 7 days.
干预措施: Placebo (Drug)
MAD portion - Cohort 8 (50mg)
An eligible subject will receive 50 mg PS1 or Placebo tablets once daily in a fed condition for 28±1 days and be followed for additional 7 days.
干预措施: Placebo (Drug)
结局指标
主要结局
Incidence of dose-limiting toxicity (DLT) during the DLT observation period
时间窗: Day 1~ Day 8 (SAD cohort); Day 1~ Day 35 (MAD cohort)
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.
Incidence of dose-limiting toxicity (DLT) during the DLT observation period and the maximum tolerated dose (MTD) of PS1
时间窗: DLT observation period: from Day 1 to EOS - For SAD and FE cohorts in healthy subjects: from Day 1 to Day 8±1 - For MAD cohorts in T2DM patients: from Day 1 to Day 35±1
Dose escalation will be terminated based on the following criteria: \- Among the six subjects who received PS1 in a cohort, more than one subject experienced DLT(s). MTD will basically be declared as the highest dose level at which ≤1/6 of PS1-treated subjects in a cohort experienced DLT(s). 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 3 days\* \* Note: For Cohorts 7 and 8, AEs requiring specific definitions will be referenced under the heading 'For MAD cohorts (Cohorts 7 and 8)' below, while the remaining AEs will be followed the standard procedures outlined herein. that occurs in the DLT observation period and is causally related (possibly, probably, or definitely related) to the test article judged by the investigator.
次要结局
- Incidence of adverse events (AEs) and serious adverse events (SAEs)(SAD, FE: up to 4 weeks; MAD: up to 8 weeks)
- Number of participants with abnormalities in Vital signs(SAD, FE: Baseline,1~2 weeks; MAD: Baseline,1~6 weeks)
- Acute kidney injury (AKI) marker(SAD, FE: Baseline, 1~2 weeks; MAD: Baseline, 1~6 weeks)
- Number of participants with abnormalities in Physical examination(SAD, FE: Baseline, 1~2 weeks; MAD: Baseline, 1~6 weeks)
- Number of participants with abnormalities in 12-lead electrocardiogram (EKG)(SAD, FE: Baseline, 1~2 weeks; MAD: Baseline, 1~6 weeks)
- Exploratory Endpoints (For MAD only)(MAD: Baseline, 1~6 weeks)
- Potential efficacy (For Cohort 7 and 8 only)(MAD: Baseline, 1~6 weeks)
- Number of participants with abnormalities in Laboratory examinations(SAD, FE: Baseline,1~2 weeks; MAD: Baseline,1~6 weeks)
- Pharmacokinetics (PK) of PS1(Day 1 and 2 (SAD, FE and MAD portion), Day 28 and 29 (MAD portion only))
- Incidence of adverse events (AEs) and serious adverse events (SAEs)(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in vital signs (Systolic Blood Pressure & Diastolic Blood Pressure) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in Laboratory examinations - Hematology (Hemoglobin and mean corpuscular hemoglobin concentration, MCHC) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in acute kidney injury (AKI)-NGAL markers at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in 12-lead electrocardiogram (EKG) (PR interval, QRS interval, and QT interval) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Abnormalities in Physical examination(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Pharmacokinetics (PK) of PS1(Day 1 and 2 (SAD, FE in healthy volunteers and SAD in T2DM subjects and MAD portion in T2DM subjects ), Day 28 and 29 (MAD portion only))
- Potential efficacy (For Cohort 7 and 8 only)(MAD in T2DM subjects: Approximately 7 weeks)
- Changes from baseline of postprandial plasma glucose (PPG), at each post-treatment visit in T2DM patients(SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes from baseline of postprandial serum insulin (PSI) at each post-treatment visit in T2DM patients(SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes from baseline of fasting serum insulin (FSI) at each post-treatment visit in T2DM patients(SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in acute kidney injury (AKI)-KIM-1 markers at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in Laboratory examinations - Biochemistry at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in Laboratory examinations - Urinalysis at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in vital signs (Pulse rate) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in vital signs (Respiratory Rate) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in vital signs (Temperature) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in Laboratory examinations - Hematology (hematocrit and WBC differentials (neutrophils, eosinophils, basophils, lymphocytes, monocytes)) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in Laboratory examinations - Hematology (RBC) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in Laboratory examinations - Hematology (platelet and WBC) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in Laboratory examinations - Hematology (mean corpuscular volume, MCV) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in Laboratory examinations - Hematology (mean corpuscular hemoglobin, MCH) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)
- Changes in 12-lead electrocardiogram (EKG) (Ventricular rate) at each post-treatment measurement from baseline(SAD, FE in healthy volunteers: Approximately 3 weeks; SAD in T2DM subjects: Approximately 4 weeks; MAD in T2DM subjects: Approximately 7 weeks)