Type II Diabetes
Conditions
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 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.
Interventions
DRUGPS1
PS1 will be provided as a 120 mg tablet with 25 mg active pharmaceutical ingredient.
DRUGPlacebo
Placebo will be provided as a 120 mg tablet.
Sponsors
Pharmasaga Co. Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
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).
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
A subject is eligible for the study if all of the following apply: 1. Both genders aged 18 to 80 years, inclusive at screening 2. Body mass index (BMI) between 18.5 and 40.0 kg/m2 3. 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. 4. Is willing to follow the trial life style instruction and protocol procedure 5. Able to understand and sign the informed consent form Inclusion criteria applied for healthy subjects (Cohorts 1\~4) 6. 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 7. With HbA1c value of \< 6.5% and fasting plasma glucose \< 110 mg/dL at Screening 8. With estimated glomerular filtration rate (eGFR) \> 80 ml/min/1.73m2 Inclusion criteria applied for T2DM patients (Cohorts A, B, 7, and 8) 9. Diagnosis of T2DM 10. T2DM treated with diet and exercise alone currently, for at least 2 weeks prior to Screening 11. With HbA1c level between 5.7% to 9.0% or fasting plasma glucose level between 100 mg/dL to 250 mg/dL at Screening 12. With estimated glomerular filtration rate (eGFR) \> 60 ml/min /1.73m2 13. 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.
Exclusion criteria
Any subject meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicity (DLT) during the DLT observation period and the maximum tolerated dose (MTD) of PS1 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | All adverse events (AEs) will be assessed for severity by the investigator based on NCI-CTCAE v5.0 |
| 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 | Vital signs (Systolic Blood Pressure \& Diastolic Blood Pressure)(Unit: mmHg) |
| 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 | Number of participants with abnormal laboratory - Hematology physiological parameter tests results (Hemoglobin and mean corpuscular hemoglobin concentration, MCHC) (Unit: g/dL) |
| 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 | Urine samples will be collected for analyzing acute kidney injury (AKI) markers, NGAL. |
| 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 | PR interval, QRS interval, and QT interval will be recorded. \[Unit: msec\] |
| 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 | Number of participants with abnormal Physical examination findings, 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 |
| 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) | AUC\_Area under the serum concentration-time profile |
| Potential efficacy (For Cohort 7 and 8 only) | MAD in T2DM subjects: Approximately 7 weeks | Changes from baseline of fasting plasma glucose (FPG) at each post-treatment visit; Changes from baseline of C-peptide at each post-treatment visit; Changes from baseline of hemoglobin A1c (HbA1c) at Visit 10 and Visit 11. |
| 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 | Postprandial plasma glucose (PPG) data. |
| 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 | Postprandial serum insulin (PSI) data. |
| 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 | Fasting serum insulin (FSI) data. |
| 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 | Urine samples will be collected for analyzing acute kidney injury (AKI) markers, KIM-1. |
| 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 | Number of participants with abnormal laboratory - Biochemistry physiological parameter tests results |
| 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 | Number of participants with abnormal laboratory - Urinalysis physiological parameter tests results |
| 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 | Vital signs (Pulse rate) (Unit: beats/min) |
| 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 | Vital signs (Respiratory Rate) (Unit: breaths/min) |
| 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 | Vital signs (Temperature) (Unit: Celsius) |
| 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 | Number of participants with abnormal laboratory - Hematology physiological parameter tests results (hematocrit and WBC differentials (neutrophils, eosinophils, basophils, lymphocytes, monocytes)) (Unit: %) |
| 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 | Number of participants with abnormal laboratory - Hematology physiological parameter tests results (RBC) (Unit: 10\^6/uL) |
| 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 | Number of participants with abnormal laboratory - Hematology physiological parameter tests results (platelet and WBC) (Unit: 10\^3/uL) |
| 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 | Number of participants with abnormal laboratory - Hematology physiological parameter tests results (mean corpuscular volume, MCV) (Unit: fL) |
| 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 | Number of participants with abnormal laboratory - Hematology physiological parameter tests results (mean corpuscular hemoglobin, MCH) (Unit: pg) |
| 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 | Ventricular rate will be recorded. \[Unit: beats/min\] |
Countries
Taiwan
Contacts
PRINCIPAL_INVESTIGATORMingche Liu, MD., PhD
Taipei Medical University Hospital
Outcome results
None listed