A Clinical Study to Access the Pharmacokinetics of HMS5552 in Renal Impaired Subjects and Healthy Volunteers

Study Overview
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Brief Summary
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The objectives of this study is to access the pharmacokinetics and safety of HMS5552 in single dose in renal impaired subjects and matched healthy adult subjects.

Detailed Description
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This is an open-label and paralleled study with single oral dose of HMS5552 given to renal impaired subjects and body index matched healthy volunteers. The primary objective is to access the pharmacokinetic profiles of HMS5552 in 25 mg dose in renal impaired subjects and (gender, age and BMI) matched healthy adult subjects. The secondary objective is to characterize the safety profiles of HMS5552 in single dose in renal impaired subjects. The subjects include ESRD subjects without dialysis (P1 group), severe (P2 group), moderate (P3 group), mild (P4 group), and healthy subjects (H Group) matched with renal impairment subjects in gender, age and BMI. The number of subjects in each group was 6-8. The study is divided into two parts: Part 1: ESRD subjects without dialysis and matched healthy subjects (P1 and H groups; n = 8 for each group); Part 2: subjects with severe, moderate and mild renal impairment (P2, P3 and P4 groups; n = 6-8 in each group). The study initiates from Part 1. The data will be evaluated at the end of Part 1 as the medium term. Compared with the matched healthy subjects, if the mean AUC of HMS5552 (either AUClast or AUCinf) increased by ≥ 100% in ESRD subjects without dialysis, which means Part 2 will need to be conducted. The process of Part 2 is the same as that of Part 1

Official Title
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An Open-Label, Paralleled Study of the Pharmacokinetics of HMS5552 Following a Single Oral Dose in Renal Impaired Subjects and Matched Healthy Volunteers

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: HMS5552


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For renal impaired subjects: Male and female subjects between ages of 18 and 65 years, no less than 3 subjects in each gender. Body weight≥50kg for male and ≥45kg for female； BMI: 18.5 30 kg/m2 eGFR: P1 < 15 mL/min/1.73 m2；P2: 15～29 mL/min/1.73 m2；P3: eGFR 30～59 mL/min/1.73 m2；P4: 60～89 mL/min/1.73 m2，and ACR≥ 3 mg/mmol； Normal physical conditions, vital signs,12 lead ECG and laboratory recording, blood potassium 3.5 5.5mmol/L; Left ventricular ejection fraction (LVEF) ≥50% Willing to sign the informed consent form (ICF) and take reliable contraceptive measures within 6 months after taking the last dose of study drug; Willing to adhere to the protocol requirement. For healthy volunteers: Male and female subjects between ages of 18 and 65 years, no less than 3 subjects in each gender. Body weight≥50kg for male and ≥45kg for female； BMI: 18.5 30 kg/m2 MDRD eGFR: ≥90 mL/min/1.73 m2； Gender, age (±5 years) and BMI (±15%) matched with corresponding subject in P1 group Normal physical conditions, vital signs,12 lead ECG and laboratory recording Systolic pressure: 90～140 mmHg，diastolic pressure:50～90 mmHg； Willing to sign the informed consent form (ICF) and take reliable contraceptive measures within 6 months after taking the last dose of study drug; Willing to adhere to the protocol requirement. Exclusion Criteria: Subjects with impaired renal function cannot be enrolled if they meet one of the following criteria: Acute renal failure; History of allergy; In addition to renal impaired function, investigators adjudicate subjects have diseases that may affect drug absorption, distribution, metabolism or excretion; Any other disease may receive treatment or surgery during the study Abnormal of ECG performance or laboratory recording; Family history of QT prolongation syndrome; Have unstable cardiovascular disease, lung disease, gastrointestinal disease, liver disease, blood disease, mental disease, nervous system disease, immune deficiency disease or any malignant tumor; History of cardiovascular and cerebrovascular disease; Hear failure (NYHA) class III or IV; Severe anemia, CHC<6.0g/dl at screening; Severe infection, trauma, gastrointestinal operation or other surgery within 4 weeks before screening; History of a) Type 1 diabetes, b) Acute complications of diabetes; Serious hypoglycemia events within 3 months before screening; More than 5 cigarettes per day within 3 months before screening; Alcohol addicts; History of drug abuse; Healthy subjects cannot be enrolled if they meet one of the following criteria: History of allergy; Investigators adjudicate subjects have diseases that may affect drug absorption, distribution, metabolism or excretion; Any other disease may receive treatment or surgery during the study Abnormal of ECG performance or laboratory recording; Family history of QT prolongation syndrome; Have unstable cardiovascular disease, lung disease, gastrointestinal disease, liver disease, blood disease, mental disease, nervous system disease, immune deficiency disease or any malignant tumor; history of cardiovascular and cerebrovascular disease within 6 months before screening; severe infection, trauma, gastrointestinal operation or other surgery within 4 weeks before screening; Anemia caused by any reason; History of hypoglycemia (<3.9mmol/L); More than 5 cigarettes per day within 3 months before screening; Alcohol addicts; History of drug abuse;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Undialyzed ESRD subjects (P1)<br>Part 1: Undialyzed end stage renal disease (ESRD) patients to receive a single dose of HMS5552 ( 25mg ) tablets orally . | Drug: HMS5552<br>* single dose of HMS5552 25mg<br>|
| Experimental: Healthy volunteers (H)<br>Part 1: Matched healthy volunteers to receive a single dose of HMS5552 ( 25mg ) tablets orally Matching principle: H group and P1 group: 1:1 . The matched subjects should be in the same gender, age difference ±5 years, BMI difference ±15% | Drug: HMS5552<br>* single dose of HMS5552 25mg<br>|
| Experimental: Severe renal impaired subjects (P2)<br>Part 2：Severe renal impaired subjects to receive a single dose of HMS5552 ( 25mg ) tablets orally Matching principle: P2 group and H group: 1:1 . The matched subjects should be in the same gender, age difference ±5 years, BMI difference ±15% | Drug: HMS5552<br>* single dose of HMS5552 25mg<br>|
| Experimental: Moderate renal impaired subjects (P3)<br>Part 2：Moderate renal impaired subjects to receive a single dose of HMS5552 ( 25mg ) tablets orally Matching principle: P3 group and H group: 1:1 . The matched subjects should be in the same gender, age difference ±5 years, BMI difference ±15% | Drug: HMS5552<br>* single dose of HMS5552 25mg<br>|
| Experimental: Mild renal impaired subjects (P4)<br>Part 2：Mild renal impaired subjects to receive a single dose of HMS5552 ( 25mg ) tablets orally Matching principle: P4 group and H group: 1:1 . The matched subjects should be in the same gender, age difference ±5 years, BMI difference ±15% | Drug: HMS5552<br>* single dose of HMS5552 25mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of Cmax | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of AUClast | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of AUCinf | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. | Up to 72 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of Cmax,u (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of AUClast,u (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of AUCinf,u (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of Tmax (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of T1/2 (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of CL/F (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of Vz/F (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of fu (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of Ae (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose | 
| The single dose pharmacokinetics of HMS5552 will be described by estimating parameters of CLr (if applicable) | Plasma will be collected at predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hour post-dose. Urine will be collected at predose, 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 hour post-dose. | Up to 72 hours post-dose |