Diabetes Mellitus, Type 2
Conditions
Keywords
GKA,T2DM,HMS5552
Brief summary
This study evaluates the safety, tolerability, efficacy and population PK of HMS5552 in type 2 diabetic adult subjects,there will be 5 groups ,4 groups will receive HMS5552,while 1 will receive placebo.
Detailed description
Glucokinase (GK, also called hexokinase IV or D) can phosphosphorylate glucose to glucose-6-phosphate (G-6-P) in pancreatic β-cells and liver cells, which represents the first step of glucose metabolism. GK also acts as a glucose sensor and exerts a key role in maintaining glucose homeostasis. HMS5552 is a 4th-generation GK agonist or activator (GKA), which was originally licensed from Roche and subsequently developed by Hua Medicine. HMS5552 has been shown to activate GK in pancreatic beta cells, liver and intestinal epithelial cells. It regulates systemic blood glucose through a variety of mechanisms including directly enhancing insulin release (pancreas), inhibiting production of endogenous glucose (liver) and by indirectly promoting GLP-1 release (enteroendocrine L-cells).
Interventions
DRUGHMS5552
75mgQD
OTHERPlacebo
QD/BID
Sponsors
Tigermed Consulting Co., Ltd
Hua Medicine Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Male & female, 40\ 75 years old 2. T2DM patients，anti-hyperglycemic drug-naïve and on diet & exercise for at least 3 months, or with glucose controlled by Metformin or α-glucosidase inhibitor alone 3. HbA1c 7.5\ 10.5% at screening and pre-randomization 4. Fasting plasma glucose (FPG)7.0\ 11.1 millimole/liter (mmol/L, local lab) at screening, and 7.0\ 13.3 millimole/liter (mmol/L, central lab) at pre-randomization 5. BMI: 19\ 30kg/m\^2 & TG\<5.5mmol/L
Exclusion criteria
1. T1D，secondary DM, pre-DM 2. kidney diseases or eGFR MDRD\<60ml/min/1.73m\^2 3. unstable CVDs 4. liver diseases 5. mental or CNS diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| After 12-week Treatment, the Change From Baseline in HbA1c | Baseline and 12 weeks | Assess the percentage of Hemoglobin A1c (HbA1c) changes at week 12. In the group HMS5552 dose3, a subject without follow-up data for HbA1c available was excluded. And in the group HMS5552 dose4, two subjects without follow-up data for HbA1c available were excluded. So the overall number of baseline participants is not consistent with numbers provided in any of the rows in the participant flow module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2hPPG | Baseline and 12 weeks | Using a standard meal tolerance test, to assess 2-h postprandial glucose (2hPPG). In this test, subjects were received meals standardised by China National Cereals, which supplied by Oils and Foodstuffs Corporation and contained 353 kcal, 75 g carbohydrate, 1.48 g fat, and 8.0 g protein. Collect the blood samples to detect blood glucose 2 hours after starting the meal. |
| Change From Baseline in FPG | Baseline and 12 weeks | — |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HMS5552 Dose 1 HMS5552: 75mgQD | 53 |
| HMS5552 Dose 2 HMS5552: 100mgQD | 50 |
| HMS5552 Dose 3 HMS5552: 50mgBID | 50 |
| HMS5552 Dose 4 HMS5552: 75mgBID | 49 |
| Placebo Placebo: BID/QD | 53 |
| Total | 255 |
Baseline characteristics
| Characteristic | Total | Placebo | HMS5552 Dose 4 | HMS5552 Dose 3 | HMS5552 Dose 2 | HMS5552 Dose 1 |
|---|---|---|---|---|---|---|
| 2h PPG | 17.509 mmol/L STANDARD_DEVIATION 3.3052 | 16.950 mmol/L STANDARD_DEVIATION 3.7282 | 17.884 mmol/L STANDARD_DEVIATION 3.1303 | 17.243 mmol/L STANDARD_DEVIATION 3.0943 | 17.429 mmol/L STANDARD_DEVIATION 3.2023 | 18.042 mmol/L STANDARD_DEVIATION 3.3004 |
| Age, Continuous | 55.88 years STANDARD_DEVIATION 8.271 | 54.73 years STANDARD_DEVIATION 8.499 | 55.42 years STANDARD_DEVIATION 7.659 | 54.92 years STANDARD_DEVIATION 8.137 | 56.7 years STANDARD_DEVIATION 7.67 | 57.58 years STANDARD_DEVIATION 9.159 |
| Body Mass Index (BMI) units: kg/m^2 | 25.321 kg/m^2 STANDARD_DEVIATION 2.5419 | 25.188 kg/m^2 STANDARD_DEVIATION 2.6113 | 25.321 kg/m^2 STANDARD_DEVIATION 2.5419 | 24.686 kg/m^2 STANDARD_DEVIATION 2.3112 | 25.010 kg/m^2 STANDARD_DEVIATION 2.9374 | 24.718 kg/m^2 STANDARD_DEVIATION 2.8672 |
| Diagnosis time | 3.23 years STANDARD_DEVIATION 3.984 | 3.41 years STANDARD_DEVIATION 4.195 | 2.82 years STANDARD_DEVIATION 3.23 | 3.27 years STANDARD_DEVIATION 4.22 | 3.24 years STANDARD_DEVIATION 4.304 | 3.37 years STANDARD_DEVIATION 4.053 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 255 Participants | 53 Participants | 49 Participants | 50 Participants | 50 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| FPG | 9.518 mmol/L STANDARD_DEVIATION 1.8663 | 9.277 mmol/L STANDARD_DEVIATION 1.7608 | 9.859 mmol/L STANDARD_DEVIATION 1.9902 | 9.390 mmol/L STANDARD_DEVIATION 1.5317 | 9.127 mmol/L STANDARD_DEVIATION 1.4868 | 9.933 mmol/L STANDARD_DEVIATION 2.3356 |
| HbA1c | 8.38 percentage of glycated hemoglobin STANDARD_DEVIATION 0.712 | 8.39 percentage of glycated hemoglobin STANDARD_DEVIATION 0.78 | 8.46 percentage of glycated hemoglobin STANDARD_DEVIATION 0.67 | 8.33 percentage of glycated hemoglobin STANDARD_DEVIATION 0.653 | 8.27 percentage of glycated hemoglobin STANDARD_DEVIATION 0.639 | 8.44 percentage of glycated hemoglobin STANDARD_DEVIATION 0.803 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 255 Participants | 53 Participants | 49 Participants | 50 Participants | 50 Participants | 53 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 255 participants | 53 participants | 49 participants | 50 participants | 50 participants | 53 participants |
| Sex: Female, Male Female | 104 Participants | 22 Participants | 18 Participants | 16 Participants | 22 Participants | 26 Participants |
| Sex: Female, Male Male | 151 Participants | 31 Participants | 31 Participants | 34 Participants | 28 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 50 | 0 / 51 | 0 / 51 | 0 / 53 |
| other Total, other adverse events | 16 / 53 | 21 / 50 | 13 / 51 | 18 / 51 | 15 / 53 |
| serious Total, serious adverse events | 1 / 53 | 1 / 50 | 1 / 51 | 0 / 51 | 0 / 53 |
Outcome results
Primary
After 12-week Treatment, the Change From Baseline in HbA1c
Assess the percentage of Hemoglobin A1c (HbA1c) changes at week 12. In the group HMS5552 dose3, a subject without follow-up data for HbA1c available was excluded. And in the group HMS5552 dose4, two subjects without follow-up data for HbA1c available were excluded. So the overall number of baseline participants is not consistent with numbers provided in any of the rows in the participant flow module.
Time frame: Baseline and 12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| HMS5552 Dose 1 | After 12-week Treatment, the Change From Baseline in HbA1c | -0.39 Percentage of glycated hemoglobin |
| HMS5552 Dose 2 | After 12-week Treatment, the Change From Baseline in HbA1c | -0.65 Percentage of glycated hemoglobin |
| HMS5552 Dose 3 | After 12-week Treatment, the Change From Baseline in HbA1c | -0.79 Percentage of glycated hemoglobin |
| HMS5552 Dose 4 | After 12-week Treatment, the Change From Baseline in HbA1c | -1.12 Percentage of glycated hemoglobin |
| Placebo | After 12-week Treatment, the Change From Baseline in HbA1c | -0.35 Percentage of glycated hemoglobin |
Secondary
Change From Baseline in 2hPPG
Using a standard meal tolerance test, to assess 2-h postprandial glucose (2hPPG). In this test, subjects were received meals standardised by China National Cereals, which supplied by Oils and Foodstuffs Corporation and contained 353 kcal, 75 g carbohydrate, 1.48 g fat, and 8.0 g protein. Collect the blood samples to detect blood glucose 2 hours after starting the meal.
Time frame: Baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HMS5552 Dose 1 | Change From Baseline in 2hPPG | -4.669 mmol/L | Standard Deviation 2.325 |
| HMS5552 Dose 2 | Change From Baseline in 2hPPG | -4.945 mmol/L | Standard Deviation 3.387 |
| HMS5552 Dose 3 | Change From Baseline in 2hPPG | -3.898 mmol/L | Standard Deviation 3.535 |
| HMS5552 Dose 4 | Change From Baseline in 2hPPG | -4.899 mmol/L | Standard Deviation 3.921 |
| Placebo | Change From Baseline in 2hPPG | -1.987 mmol/L | Standard Deviation 3.312 |
Secondary
Change From Baseline in FPG
Time frame: Baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HMS5552 Dose 1 | Change From Baseline in FPG | -0.307 mmol/L | Standard Deviation 2 |
| HMS5552 Dose 2 | Change From Baseline in FPG | -0.382 mmol/L | Standard Deviation 1.602 |
| HMS5552 Dose 3 | Change From Baseline in FPG | -0.758 mmol/L | Standard Deviation 2.15 |
| HMS5552 Dose 4 | Change From Baseline in FPG | -1.319 mmol/L | Standard Deviation 2.258 |
| Placebo | Change From Baseline in FPG | -0.801 mmol/L | Standard Deviation 1.752 |
Post Hoc
Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index
Disposition index, i.e DI, by the insulin secretion sensitivity index-2 (ISSI-2). This is an calculated value which represents the ability of a person's pancreatic beta cells to lower blood glucose. A higher number means the pancreas is better able to secrete insulin and improve glucose levels. HOMA IR is an index used to evaluate the individual's insulin resistance level. The HOMA-IR index of normal individuals is 1. With the increase of insulin resistance, HOMA-IR index will be higher than 1.
Time frame: Baseline and week 12
Population: Both of disposition index and HOMA-IR could reflect the function of β cell.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| HMS5552 Dose 1 | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | Disposition Index | 0.292 units on a scale |
| HMS5552 Dose 1 | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | HOMA-IR | -0.530 units on a scale |
| HMS5552 Dose 2 | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | Disposition Index | 0.198 units on a scale |
| HMS5552 Dose 2 | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | HOMA-IR | -0.520 units on a scale |
| HMS5552 Dose 3 | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | Disposition Index | 0.216 units on a scale |
| HMS5552 Dose 3 | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | HOMA-IR | -0.550 units on a scale |
| HMS5552 Dose 4 | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | HOMA-IR | -1.185 units on a scale |
| HMS5552 Dose 4 | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | Disposition Index | 0.140 units on a scale |
| Placebo | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | Disposition Index | 0.080 units on a scale |
| Placebo | Change From Baseline in MMTT (Mixed Meal Tolerance Test) β-cell Function Index | HOMA-IR | -0.680 units on a scale |