Type 2 Diabetes Mellitus
Conditions
Keywords
Pharmacological therapy
Brief summary
The purposes of this study is to evaluate the efficacy and safety of SYR-472 when administered at a dose of 100 mg once weekly as an add-on to insulin therapy compared with placebo in patients with type 2 diabetes mellitus and inadequate glycemic control despite treatment with insulin preparations in addition to diet and/or exercise therapy; and to evaluate the long-term efficacy and safety of SYR-472 when administered at a dose of 100 mg once weekly as an add-on to insulin therapy in patients with type 2 diabetes mellitus and inadequate glycemic control despite treatment with insulin preparations in addition to diet and/or exercise therapy.
Detailed description
This is a phase 4, multicenter, randomized, double-blind, parallel-group, comparative study using placebo (Treatment Period I) and a phase 4, multicenter, open-label, long-term study (Treatment Period II) to evaluate the efficacy and safety of SYR-472 when administered at a dose of 100 mg as an add-on to insulin therapy in patients with type 2 diabetes mellitus and inadequate glycemic control despite treatment with insulin preparations in addition to diet and/or exercise therapy.
Interventions
DRUGSYR-472
SYR-472 tablets
DRUGPlacebo
Placebo tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participant eligibility is determined according to the following criteria: 1. The participant has a diagnosis of type 2 diabetes mellitus. 2. The participant has a fasting C-peptide level of 0.6 ng/mL or higher at the start of the screening period (Week -6) and Week -2 of the screening period. 3. The participant has a Haemoglobin A1c (HbA1c) value of 7.5% or higher but less than 10.0% at Week -2 of the screening period. 4. The participant has an HbA1c value difference between the start of the screening period (Week -6) and Week -2 of the screening period within 10.0%\* (\* rounded to one decimal place) of the HbA1c value at the start of the screening period (Week -6). 5. The participant has been on a fixed diet and/or exercise therapy (if any) from at least 6 weeks prior to the start of the screening period (Week -6). 6. The participant is being treated with insulin preparations alone (≥8 units/day and ≤40 units/day) \*\* from at least 6 weeks prior to the start of the screening period (Week -6) at a fixed dose and regimen of the insulin preparation. * The participant on any one of the following insulin monotherapies: mixed (rapid-acting or short-acting insulin containing no more than 30% volume), intermediate-acting, or long-acting soluble insulin preparations 7. The participant is deemed appropriate for treatment with a combination of insulin and another antidiabetic drug at the start of the screening period (Week -6) by the investigator or subinvestigator. 8. The participants with controlled and stable blood pressure will not need any change in the dose of antihypertensive drugs (including discontinuation and suspension) or additional antihypertensive drugs during the study period as assessed by the investigator or subinvestigator. 9. The participant is male or female and aged 20 years or older at the time of informed consent. 10. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent until one month after the end of the study. 11. In the opinion of the investigator or subinvestigator, the participant is capable of understanding and complying with protocol requirements. 12. The participant signs and dates a written, informed consent form prior to the initiation of any study procedures.
Exclusion criteria
Any participant who meets any of the following criteria will not qualify for entry into the study: 1. The participants has clinical manifestations of hepatic impairment \[e.g., Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥2.5 times the upper limit of normal or total bilirubin of ≥2.0 mg/dL at the start of the screening period (Week -6) or at Week -2 of the screening period\]. 2. The participant has moderate or severe renal impairment or end-stage renal failure \[e.g., creatinine clearance (Ccr) \<50 mL/min at the start of the screening period (Week -6) or Week -2 of the screening period\]. 3. The participant has any serious cardiac diseases, cerebrovascular disorders, or serious pancreatic or hematological diseases (e.g., participants who require inpatient treatment or are hospitalized for treatment within 24 weeks prior to the start of the screening period). 4. The participant has, in the judgment of the investigator or subinvestigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at the start of the screening period (Week - 6) or Week -2 of the screening period. 5. The participant has a systolic blood pressure of 180 mmHg or higher or a diastolic blood pressure of 110 mmHg or higher during the screening period. 6. The participant is on at least two antidiabetic therapies other than one insulin preparation one day before 6 weeks prior to the start of the screening period (Week -6) (43 days prior to the start of the screening period). 7. The participants altered the dose and regimen of their insulin preparation within 6 weeks prior to the start of the screening period or during the screening period. 8. The participant experienced hypoglycemia (participants with a blood glucose level of ≤70 mg/dL or hypoglycemic symptoms) within 6 weeks prior to the start of the screening period or during the screening period (at least twice per week). 9. The participant has a fasting blood glucose level of 240 mg/dL or higher at the start of the screening period (Week -6) or at Week -2 of the screening period. 10. The participant has malignancies. 11. The participant has a history of hypersensitivity or allergies to dipeptidyl peptidase 4 (DPP-4) inhibitors or insulin preparations. 12. The participant has a history of gastrectomy or small intestinal resection. 13. The participant is habitual drinker consuming a daily average of more than 100 mL of alcohol. 14. The participant has a history of drug abuse (defined as the use of an illegal drug) or alcohol dependence. 15. The participant is required to take excluded medications during the study period. 16. The participant has received SYR-472 in a previous clinical study. 17. The participant is deemed to be in a condition contraindicating treatment as specified in the package insert of insulin preparations by the investigator or subinvestigator. 18. The participant received any investigational products (including study drugs in a post-marketing clinical study) within 12 weeks prior to the start of the screening period. 19. The participant is participating in other clinical studies at the time of informed consent. 20. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period. 21. The participant is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 22. The participant is hospitalized during the screening period or deemed as requiring hospitalization during the study period by the investigator or subinvestigator, unless the hospitalization is for short-term evaluations including complete health checkups. 23. The participant is deemed to be ineligible for the study for any other reason by the investigator or subinvestigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline at the End of Treatment Period I (End of Treatment Period I - End of the Screening Period) | End of the screening period (Week 0) and End of Treatment Period I (Up to Week 12) | — |
| Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) That Occurred Before Start of Treatment Period II | Up to Week 12 | Reported data is the number of participants reporting one or more TEAEs that occurred before start of Treatment Period II in Treatment Group I and Treatment Group II. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose | Baseline and Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 53, End of Treatment Period I (Up to Week 12) and End of Treatment Period II (Up to Week 52) | Reported data was the change from baseline in fasting plasma glucose at each time point. |
| Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I | Pre-meal and 0.5, 1, and 2 hr after-meal at Week 0 and 0.5, 1, and 2 hr after-meal at the End of Treatment Period I (Up to Week 12) | Reported data was the change from pre-meal in plasma glucose measured by the meal tolerance test at each time point. |
| Number of Participants With Markedly Abnormal Values of Vital Signs Before Start of Treatment Period II | Up to Week 12 | Here mmHg is Millimeter of mercury. |
| Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Baseline and Day 2, 3, 4, 5, 6, 7, and 8 in each Treatment Period (I and II) (Totally up to Week 17) | Reported data was the change from baseline in self-monitoring of blood glucose before breakfast. |
| Number of Participants With Markedly Abnormal Values of Laboratory Parameters (Total Bilirubin >2.0) Before Start of Treatment Period II | Up to Week 12 | — |
| Number of Participants With Total Hypoglycaemia After 1st Dose of Study Drug and Before Start of Treatment Period II | Up to Week 53 | — |
| Number of Participants With Markedly Abnormal Values of ECG Parameters Before Start of Treatment Period II | Up to Week 12 | Here QTcF is Corrected QT interval by Fridericia formula, and msec is millisecond. |
| Change From Baseline in HbA1c | Baseline and Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, End of Treatment Period I (Up to Week 12) and End of Treatment Period II (Up to Week 52) | Reported data was the change from baseline in HbA1c at each time point. |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 43 investigative sites in Japan, from 27 December 2014 to 28 December 2016.
Pre-assignment details
Participants with a historical diagnosis of type 2 diabetes mellitus with inadequate glycemic control despite treatment with insulin therapy were enrolled in 1 of the 2 groups: Group I: 100 milligram (mg) SYR-472 in Period I followed by 100 mg SYR-472 in Period II, Group II: SYR-472 Placebo in Period I followed by 100 mg SYR-472 in Period II.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group I SYR-472 100 mg, one tablet, orally before breakfast, weekly for up to Week 12 as Period I, followed by SYR-472 100 mg, one tablet, orally before breakfast, weekly for up to Week 52 as Period II of this study. Participants treated with insulin therapy throughout study. | 116 |
| Treatment Group II SYR-472 placebo, one tablet, orally before breakfast, weekly for up to Week 12 as Period I, followed by SYR-472 100 mg, one tablet, orally before breakfast, weekly for up to Week 52 as Period II of this study. Participants treated with insulin therapy throughout study. | 124 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Change Insulin Dosage Exceeding Criteria | 0 | 2 |
| Overall Study | Inconvenient Schedule | 2 | 0 |
| Overall Study | Lack of Efficacy | 2 | 3 |
| Overall Study | Pretreatment Event/Adverse Event | 9 | 10 |
| Overall Study | Voluntary Withdrawal | 3 | 6 |
Baseline characteristics
| Characteristic | Total | Treatment Group I | Treatment Group II |
|---|---|---|---|
| 1,5-Anhydroglucitol | 3.33 Microgram (μg)/mL STANDARD_DEVIATION 2.688 | 3.39 Microgram (μg)/mL STANDARD_DEVIATION 2.349 | 3.28 Microgram (μg)/mL STANDARD_DEVIATION 2.978 |
| 2-hour (hr) Postprandial Plasma Glucose | 288.0 mg/dL STANDARD_DEVIATION 52.97 | 290.0 mg/dL STANDARD_DEVIATION 52.08 | 286.1 mg/dL STANDARD_DEVIATION 54.03 |
| Age, Continuous | 58.2 Years STANDARD_DEVIATION 10.99 | 57.9 Years STANDARD_DEVIATION 10.89 | 58.5 Years STANDARD_DEVIATION 11.11 |
| BMI | 25.27 kg/m^2 STANDARD_DEVIATION 3.49 | 25.39 kg/m^2 STANDARD_DEVIATION 3.593 | 25.16 kg/m^2 STANDARD_DEVIATION 3.402 |
| Creatinine Clearance (Ccr) | 108.3 Milliliter (mL)/minute (min) STANDARD_DEVIATION 38.24 | 109.3 Milliliter (mL)/minute (min) STANDARD_DEVIATION 36.09 | 107.4 Milliliter (mL)/minute (min) STANDARD_DEVIATION 40.28 |
| Daily Dose of Insulin Preparation at Week -6 | 19.3 Unit STANDARD_DEVIATION 9.09 | 19.8 Unit STANDARD_DEVIATION 9.32 | 18.8 Unit STANDARD_DEVIATION 8.88 |
| Duration of Diabetes | 135.0 Months STANDARD_DEVIATION 91.69 | 125.9 Months STANDARD_DEVIATION 92.75 | 143.6 Months STANDARD_DEVIATION 90.23 |
| Fasting C-Peptide | 1.12 Nanogram (ng)/mL STANDARD_DEVIATION 0.593 | 1.07 Nanogram (ng)/mL STANDARD_DEVIATION 0.527 | 1.16 Nanogram (ng)/mL STANDARD_DEVIATION 0.647 |
| Fasting Plasma Glucose | 164.1 Milligram (mg)/ Deciliter (dL) STANDARD_DEVIATION 33.56 | 160.6 Milligram (mg)/ Deciliter (dL) STANDARD_DEVIATION 32.86 | 167.3 Milligram (mg)/ Deciliter (dL) STANDARD_DEVIATION 34.02 |
| Glycoalbumin | 23.62 Percent STANDARD_DEVIATION 3.31 | 23.53 Percent STANDARD_DEVIATION 3.343 | 23.70 Percent STANDARD_DEVIATION 3.29 |
| Haemoglobin A1c (HbA1c) | 8.46 Percent STANDARD_DEVIATION 0.675 | 8.42 Percent STANDARD_DEVIATION 0.677 | 8.50 Percent STANDARD_DEVIATION 0.675 |
| Insulinogenic Index | 0.34 microunits*dL/mg*mL STANDARD_DEVIATION 0.525 | 0.29 microunits*dL/mg*mL STANDARD_DEVIATION 0.279 | 0.38 microunits*dL/mg*mL STANDARD_DEVIATION 0.687 |
| Region of Enrollment Japan | 240 Participants | 116 Participants | 124 Participants |
| Sex: Female, Male Female | 68 Participants | 26 Participants | 42 Participants |
| Sex: Female, Male Male | 172 Participants | 90 Participants | 82 Participants |
| Type of Insulin Preparation Intermediate-Acting | 12 Participants | 3 Participants | 9 Participants |
| Type of Insulin Preparation Long-Acting | 133 Participants | 65 Participants | 68 Participants |
| Type of Insulin Preparation Pre-Mixed | 95 Participants | 48 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 59 / 116 | 54 / 119 |
| serious Total, serious adverse events | 16 / 116 | 9 / 119 |
Outcome results
Primary
Change in HbA1c From Baseline at the End of Treatment Period I (End of Treatment Period I - End of the Screening Period)
Time frame: End of the screening period (Week 0) and End of Treatment Period I (Up to Week 12)
Population: Full Analysis Set: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group I | Change in HbA1c From Baseline at the End of Treatment Period I (End of Treatment Period I - End of the Screening Period) | -0.56 Percent | Standard Error 0.07 |
| Treatment Group II | Change in HbA1c From Baseline at the End of Treatment Period I (End of Treatment Period I - End of the Screening Period) | 0.07 Percent | Standard Error 0.067 |
p-value: <0.000195% CI: [-0.826, -0.443]ANCOVA
Primary
Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) That Occurred Before Start of Treatment Period II
Reported data is the number of participants reporting one or more TEAEs that occurred before start of Treatment Period II in Treatment Group I and Treatment Group II.
Time frame: Up to Week 12
Population: Safety Analysis Set: The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group I | Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) That Occurred Before Start of Treatment Period II | 51 Participants |
| Treatment Group II | Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) That Occurred Before Start of Treatment Period II | 59 Participants |
Secondary
Change From Baseline in Fasting Plasma Glucose
Reported data was the change from baseline in fasting plasma glucose at each time point.
Time frame: Baseline and Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 53, End of Treatment Period I (Up to Week 12) and End of Treatment Period II (Up to Week 52)
Population: Full Analysis Set: All randomized participants who received at least one dose of study drug. The analyzed numbers for each arm were participants who were evaluable for this outcome measure at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 4 | -12.6 mg/dL | Standard Deviation 32.19 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 36 | -6.0 mg/dL | Standard Deviation 35.58 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 20 | -3.1 mg/dL | Standard Deviation 39.65 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 40 | -3.7 mg/dL | Standard Deviation 40.45 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 12 | -2.0 mg/dL | Standard Deviation 39.65 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 44 | -4.9 mg/dL | Standard Deviation 36.88 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 24 | -3.0 mg/dL | Standard Deviation 36.08 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 48 | -8.8 mg/dL | Standard Deviation 38 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 8 | -9.3 mg/dL | Standard Deviation 32.13 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 52 | -10.0 mg/dL | Standard Deviation 43.4 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 28 | -4.5 mg/dL | Standard Deviation 38.76 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 53 | -1.3 mg/dL | Standard Deviation 45.44 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 16 | -1.4 mg/dL | Standard Deviation 41.31 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | End of Treatment Period I | -2.8 mg/dL | Standard Deviation 39.4 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 32 | -6.9 mg/dL | Standard Deviation 39.46 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | End of Treatment Period II | -8.1 mg/dL | Standard Deviation 42.48 |
| Treatment Group I | Change From Baseline in Fasting Plasma Glucose | Week 2 | -10.3 mg/dL | Standard Deviation 29.73 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | End of Treatment Period II | -18.3 mg/dL | Standard Deviation 35.81 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 2 | 0.1 mg/dL | Standard Deviation 28.98 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 4 | -4.0 mg/dL | Standard Deviation 36.49 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 8 | -0.9 mg/dL | Standard Deviation 39.37 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 12 | 2.0 mg/dL | Standard Deviation 42.04 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 16 | -9.0 mg/dL | Standard Deviation 37.24 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 20 | -10.4 mg/dL | Standard Deviation 38.68 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 24 | -10.3 mg/dL | Standard Deviation 39.79 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 28 | -10.5 mg/dL | Standard Deviation 37.5 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 32 | -12.9 mg/dL | Standard Deviation 35.75 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 36 | -14.9 mg/dL | Standard Deviation 33.97 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 40 | -14.7 mg/dL | Standard Deviation 36.34 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 44 | -18.0 mg/dL | Standard Deviation 38.43 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 48 | -19.8 mg/dL | Standard Deviation 35.38 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 52 | -21.0 mg/dL | Standard Deviation 33.99 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | Week 53 | -13.2 mg/dL | Standard Deviation 34.49 |
| Treatment Group II | Change From Baseline in Fasting Plasma Glucose | End of Treatment Period I | 0.8 mg/dL | Standard Deviation 42.44 |
Secondary
Change From Baseline in HbA1c
Reported data was the change from baseline in HbA1c at each time point.
Time frame: Baseline and Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, End of Treatment Period I (Up to Week 12) and End of Treatment Period II (Up to Week 52)
Population: Full Analysis Set: All randomized participants who received at least one dose of study drug. The analyzed numbers for each arm were participants who were evaluable for this outcome measure at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Group I | Change From Baseline in HbA1c | Week 2 | -0.16 Percent | Standard Deviation 0.24 |
| Treatment Group I | Change From Baseline in HbA1c | Week 4 | -0.38 Percent | Standard Deviation 0.327 |
| Treatment Group I | Change From Baseline in HbA1c | Week 8 | -0.50 Percent | Standard Deviation 0.573 |
| Treatment Group I | Change From Baseline in HbA1c | Week 12 | -0.55 Percent | Standard Deviation 0.708 |
| Treatment Group I | Change From Baseline in HbA1c | Week 16 | -0.51 Percent | Standard Deviation 0.793 |
| Treatment Group I | Change From Baseline in HbA1c | Week 20 | -0.42 Percent | Standard Deviation 0.836 |
| Treatment Group I | Change From Baseline in HbA1c | Week 24 | -0.38 Percent | Standard Deviation 0.864 |
| Treatment Group I | Change From Baseline in HbA1c | Week 28 | -0.42 Percent | Standard Deviation 0.884 |
| Treatment Group I | Change From Baseline in HbA1c | Week 32 | -0.41 Percent | Standard Deviation 0.872 |
| Treatment Group I | Change From Baseline in HbA1c | Week 36 | -0.42 Percent | Standard Deviation 0.817 |
| Treatment Group I | Change From Baseline in HbA1c | Week 40 | -0.35 Percent | Standard Deviation 0.884 |
| Treatment Group I | Change From Baseline in HbA1c | Week 44 | -0.34 Percent | Standard Deviation 0.895 |
| Treatment Group I | Change From Baseline in HbA1c | Week 48 | -0.44 Percent | Standard Deviation 0.804 |
| Treatment Group I | Change From Baseline in HbA1c | Week 52 | -0.48 Percent | Standard Deviation 0.799 |
| Treatment Group I | Change From Baseline in HbA1c | End of Treatment Period I | -0.56 Percent | Standard Deviation 0.71 |
| Treatment Group I | Change From Baseline in HbA1c | End of Treatment Period II | -0.43 Percent | Standard Deviation 0.827 |
| Treatment Group II | Change From Baseline in HbA1c | End of Treatment Period II | -0.60 Percent | Standard Deviation 0.831 |
| Treatment Group II | Change From Baseline in HbA1c | Week 2 | 0.01 Percent | Standard Deviation 0.229 |
| Treatment Group II | Change From Baseline in HbA1c | Week 32 | -0.57 Percent | Standard Deviation 0.791 |
| Treatment Group II | Change From Baseline in HbA1c | Week 4 | -0.06 Percent | Standard Deviation 0.396 |
| Treatment Group II | Change From Baseline in HbA1c | Week 48 | -0.69 Percent | Standard Deviation 0.794 |
| Treatment Group II | Change From Baseline in HbA1c | Week 8 | -0.04 Percent | Standard Deviation 0.612 |
| Treatment Group II | Change From Baseline in HbA1c | Week 36 | -0.58 Percent | Standard Deviation 0.74 |
| Treatment Group II | Change From Baseline in HbA1c | Week 12 | 0.08 Percent | Standard Deviation 0.793 |
| Treatment Group II | Change From Baseline in HbA1c | End of Treatment Period I | 0.07 Percent | Standard Deviation 0.788 |
| Treatment Group II | Change From Baseline in HbA1c | Week 16 | -0.16 Percent | Standard Deviation 0.84 |
| Treatment Group II | Change From Baseline in HbA1c | Week 40 | -0.62 Percent | Standard Deviation 0.779 |
| Treatment Group II | Change From Baseline in HbA1c | Week 20 | -0.41 Percent | Standard Deviation 0.797 |
| Treatment Group II | Change From Baseline in HbA1c | Week 52 | -0.70 Percent | Standard Deviation 0.711 |
| Treatment Group II | Change From Baseline in HbA1c | Week 24 | -0.49 Percent | Standard Deviation 0.812 |
| Treatment Group II | Change From Baseline in HbA1c | Week 44 | -0.67 Percent | Standard Deviation 0.772 |
| Treatment Group II | Change From Baseline in HbA1c | Week 28 | -0.55 Percent | Standard Deviation 0.832 |
Secondary
Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I
Reported data was the change from pre-meal in plasma glucose measured by the meal tolerance test at each time point.
Time frame: Pre-meal and 0.5, 1, and 2 hr after-meal at Week 0 and 0.5, 1, and 2 hr after-meal at the End of Treatment Period I (Up to Week 12)
Population: Full Analysis Set: All randomized participants who received at least one dose of study drug. The analyzed numbers for each arm were participants who were evaluable for this outcome measure at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Group I | Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I | Pre-meal at the End of Treatment Period I | -9.5 mg/dL | Standard Deviation 34.13 |
| Treatment Group I | Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I | 0.5 hr at the End of Treatment Period I | -17.6 mg/dL | Standard Deviation 36.82 |
| Treatment Group I | Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I | 1 hr at the End of Treatment Period I | -28.6 mg/dL | Standard Deviation 43.08 |
| Treatment Group I | Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I | 2 hr at the End of Treatment Period I | -29.9 mg/dL | Standard Deviation 42.23 |
| Treatment Group II | Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I | 2 hr at the End of Treatment Period I | 2.3 mg/dL | Standard Deviation 59.89 |
| Treatment Group II | Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I | Pre-meal at the End of Treatment Period I | 0.5 mg/dL | Standard Deviation 45.17 |
| Treatment Group II | Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I | 1 hr at the End of Treatment Period I | -1.2 mg/dL | Standard Deviation 51.02 |
| Treatment Group II | Change From Baseline in Plasma Glucose Measured by the Meal Tolerance Test in Treatment Period I | 0.5 hr at the End of Treatment Period I | 3.5 mg/dL | Standard Deviation 51.12 |
Secondary
Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast
Reported data was the change from baseline in self-monitoring of blood glucose before breakfast.
Time frame: Baseline and Day 2, 3, 4, 5, 6, 7, and 8 in each Treatment Period (I and II) (Totally up to Week 17)
Population: Safety Analysis Set: The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period. The analyzed numbers for each arm were participants who were evaluable for this outcome measure at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 5 on Treatment Period II | -5.2 mg/dL | Standard Deviation 41.24 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 2 on Treatment Period I | 9.7 mg/dL | Standard Deviation 41.21 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 3 on Treatment Period I | 4.3 mg/dL | Standard Deviation 35.22 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 4 on Treatment Period I | 1.6 mg/dL | Standard Deviation 43.99 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 5 on Treatment Period I | -6.7 mg/dL | Standard Deviation 41.51 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 6 on Treatment Period I | -7.0 mg/dL | Standard Deviation 33.79 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 7 on Treatment Period I | -0.2 mg/dL | Standard Deviation 38.15 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 8 on Treatment Period I | -3.8 mg/dL | Standard Deviation 39.63 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 2 on Treatment Period II | -6.8 mg/dL | Standard Deviation 41.98 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 3 on Treatment Period II | -10.2 mg/dL | Standard Deviation 39.95 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 4 on Treatment Period II | -5.7 mg/dL | Standard Deviation 45.52 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 6 on Treatment Period II | -8.5 mg/dL | Standard Deviation 39.04 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 7 on Treatment Period II | -7.7 mg/dL | Standard Deviation 35.93 |
| Treatment Group I | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 8 on Treatment Period II | -9.4 mg/dL | Standard Deviation 35.91 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 4 on Treatment Period II | -1.7 mg/dL | Standard Deviation 49.4 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 5 on Treatment Period II | -2.8 mg/dL | Standard Deviation 47.25 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 8 on Treatment Period I | 2.0 mg/dL | Standard Deviation 37.7 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 2 on Treatment Period I | 5.6 mg/dL | Standard Deviation 39.02 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 7 on Treatment Period II | -4.9 mg/dL | Standard Deviation 44.21 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 3 on Treatment Period I | -0.9 mg/dL | Standard Deviation 41.35 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 2 on Treatment Period II | 7.1 mg/dL | Standard Deviation 51.9 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 4 on Treatment Period I | -3.0 mg/dL | Standard Deviation 41.55 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 6 on Treatment Period II | -3.4 mg/dL | Standard Deviation 40.67 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 5 on Treatment Period I | -0.9 mg/dL | Standard Deviation 38.22 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 3 on Treatment Period II | 5.8 mg/dL | Standard Deviation 44.25 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 6 on Treatment Period I | 2.2 mg/dL | Standard Deviation 43.78 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 8 on Treatment Period II | -7.8 mg/dL | Standard Deviation 43.85 |
| Treatment Group II | Change From Baseline in Self-Monitoring of Blood Glucose Before Breakfast | Day 7 on Treatment Period I | -0.3 mg/dL | Standard Deviation 37.55 |
Secondary
Number of Participants With Markedly Abnormal Values of ECG Parameters Before Start of Treatment Period II
Here QTcF is Corrected QT interval by Fridericia formula, and msec is millisecond.
Time frame: Up to Week 12
Population: Safety Analysis Set: The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period. The analyzed numbers for each arm were participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment Group I | Number of Participants With Markedly Abnormal Values of ECG Parameters Before Start of Treatment Period II | QTcF Interval >450 msec | 2 Participants |
| Treatment Group I | Number of Participants With Markedly Abnormal Values of ECG Parameters Before Start of Treatment Period II | Change from Baseline in QTcF Interval >30 msec | 2 Participants |
| Treatment Group II | Number of Participants With Markedly Abnormal Values of ECG Parameters Before Start of Treatment Period II | QTcF Interval >450 msec | 4 Participants |
| Treatment Group II | Number of Participants With Markedly Abnormal Values of ECG Parameters Before Start of Treatment Period II | Change from Baseline in QTcF Interval >30 msec | 1 Participants |
Secondary
Number of Participants With Markedly Abnormal Values of Laboratory Parameters (Total Bilirubin >2.0) Before Start of Treatment Period II
Time frame: Up to Week 12
Population: Safety Analysis Set: The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period. The analyzed numbers for each arm were participants who were evaluable for this outcome measure..
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group I | Number of Participants With Markedly Abnormal Values of Laboratory Parameters (Total Bilirubin >2.0) Before Start of Treatment Period II | 1 Participants |
| Treatment Group II | Number of Participants With Markedly Abnormal Values of Laboratory Parameters (Total Bilirubin >2.0) Before Start of Treatment Period II | 1 Participants |
Secondary
Number of Participants With Markedly Abnormal Values of Vital Signs Before Start of Treatment Period II
Here mmHg is Millimeter of mercury.
Time frame: Up to Week 12
Population: Safety Analysis Set: The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period. The analyzed numbers for each arm were participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment Group I | Number of Participants With Markedly Abnormal Values of Vital Signs Before Start of Treatment Period II | Diastolic Blood Pressure <50 mmHg | 1 Participants |
| Treatment Group I | Number of Participants With Markedly Abnormal Values of Vital Signs Before Start of Treatment Period II | Pulse <50 Beats per minute(bpm) | 1 Participants |
| Treatment Group II | Number of Participants With Markedly Abnormal Values of Vital Signs Before Start of Treatment Period II | Diastolic Blood Pressure <50 mmHg | 1 Participants |
| Treatment Group II | Number of Participants With Markedly Abnormal Values of Vital Signs Before Start of Treatment Period II | Pulse <50 Beats per minute(bpm) | 2 Participants |
Secondary
Number of Participants With Total Hypoglycaemia After 1st Dose of Study Drug and Before Start of Treatment Period II
Time frame: Up to Week 53
Population: Safety Analysis Set: The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period. The analyzed numbers for each arm were participants who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group I | Number of Participants With Total Hypoglycaemia After 1st Dose of Study Drug and Before Start of Treatment Period II | 17 Participants |
| Treatment Group II | Number of Participants With Total Hypoglycaemia After 1st Dose of Study Drug and Before Start of Treatment Period II | 16 Participants |