Diabetes Mellitus
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to evaluate the efficacy and safety of alogliptin and metformin fixed-dose combination (FDC) as compared with alogliptin alone or metformin alone on Type 2 Diabetes Mellitus (T2DM).
Detailed description
The drug being tested in this study is a fixed-dose combination tablet of alogliptin and metformin to treat people who have diabetes. This study will look at glycemic control in people who take alogliptin and metformin FDC compared with alogliptin or metformin alone. The study will enroll approximately 640 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): * Alogliptin 12.5 mg twice daily (BID) * Metformin hydrochloride (HCl) 500 mg BID * Alogliptin 12.5 mg and Metformin HCl 500 mg FDC BID * Placebo (dummy inactive pill) - this is a tablet/capsule that looks like the study drug but has no active ingredient. All participants will be asked to take 2 tablets and 1 capsule twice a day at the same time each day throughout the study. All participants will be asked to record any hypoglycemic events in a diary. This multi-center trial will be conducted in China, South Korea, Taiwan and Malaysia. The overall time to participate in this study is 34 weeks. Participants will make 11 visits to the clinic.
Interventions
DRUGAlogliptin
Alogliptin tablets
DRUGMetformin HCl
Metformin HCl capsules
DRUGAlogliptin and Metformin Fixed-Dose Combination (FDC)
Alogliptin and metformin FDC tablets
Alogliptin placebo-matching tablets
Metformin placebo-matching capsules
DRUGAlogliptin and Metformin FDC Placebo
Alogliptin and metformin FDC placebo-matching tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. Has a historical diagnosis of Type 2 diabetes mellitus (T2DM). 4. Male or female and aged 18 to 75 years, inclusive. 5. Body mass index (BMI) between 20 and 45 kg/m\^2, inclusive. 6. A female of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study. 7. Is experiencing inadequate glycemic control defined as glycosylated hemoglobin (HbA1c) concentration between 7.5% and 10%, inclusive, and has been treated with diet and exercise for at least 2 months prior to Screening. (Exception: a participant who has received any other diabetic therapy for less than 7 days in total within the 2 months prior to the screening, can be included). 8. If male, has a hemoglobin \>12 g/dL (\>120 g/L) at Screening or if female, has a hemoglobin \>10 g/dL (\>100 g/L) at Screening. 9. If male, has a serum creatinine \<1.5 mg/dL at Screening or if female, has a serum creatinine \<1.4 mg/dL at Screening, and estimated glomerular filtration rate (eGFR) \>60 mL/min/1.73 m\^2 based on calculation using the Modification of Diet in Renal Disease (MDRD) at Screening. 10. Willing and able to monitor their own blood glucose concentrations using a home glucose monitor and complete a subject diary.
Exclusion criteria
1. Participated in another clinical study within 90 days prior to Screening. 2. Received any investigational compound within 30 days prior to Randomization. 3. Received a dipeptidyl peptidase-4 (DPP-4) inhibitor within 3 months prior to screening. 4. History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening. 5. History of treatment for diabetic gastric paresis, gastric banding, or gastric bypass surgery. 6. History of diabetic ketoacidosis or hyperosmolar non-ketotic coma. 7. Chronic pancreatitis and/or history of acute pancreatitis. 8. Systolic blood pressure \>180 mm Hg and/or diastolic blood pressure \>110 mm Hg at Screening. 9. History of any hemoglobinopathy or diagnosis of chronic anemia. 10. New York Heart Association Class III or IV heart failure. (Participants who are stable at Class I or II and are currently treated, are candidates for the study.) 11. History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 6 months prior to Screening. 12. History of any cancer, other than squamous cell or basal cell carcinoma of the skin, which has not been in full remission for at least 5 years prior to Screening. Participants with a history of treated cervical intraepithelial neoplasia \[CIN\] I or CIN II are allowed. 13. Significant clinical sign or symptom of hepatopathy, acute or chronic hepatitis, human immunodeficiency virus or alanine aminotransferase (ALT) is 2.5 times above upper limit of normal value. 14. History of angioedema in association with use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). 15. History of hypersensitivity or allergies to any DPP-4 inhibitor and/or metformin or related compounds. 16. Has used oral or systemically injected glucocorticoids (including intra-articular injection) or has used weight-loss drugs within 2 months prior to Screening. (Inhaled or topical corticosteroids were allowed.) 17. History of alcohol or substance abuse within 2 years prior to Screening. 18. Has used medicine for weight loss within 60 days prior to Screening (such as Xenical, Sibutramine, Phenylpropanolamine or similar nonprescription drugs). 19. History of organ transplantation. 20. 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. 21. Has, in the judgment of the investigator, any major illness or debility that may prohibit the participant from completing the study. 22. If female, 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26 (or Early Termination) | Baseline and Week 26 (or Early termination) | The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Week 26 or early termination relative to baseline. Negative change indicates better glycemic control. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Baseline and Weeks 4, 8, 12, 16, 20 and 26 | The change between the FPG value collected at Weeks 4, 8, 12, 16, 20 and 26 relative to baseline. Negative change indicates better glycemic control. |
| Time to Hyperglycemic Rescue Event | From the date of randomization through Week 26 | Rescue is defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days of first sample: After \>1 week of treatment but prior to Week 4 visit: A single FPG ≥275 mg/dL (≥15.27 mmol/L); From the Week 4 but prior to the Week 8 visit: A single FPG ≥250 mg/dL (≥13.88 mmol/L); From the Week 8 visit but prior to the Week 12 visit: A single FPG ≥225 mg/dL (≥12.49 mmol/L); From the Week 12 visit through the end-of-treatment visit (week 26): HbA1c ≥8.5% and ≤0.5% reduction in HbA1c from baseline. Time to hyperglycemic rescue was censored if the participant did not experience a hyperglycemic rescue event. |
| Percentage of Participants Requiring Hyperglycemic Rescue | Baseline up to Week 26 | Rescue is defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days of first sample: After \>1 week of treatment but prior to Week 4 visit: A single FPG ≥275 mg/dL (≥15.27 mmol/L); From the Week 4 but prior to the Week 8 visit: A single FPG ≥250 mg/dL (≥13.88 mmol/L); From the Week 8 visit but prior to the Week 12 visit: A single FPG ≥225 mg/dL (≥12.49 mmol/L); From the Week 12 visit through the end-of-treatment visit (week 26): HbA1c ≥8.5% and ≤0.5% reduction in HbA1c from baseline. |
| Percentage of Participants With Marked Hyperglycemia | Baseline up to Week 26 | Marked hyperglycemia is defined as FPG level ≥200 mg/dL (11.1 mmol/L). |
| Change From Baseline in Body Weight at Weeks 12 and 26 | Baseline and Weeks 12 and 26 | Change in participant's body weight at Weeks 12 and 26 relative to baseline. |
| Percentage of Participants With Glycosylated Hemoglobin ≤6.5% | Week 26 | Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤6.5%. |
| Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Baseline and Weeks 4, 8, 12, 16 and 20 | The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Weeks 4, 8, 12, 16 and 20 relative to baseline. Negative change indicates better glycemic control. |
| Percentage of Participants With Glycosylated Hemoglobin ≤7.5% | Week 26 | Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤7.5%. |
| Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥0.5% | Baseline and Week 26 | Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥0.5%. |
| Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.0% | Baseline and Week 26 | Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥1.0%. |
| Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.5% | Baseline and Week 26 | Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥1.5%. |
| Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥2.0% | Baseline and Week 26 | Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥2.0%. |
| Percentage of Participants With Glycosylated Hemoglobin ≤7.0% | Week 26 | Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤7%. |
Countries
China, Malaysia, South Korea, Taiwan
Participant flow
Recruitment details
Participants took part in the study at 59 investigative sites in China, Malaysia, South Korea and Taiwan from 26 August 2013 to 05 October 2015.
Pre-assignment details
Participants with a diagnosis of type 2 diabetes mellitus were enrolled equally in 1 of 4 treatment groups, twice a day placebo, alogliptin 12.5 mg, metformin hydrochloride (HCl) 500 mg, or alogliptin 12.5 mg and metformin HCl 500 mg fixed dose combination (FDC).
Participants by arm
| Arm | Count |
|---|---|
| Metformin HCl 500 mg Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks. | 162 |
| Alogliptin 12.5 mg Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks. | 163 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks. | 159 |
| Placebo Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks. | 163 |
| Total | 647 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 2 |
| Overall Study | Lack of Efficacy | 14 | 24 | 7 | 41 |
| Overall Study | Lost to Follow-up | 0 | 1 | 2 | 2 |
| Overall Study | Major Protocol Deviation | 3 | 1 | 0 | 1 |
| Overall Study | Randomized but not Treated | 1 | 1 | 0 | 0 |
| Overall Study | Reason not Specified | 0 | 1 | 1 | 2 |
| Overall Study | Voluntary Withdrawal | 8 | 8 | 2 | 11 |
Baseline characteristics
| Characteristic | Metformin HCl 500 mg | Alogliptin 12.5 mg | Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.6 years STANDARD_DEVIATION 9.91 | 55.4 years STANDARD_DEVIATION 9.62 | 53.4 years STANDARD_DEVIATION 10.46 | 52.2 years STANDARD_DEVIATION 10.17 | 53.6 years STANDARD_DEVIATION 10.08 |
| Body Mass Index (BMI) | 26.30 kg/m^2 STANDARD_DEVIATION 3.566 | 26.16 kg/m^2 STANDARD_DEVIATION 3.923 | 26.16 kg/m^2 STANDARD_DEVIATION 3.508 | 26.56 kg/m^2 STANDARD_DEVIATION 4.218 | 26.30 kg/m^2 STANDARD_DEVIATION 3.811 |
| Female Reproductive Status Female of Childbearing Potential | 25 participants | 12 participants | 21 participants | 18 participants | 76 participants |
| Female Reproductive Status Not Applicable (Participant is Male) | 82 participants | 98 participants | 91 participants | 95 participants | 366 participants |
| Female Reproductive Status Postmenopausal | 47 participants | 45 participants | 37 participants | 45 participants | 174 participants |
| Female Reproductive Status Surgically Sterile | 8 participants | 8 participants | 10 participants | 5 participants | 31 participants |
| Height | 163.8 cm STANDARD_DEVIATION 8.72 | 165.0 cm STANDARD_DEVIATION 8.06 | 164.3 cm STANDARD_DEVIATION 7.66 | 164.2 cm STANDARD_DEVIATION 9.19 | 164.3 cm STANDARD_DEVIATION 8.42 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 participants | 1 participants | 0 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 161 participants | 162 participants | 159 participants | 161 participants | 643 participants |
| Race/Ethnicity, Customized Hispanic or Latino (No) | 162 participants | 163 participants | 158 participants | 163 participants | 646 participants |
| Race/Ethnicity, Customized Hispanic or Latino (Yes) | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Multiracial | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment China | 129 participants | 129 participants | 128 participants | 130 participants | 516 participants |
| Region of Enrollment Korea, Republic of | 9 participants | 10 participants | 10 participants | 10 participants | 39 participants |
| Region of Enrollment Malaysia | 19 participants | 19 participants | 18 participants | 19 participants | 75 participants |
| Region of Enrollment Taiwan, Province of China | 5 participants | 5 participants | 3 participants | 4 participants | 17 participants |
| Sex: Female, Male Female | 80 Participants | 65 Participants | 68 Participants | 68 Participants | 281 Participants |
| Sex: Female, Male Male | 82 Participants | 98 Participants | 91 Participants | 95 Participants | 366 Participants |
| Smoking Classification Has Never Smoked | 125 participants | 112 participants | 113 participants | 112 participants | 462 participants |
| Smoking Classification Is a Current Smoker | 27 participants | 35 participants | 38 participants | 36 participants | 136 participants |
| Smoking Classification Is an Ex-smoker | 10 participants | 16 participants | 8 participants | 15 participants | 49 participants |
| Weight | 70.79 kg STANDARD_DEVIATION 12.357 | 71.21 kg STANDARD_DEVIATION 11.669 | 70.73 kg STANDARD_DEVIATION 11.489 | 71.79 kg STANDARD_DEVIATION 13.949 | 71.13 kg STANDARD_DEVIATION 12.388 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 33 / 161 | 26 / 162 | 25 / 158 | 35 / 161 |
| serious Total, serious adverse events | 5 / 161 | 4 / 162 | 4 / 158 | 5 / 161 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26 (or Early Termination)
The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Week 26 or early termination relative to baseline. Negative change indicates better glycemic control.
Time frame: Baseline and Week 26 (or Early termination)
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. Last observation carried forward (LOCF) imputation was utilized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin HCl 500 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26 (or Early Termination) | -0.32 percentage of glycosylated hemoglobin | Standard Deviation 1.067 |
| Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26 (or Early Termination) | -1.23 percentage of glycosylated hemoglobin | Standard Deviation 0.877 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26 (or Early Termination) | -1.06 percentage of glycosylated hemoglobin | Standard Deviation 0.97 |
| Placebo | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26 (or Early Termination) | -1.72 percentage of glycosylated hemoglobin | Standard Deviation 1.024 |
p-value: <0.000195% CI: [-0.7, -0.278]ANCOVA
p-value: <0.000195% CI: [-0.889, -0.467]ANCOVA
Secondary
Change From Baseline in Body Weight at Weeks 12 and 26
Change in participant's body weight at Weeks 12 and 26 relative to baseline.
Time frame: Baseline and Weeks 12 and 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized. n in the category is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Metformin HCl 500 mg | Change From Baseline in Body Weight at Weeks 12 and 26 | Week 12 (n=153,151,149,145) | -0.71 kg | Standard Deviation 1.735 |
| Metformin HCl 500 mg | Change From Baseline in Body Weight at Weeks 12 and 26 | Week 26 (n=156,156,156,152) | -0.93 kg | Standard Deviation 2.24 |
| Alogliptin 12.5 mg | Change From Baseline in Body Weight at Weeks 12 and 26 | Week 26 (n=156,156,156,152) | -0.22 kg | Standard Deviation 2.291 |
| Alogliptin 12.5 mg | Change From Baseline in Body Weight at Weeks 12 and 26 | Week 12 (n=153,151,149,145) | -0.19 kg | Standard Deviation 1.696 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in Body Weight at Weeks 12 and 26 | Week 12 (n=153,151,149,145) | -0.14 kg | Standard Deviation 1.73 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in Body Weight at Weeks 12 and 26 | Week 26 (n=156,156,156,152) | -0.57 kg | Standard Deviation 2.336 |
| Placebo | Change From Baseline in Body Weight at Weeks 12 and 26 | Week 12 (n=153,151,149,145) | -0.32 kg | Standard Deviation 1.837 |
| Placebo | Change From Baseline in Body Weight at Weeks 12 and 26 | Week 26 (n=156,156,156,152) | -0.33 kg | Standard Deviation 2.22 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26
The change between the FPG value collected at Weeks 4, 8, 12, 16, 20 and 26 relative to baseline. Negative change indicates better glycemic control.
Time frame: Baseline and Weeks 4, 8, 12, 16, 20 and 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized. n in the category is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin HCl 500 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 4 (n=157,154,155,156) | -1.42 mg/dL | Standard Deviation 1.344 |
| Metformin HCl 500 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 12 (n=160,158,158,157) | -1.48 mg/dL | Standard Deviation 1.527 |
| Metformin HCl 500 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 8 (n=160,158,158,157) | -1.50 mg/dL | Standard Deviation 1.571 |
| Metformin HCl 500 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 16 (n=160,158,158,157) | -1.62 mg/dL | Standard Deviation 1.599 |
| Metformin HCl 500 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 20 (n=160,158,158,157) | -1.57 mg/dL | Standard Deviation 1.634 |
| Metformin HCl 500 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 26 (n=160,158,158,157) | -1.45 mg/dL | Standard Deviation 1.674 |
| Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 20 (n=160,158,158,157) | -1.19 mg/dL | Standard Deviation 2.248 |
| Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 4 (n=157,154,155,156) | -1.01 mg/dL | Standard Deviation 1.794 |
| Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 8 (n=160,158,158,157) | -1.17 mg/dL | Standard Deviation 1.788 |
| Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 26 (n=160,158,158,157) | -1.06 mg/dL | Standard Deviation 2.307 |
| Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 16 (n=160,158,158,157) | -1.25 mg/dL | Standard Deviation 2.148 |
| Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 12 (n=160,158,158,157) | -1.33 mg/dL | Standard Deviation 1.938 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 20 (n=160,158,158,157) | -2.26 mg/dL | Standard Deviation 1.995 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 26 (n=160,158,158,157) | -2.06 mg/dL | Standard Deviation 2.274 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 8 (n=160,158,158,157) | -2.13 mg/dL | Standard Deviation 1.808 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 12 (n=160,158,158,157) | -2.14 mg/dL | Standard Deviation 1.779 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 16 (n=160,158,158,157) | -2.17 mg/dL | Standard Deviation 1.923 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 4 (n=157,154,155,156) | -2.01 mg/dL | Standard Deviation 2.157 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 16 (n=160,158,158,157) | -0.07 mg/dL | Standard Deviation 2.02 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 26 (n=160,158,158,157) | -0.04 mg/dL | Standard Deviation 2.06 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 12 (n=160,158,158,157) | -0.08 mg/dL | Standard Deviation 2.112 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 4 (n=157,154,155,156) | 0.02 mg/dL | Standard Deviation 1.532 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 8 (n=160,158,158,157) | -0.08 mg/dL | Standard Deviation 1.682 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 | Week 20 (n=160,158,158,157) | -0.12 mg/dL | Standard Deviation 2.092 |
Secondary
Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20
The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Weeks 4, 8, 12, 16 and 20 relative to baseline. Negative change indicates better glycemic control.
Time frame: Baseline and Weeks 4, 8, 12, 16 and 20
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized. n in the category is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin HCl 500 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 4 (n=157,156,154,156) | -0.57 percentage of glycosylated hemoglobin | Standard Deviation 0.483 |
| Metformin HCl 500 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 8 (n=160,160,158,157) | -0.90 percentage of glycosylated hemoglobin | Standard Deviation 0.682 |
| Metformin HCl 500 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 12 (n=160,160,158,157) | -1.06 percentage of glycosylated hemoglobin | Standard Deviation 0.793 |
| Metformin HCl 500 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 16 (n=160,160,158,157) | -1.18 percentage of glycosylated hemoglobin | Standard Deviation 0.816 |
| Metformin HCl 500 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 20 (n=160.160,158,157) | -1.24 percentage of glycosylated hemoglobin | Standard Deviation 0.852 |
| Alogliptin 12.5 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 4 (n=157,156,154,156) | -0.41 percentage of glycosylated hemoglobin | Standard Deviation 0.57 |
| Alogliptin 12.5 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 16 (n=160,160,158,157) | -1.06 percentage of glycosylated hemoglobin | Standard Deviation 0.9 |
| Alogliptin 12.5 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 12 (n=160,160,158,157) | -1.01 percentage of glycosylated hemoglobin | Standard Deviation 0.839 |
| Alogliptin 12.5 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 8 (n=160,160,158,157) | -0.78 percentage of glycosylated hemoglobin | Standard Deviation 0.756 |
| Alogliptin 12.5 mg | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 20 (n=160.160,158,157) | -1.11 percentage of glycosylated hemoglobin | Standard Deviation 0.925 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 20 (n=160.160,158,157) | -1.74 percentage of glycosylated hemoglobin | Standard Deviation 0.969 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 8 (n=160,160,158,157) | -1.29 percentage of glycosylated hemoglobin | Standard Deviation 0.732 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 16 (n=160,160,158,157) | -1.71 percentage of glycosylated hemoglobin | Standard Deviation 0.937 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 12 (n=160,160,158,157) | -1.57 percentage of glycosylated hemoglobin | Standard Deviation 0.873 |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 4 (n=157,156,154,156) | -0.80 percentage of glycosylated hemoglobin | Standard Deviation 0.489 |
| Placebo | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 16 (n=160,160,158,157) | -0.33 percentage of glycosylated hemoglobin | Standard Deviation 0.957 |
| Placebo | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 8 (n=160,160,158,157) | -0.29 percentage of glycosylated hemoglobin | Standard Deviation 0.738 |
| Placebo | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 20 (n=160.160,158,157) | -0.33 percentage of glycosylated hemoglobin | Standard Deviation 1.006 |
| Placebo | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 4 (n=157,156,154,156) | -0.18 percentage of glycosylated hemoglobin | Standard Deviation 0.503 |
| Placebo | Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 | Week 12 (n=160,160,158,157) | -0.27 percentage of glycosylated hemoglobin | Standard Deviation 0.895 |
Secondary
Percentage of Participants Requiring Hyperglycemic Rescue
Rescue is defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days of first sample: After \>1 week of treatment but prior to Week 4 visit: A single FPG ≥275 mg/dL (≥15.27 mmol/L); From the Week 4 but prior to the Week 8 visit: A single FPG ≥250 mg/dL (≥13.88 mmol/L); From the Week 8 visit but prior to the Week 12 visit: A single FPG ≥225 mg/dL (≥12.49 mmol/L); From the Week 12 visit through the end-of-treatment visit (week 26): HbA1c ≥8.5% and ≤0.5% reduction in HbA1c from baseline.
Time frame: Baseline up to Week 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin HCl 500 mg | Percentage of Participants Requiring Hyperglycemic Rescue | 8.7 percentage of participants |
| Alogliptin 12.5 mg | Percentage of Participants Requiring Hyperglycemic Rescue | 14.8 percentage of participants |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Percentage of Participants Requiring Hyperglycemic Rescue | 4.4 percentage of participants |
| Placebo | Percentage of Participants Requiring Hyperglycemic Rescue | 25.5 percentage of participants |
Secondary
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥0.5%
Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥0.5%.
Time frame: Baseline and Week 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin HCl 500 mg | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥0.5% | 81.4 percentage of participants |
| Alogliptin 12.5 mg | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥0.5% | 74.1 percentage of participants |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥0.5% | 89.2 percentage of participants |
| Placebo | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥0.5% | 42.9 percentage of participants |
Secondary
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.0%
Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥1.0%.
Time frame: Baseline and Week 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin HCl 500 mg | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.0% | 63.4 percentage of participants |
| Alogliptin 12.5 mg | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.0% | 53.7 percentage of participants |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.0% | 83.5 percentage of participants |
| Placebo | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.0% | 25.5 percentage of participants |
Secondary
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.5%
Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥1.5%.
Time frame: Baseline and Week 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin HCl 500 mg | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.5% | 37.3 percentage of participants |
| Alogliptin 12.5 mg | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.5% | 36.4 percentage of participants |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.5% | 62.0 percentage of participants |
| Placebo | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.5% | 14.9 percentage of participants |
Secondary
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥2.0%
Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥2.0%.
Time frame: Baseline and Week 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin HCl 500 mg | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥2.0% | 17.4 percentage of participants |
| Alogliptin 12.5 mg | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥2.0% | 17.3 percentage of participants |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥2.0% | 34.8 percentage of participants |
| Placebo | Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥2.0% | 6.2 percentage of participants |
Secondary
Percentage of Participants With Glycosylated Hemoglobin ≤6.5%
Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤6.5%.
Time frame: Week 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin HCl 500 mg | Percentage of Participants With Glycosylated Hemoglobin ≤6.5% | 27.3 percentage of participants |
| Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin ≤6.5% | 21.6 percentage of participants |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Percentage of Participants With Glycosylated Hemoglobin ≤6.5% | 55.1 percentage of participants |
| Placebo | Percentage of Participants With Glycosylated Hemoglobin ≤6.5% | 11.8 percentage of participants |
Secondary
Percentage of Participants With Glycosylated Hemoglobin ≤7.0%
Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤7%.
Time frame: Week 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin HCl 500 mg | Percentage of Participants With Glycosylated Hemoglobin ≤7.0% | 55.9 percentage of participants |
| Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin ≤7.0% | 44.4 percentage of participants |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Percentage of Participants With Glycosylated Hemoglobin ≤7.0% | 77.2 percentage of participants |
| Placebo | Percentage of Participants With Glycosylated Hemoglobin ≤7.0% | 30.4 percentage of participants |
Secondary
Percentage of Participants With Glycosylated Hemoglobin ≤7.5%
Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤7.5%.
Time frame: Week 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin HCl 500 mg | Percentage of Participants With Glycosylated Hemoglobin ≤7.5% | 73.3 percentage of participants |
| Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin ≤7.5% | 60.5 percentage of participants |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Percentage of Participants With Glycosylated Hemoglobin ≤7.5% | 84.8 percentage of participants |
| Placebo | Percentage of Participants With Glycosylated Hemoglobin ≤7.5% | 46.0 percentage of participants |
Secondary
Percentage of Participants With Marked Hyperglycemia
Marked hyperglycemia is defined as FPG level ≥200 mg/dL (11.1 mmol/L).
Time frame: Baseline up to Week 26
Population: Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin HCl 500 mg | Percentage of Participants With Marked Hyperglycemia | 8.8 percentage of participants |
| Alogliptin 12.5 mg | Percentage of Participants With Marked Hyperglycemia | 12.7 percentage of participants |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Percentage of Participants With Marked Hyperglycemia | 5.7 percentage of participants |
| Placebo | Percentage of Participants With Marked Hyperglycemia | 15.9 percentage of participants |
Secondary
Time to Hyperglycemic Rescue Event
Rescue is defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days of first sample: After \>1 week of treatment but prior to Week 4 visit: A single FPG ≥275 mg/dL (≥15.27 mmol/L); From the Week 4 but prior to the Week 8 visit: A single FPG ≥250 mg/dL (≥13.88 mmol/L); From the Week 8 visit but prior to the Week 12 visit: A single FPG ≥225 mg/dL (≥12.49 mmol/L); From the Week 12 visit through the end-of-treatment visit (week 26): HbA1c ≥8.5% and ≤0.5% reduction in HbA1c from baseline. Time to hyperglycemic rescue was censored if the participant did not experience a hyperglycemic rescue event.
Time frame: From the date of randomization through Week 26
Population: Randomized set consisted of all enrolled participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metformin HCl 500 mg | Time to Hyperglycemic Rescue Event | NA days |
| Alogliptin 12.5 mg | Time to Hyperglycemic Rescue Event | NA days |
| Alogliptin 12.5 mg + Metformin HCl 500 mg FDC | Time to Hyperglycemic Rescue Event | NA days |
| Placebo | Time to Hyperglycemic Rescue Event | NA days |