Surveillance
Conditions
Keywords
drug therapy
Brief summary
The purpose of this study is to examine the safety and efficacy of long-term combination therapy with alogliptin (Nesina) and sulfonylurea in participants with type 2 diabetes mellitus who responded inadequately to treatment with sulfonylurea in addition to diet therapy and exercise therapy.
Detailed description
This is a special drug use surveillance on long-term use of alogliptin with a 1-year (12-month) observational period, designed to investigate the safety and efficacy of long-term combination therapy with alogliptin and sulfonylurea in participants with type 2 diabetes mellitus in a routine clinical setting. Participants with type 2 diabetes mellitus who responded inadequately to treatment with sulfonylurea in addition to diet therapy and exercise therapy will be enrolled in this study. The planned sample size is 1,000. The usual adult dosage for oral use is 1 alogliptin tablet (25 mg) once daily.
Interventions
None listed
Sponsors
Takeda
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Participants who did not adequately respond to the following treatment • Treatment with sulfonylurea in addition to diet therapy and exercise therapy
Exclusion criteria
1. Participants with severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus (these participants require prompt adjustment of hyperglycemia by fluid infusion and insulin, and hence use of Nesina is not appropriate). 2. Participants with severe infection, pre- or post-operative participants, or participants with serious traumatic injury (blood glucose control by insulin injection is desirable for these participants, and hence use of Nesina is not appropriate). 3. Participants with a history of hypersensitivity to any ingredient of Nesina.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting One or More Adverse Drug Reactions | Baseline up to 12 months | Adverse drug reactions are defined as adverse events (AEs) which are in the investigator's opinion of causal relationship to the study treatment. AEs are defined as any unfavorable and unintended signs, symptoms or diseases temporally associated with the use of a medicinal product reported from the first dose of study drug to the last dose of study drug. The safety analysis was planned to be assessed in alogliptin + SU and alogliptin + other arm separately. |
| Number of Participants Reporting One or More Serious Adverse Drug Reaction | Baseline up to 12 months | Serious adverse drug reactions are defined as serious adverse events (SAEs) which are in the investigator's opinion of causal relationship to the study treatment. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The safety analysis was planned to be assessed in alogliptin + SU and alogliptin + other arm separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Baseline, Months 1, 3, 6, 12, and final assessment (up to Month 12) | 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 1 month, 3 months, 6 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline. The efficacy analysis was planned to be assessed in the total alogliptin arm irrespective of SU treatment. |
| Percentage of Participants Achieving Objective Glycemic Control | Baseline and final assessment (up to Month 12) | The rate of achieving objective glycemic control in HbA1c level was calculated at baseline and final visit (last visit for a participant in the study, up to Month 12). Glycemic control was measured as \<8.0%, \<7.0%, and \<6.0% of glycosylated hemoglobin. The efficacy analysis was planned to be assessed in the total alogliptin arm irrespective of SU treatment. |
| Change From Baseline in Fasting Blood Glucose | Baseline, Months 1, 3, 6, 12, and final assessment (up to Month 12) | The change between the fasting blood glucose value collected at 1 month, 3 months, 6 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline. The efficacy analysis was planned to be assessed in the total alogliptin arm irrespective of the SU treatment. |
| Change From Baseline in Fasting Insulin Level | Months 1, 3, 6, 12, and final assessment (up to Month 12) | The change between the fasting insulin value collected at 1 month, 3 months, 6 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline. The efficacy analysis was planned to be assessed in the total alogliptin arm irrespective of SU treatment. |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 221 investigative sites in Japan from 1-Jul-11 to 31-Dec-14.
Pre-assignment details
Participants with type 2 diabetes mellitus started treatment with alogliptin as per routine clinical practice were observed. As per protocol, participants we enrolled in 1 observational group at the start and were divided into 2 groups based on Sulfonylurea (SU) use for analysis of safety endpoints. Participant data was collected for overall arm.
Participants by arm
| Arm | Count |
|---|---|
| Alogliptin + SU Alogliptin (Nesina) 25 milligram (mg), tablets, orally, once daily for up to 12 months in participants who received an SU within 3 months from the start of administration of alogliptin and during the treatment period of alogliptin as per routine clinical practice were observed in this study. | 916 |
| Alogliptin + Other Alogliptin 25 mg, tablets, orally, once daily for up to 12 months in participants who did not receive an SU within 3 months from the start of administration of alogliptin or during the treatment period of alogliptin as per routine clinical practice were observed in this study. | 160 |
| Total | 1,076 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 25 |
Baseline characteristics
| Characteristic | Total | Alogliptin + SU | Alogliptin + Other |
|---|---|---|---|
| Age, Customized Greater Than or Equal to (>=) 65 Years | 627 participants | 536 participants | 91 participants |
| Age, Customized Less Than (<) 65 Years | 449 participants | 380 participants 11.67 | 69 participants 12.19 |
| Body Mass Index (BMI) >=25 kg/m^2 | 378 participants | 318 participants | 60 participants |
| Body Mass Index (BMI) <25 kilogram per square meter (kg/m^2) | 389 participants | 326 participants | 63 participants |
| Body Mass Index (BMI) Unknown | 309 participants | 272 participants | 37 participants |
| Breakdown of Complications of Heart Disease Angina pectoris | 77 participants | 70 participants | 7 participants |
| Breakdown of Complications of Heart Disease Cardiac failure | 28 participants | 25 participants | 3 participants |
| Breakdown of Complications of Heart Disease Myocardial infarction | 30 participants | 26 participants | 4 participants |
| Breakdown of Complications of Heart Disease Other | 30 participants | 26 participants | 4 participants |
| Breakdown of Complications of Liver Damage Chronic hepatitis | 36 participants | 31 participants | 5 participants |
| Breakdown of Complications of Liver Damage Hepatic cirrhosis | 3 participants | 2 participants | 1 participants |
| Breakdown of Complications of Liver Damage Hepatic steatosis | 146 participants | 122 participants | 24 participants |
| Breakdown of Complications of Liver Damage Hepatitis alcoholic | 39 participants | 30 participants | 9 participants |
| Breakdown of Complications of Liver Damage Other | 4 participants | 4 participants | 0 participants |
| Breakdown of Complications of Renal Damage Glomerulonephritis | 3 participants | 2 participants | 1 participants |
| Breakdown of Complications of Renal Damage Nephrotic syndrome | 4 participants | 3 participants | 1 participants |
| Breakdown of Complications of Renal Damage Other | 138 participants | 113 participants | 25 participants |
| Breakdown of Complications of Renal Damage Renal failure chronic | 9 participants | 9 participants | 0 participants |
| Breakdown of Complications of Stroke-related Disease Cerebral haemorrhage | 1 participants | 1 participants | 0 participants |
| Breakdown of Complications of Stroke-related Disease Cerebral infarction | 71 participants | 64 participants | 7 participants |
| Breakdown of Diabetic Complications Diabetic nephropathy | 137 participants | 114 participants | 23 participants |
| Breakdown of Diabetic Complications Diabetic neuropathy | 81 participants | 61 participants | 20 participants |
| Breakdown of Diabetic Complications Diabetic retinopathy | 97 participants | 76 participants | 21 participants |
| Complications of Allergic Disease Had complications | 58 participants | 51 participants | 7 participants |
| Complications of Allergic Disease Had no complications | 1018 participants | 865 participants | 153 participants |
| Complications of Dyslipidemia Had complications | 681 participants | 582 participants | 99 participants |
| Complications of Dyslipidemia Had no complications | 395 participants | 334 participants | 61 participants |
| Complications of Heart Disease Had complications | 147 participants | 129 participants | 18 participants |
| Complications of Heart Disease Had no complications | 929 participants | 787 participants | 142 participants |
| Complications of Heart Failure Had complications | 28 participants | 25 participants | 3 participants |
| Complications of Heart Failure Had no complications | 1048 participants | 891 participants | 157 participants |
| Complications of Hypertension Had complications | 690 participants | 593 participants | 97 participants |
| Complications of Hypertension Had no complications | 386 participants | 323 participants | 63 participants |
| Complications of Hyperuricemia Had complications | 82 participants | 74 participants | 8 participants |
| Complications of Hyperuricemia Had no complications | 994 participants | 842 participants | 152 participants |
| Complications of Liver Damage Had complications | 216 participants | 181 participants | 35 participants |
| Complications of Liver Damage Had no complications | 860 participants | 735 participants | 125 participants |
| Complications of Malignant Tumor Had complications | 22 participants | 19 participants | 3 participants |
| Complications of Malignant Tumor Had no complications | 1054 participants | 897 participants | 157 participants |
| Complications of Renal Damage Had complications | 153 participants | 126 participants | 27 participants |
| Complications of Renal Damage Had no complications | 923 participants | 790 participants | 133 participants |
| Complications of Stroke-related Disease Had complications | 72 participants | 65 participants | 7 participants |
| Complications of Stroke-related Disease Had no complications | 1004 participants | 851 participants | 153 participants |
| Degree of Hepatic Dysfunction Grade 1 | 86 participants | 75 participants | 11 participants |
| Degree of Hepatic Dysfunction Grade 2 | 12 participants | 10 participants | 2 participants |
| Degree of Hepatic Dysfunction Normal | 710 participants | 599 participants | 111 participants |
| Degree of Hepatic Dysfunction Unknown | 268 participants | 232 participants | 36 participants |
| Degree of Renal Dysfunction Mild | 412 participants | 351 participants | 61 participants |
| Degree of Renal Dysfunction Moderate | 171 participants | 146 participants | 25 participants |
| Degree of Renal Dysfunction Normal | 176 participants | 151 participants | 25 participants |
| Degree of Renal Dysfunction Severe | 12 participants | 12 participants | 0 participants |
| Degree of Renal Dysfunction Unknown | 305 participants | 256 participants | 49 participants |
| Diabetic Complications Had complications | 230 participants | 187 participants | 43 participants |
| Diabetic Complications Had no complications | 846 participants | 729 participants | 117 participants |
| Glycosylated Hemoglobin (HbA1c) Level HbA1c <6.0 percent (%) | 18 participants | 14 participants | 4 participants |
| Glycosylated Hemoglobin (HbA1c) Level HbA1c >=6.0% to <7.0% | 174 participants | 149 participants | 25 participants |
| Glycosylated Hemoglobin (HbA1c) Level HbA1c >=7.0% to <8.0% | 373 participants | 312 participants | 61 participants |
| Glycosylated Hemoglobin (HbA1c) Level HbA1c >=8.0% | 435 participants | 374 participants | 61 participants |
| Glycosylated Hemoglobin (HbA1c) Level Unknown | 76 participants | 67 participants | 9 participants |
| Healthcare Category Inpatient | 4 participants | 3 participants | 1 participants |
| Healthcare Category Outpatient | 1047 participants | 891 participants | 156 participants |
| Healthcare Category Outpatient and Inpatient | 25 participants | 22 participants | 3 participants |
| Health-related Complications Had complications | 982 participants | 837 participants | 145 participants |
| Health-related Complications Had no complications | 94 participants | 79 participants | 15 participants |
| History of Alcohol Consumption No | 611 participants | 527 participants | 84 participants |
| History of Alcohol Consumption Unknown | 193 participants | 161 participants | 32 participants |
| History of Alcohol Consumption Yes | 272 participants | 228 participants | 44 participants |
| History of Allergy Did not have allergy | 873 participants | 742 participants | 131 participants |
| History of Allergy Had allergy | 86 participants | 78 participants | 8 participants |
| History of Allergy Unknown | 117 participants | 96 participants | 21 participants |
| New York Heart Association (NYHA) Heart Failure Classification NYHA Class I | 18 participants | 16 participants | 2 participants |
| New York Heart Association (NYHA) Heart Failure Classification NYHA Class II | 5 participants | 5 participants | 0 participants |
| New York Heart Association (NYHA) Heart Failure Classification NYHA Class III | 1 participants | 1 participants | 0 participants |
| New York Heart Association (NYHA) Heart Failure Classification NYHA Class IV | 1 participants | 1 participants | 0 participants |
| New York Heart Association (NYHA) Heart Failure Classification Unknown | 3 participants | 2 participants | 1 participants |
| Pregnancy Status Not pregnant | 430 participants | 378 participants | 52 participants |
| Pregnancy Status Pregnant | 0 participants | 0 participants | 0 participants |
| Presence of Medical History Did not have medical history | 765 participants | 652 participants | 113 participants |
| Presence of Medical History Had medical history | 196 participants | 165 participants | 31 participants |
| Presence of Medical History Unknown | 115 participants | 99 participants | 16 participants |
| Region of Enrollment Japan | 1076 participants | 916 participants | 160 participants |
| Sex: Female, Male Female | 430 Participants | 378 Participants | 52 Participants |
| Sex: Female, Male Male | 646 Participants | 538 Participants | 108 Participants |
| Smoking Classification Current smoker | 175 participants | 145 participants | 30 participants |
| Smoking Classification Ex-smoker | 228 participants | 189 participants | 39 participants |
| Smoking Classification Never smoked | 423 participants | 372 participants | 51 participants |
| Smoking Classification Unknown | 250 participants | 210 participants | 40 participants |
| Time From Diagnosis of Type 2 Diabetes >=10 years | 287 participants | 232 participants | 55 participants |
| Time From Diagnosis of Type 2 Diabetes >=5 to <10 years | 241 participants | 216 participants | 25 participants |
| Time From Diagnosis of Type 2 Diabetes Greater than or equal to (>=)2 to <5 years | 160 participants | 138 participants | 22 participants |
| Time From Diagnosis of Type 2 Diabetes Less than (<)2 years | 123 participants | 102 participants | 21 participants |
| Time From Diagnosis of Type 2 Diabetes Unknown | 265 participants | 228 participants | 37 participants |
| Waist circumference <85 centimeter (cm) (Male) | 59 participants | 52 participants | 7 participants |
| Waist circumference >=85 cm (Male) | 124 participants | 102 participants | 22 participants |
| Waist circumference <90 cm (Female) | 59 participants | 52 participants | 7 participants |
| Waist circumference >=90 cm (Female) | 43 participants | 39 participants | 4 participants |
| Waist circumference Unknown (Female) | 328 participants | 287 participants | 41 participants |
| Waist circumference Unknown (Male) | 463 participants | 384 participants | 79 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 916 | 1 / 160 |
| serious Total, serious adverse events | 5 / 916 | 0 / 160 |
Outcome results
Primary
Number of Participants Reporting One or More Adverse Drug Reactions
Adverse drug reactions are defined as adverse events (AEs) which are in the investigator's opinion of causal relationship to the study treatment. AEs are defined as any unfavorable and unintended signs, symptoms or diseases temporally associated with the use of a medicinal product reported from the first dose of study drug to the last dose of study drug. The safety analysis was planned to be assessed in alogliptin + SU and alogliptin + other arm separately.
Time frame: Baseline up to 12 months
Population: The safety analysis set was defined as all participants who completed the study and had safety data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alogliptin + SU | Number of Participants Reporting One or More Adverse Drug Reactions | 19 participants |
| Alogliptin + Other | Number of Participants Reporting One or More Adverse Drug Reactions | 1 participants |
Primary
Number of Participants Reporting One or More Serious Adverse Drug Reaction
Serious adverse drug reactions are defined as serious adverse events (SAEs) which are in the investigator's opinion of causal relationship to the study treatment. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The safety analysis was planned to be assessed in alogliptin + SU and alogliptin + other arm separately.
Time frame: Baseline up to 12 months
Population: The safety analysis set was defined as all participants who completed the study and had safety data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alogliptin + SU | Number of Participants Reporting One or More Serious Adverse Drug Reaction | 5 participants |
| Alogliptin + Other | Number of Participants Reporting One or More Serious Adverse Drug Reaction | 0 participants |
Secondary
Change From Baseline in Fasting Blood Glucose
The change between the fasting blood glucose value collected at 1 month, 3 months, 6 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline. The efficacy analysis was planned to be assessed in the total alogliptin arm irrespective of the SU treatment.
Time frame: Baseline, Months 1, 3, 6, 12, and final assessment (up to Month 12)
Population: The efficacy assessment population was defined as participants who completed the study and had fasting blood glucose data at baseline and post-baseline time points available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alogliptin + SU | Change From Baseline in Fasting Blood Glucose | Baseline (n = 250) | 151.1 milligram per deciliter (mg/dL) | Standard Deviation 43.07 |
| Alogliptin + SU | Change From Baseline in Fasting Blood Glucose | Change at Month 1 (n = 159) | -14.6 milligram per deciliter (mg/dL) | Standard Deviation 42.91 |
| Alogliptin + SU | Change From Baseline in Fasting Blood Glucose | Change at Month 3 (n = 175) | -13.8 milligram per deciliter (mg/dL) | Standard Deviation 40.08 |
| Alogliptin + SU | Change From Baseline in Fasting Blood Glucose | Change at Month 6 (n = 185) | -13.1 milligram per deciliter (mg/dL) | Standard Deviation 47.37 |
| Alogliptin + SU | Change From Baseline in Fasting Blood Glucose | Change at Month 12 (n = 168) | -16.4 milligram per deciliter (mg/dL) | Standard Deviation 43.97 |
| Alogliptin + SU | Change From Baseline in Fasting Blood Glucose | Change at Final Assessment (n = 250) | -13.7 milligram per deciliter (mg/dL) | Standard Deviation 49.1 |
Secondary
Change From Baseline in Fasting Insulin Level
The change between the fasting insulin value collected at 1 month, 3 months, 6 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline. The efficacy analysis was planned to be assessed in the total alogliptin arm irrespective of SU treatment.
Time frame: Months 1, 3, 6, 12, and final assessment (up to Month 12)
Population: The efficacy assessment population was defined as participants who completed the study and had fasting insulin data at baseline and post-baseline time points available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alogliptin + SU | Change From Baseline in Fasting Insulin Level | Baseline (n = 33) | 7.88 micro units per milliliter (mcU/mL) | Standard Deviation 5.674 |
| Alogliptin + SU | Change From Baseline in Fasting Insulin Level | Change at Month 1 (n = 15) | 1.27 micro units per milliliter (mcU/mL) | Standard Deviation 12.138 |
| Alogliptin + SU | Change From Baseline in Fasting Insulin Level | Change at Month 3 (n = 17) | 0.21 micro units per milliliter (mcU/mL) | Standard Deviation 3.474 |
| Alogliptin + SU | Change From Baseline in Fasting Insulin Level | Change at Month 6 (n = 20) | 0.69 micro units per milliliter (mcU/mL) | Standard Deviation 5.629 |
| Alogliptin + SU | Change From Baseline in Fasting Insulin Level | Change at Month 12 (n = 22) | 1.17 micro units per milliliter (mcU/mL) | Standard Deviation 3.521 |
| Alogliptin + SU | Change From Baseline in Fasting Insulin Level | Change at Final Assessment (n = 33) | 1.86 micro units per milliliter (mcU/mL) | Standard Deviation 5.455 |
Secondary
Change From Baseline in Glycosylated Hemoglobin (HbA1c)
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 1 month, 3 months, 6 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline. The efficacy analysis was planned to be assessed in the total alogliptin arm irrespective of SU treatment.
Time frame: Baseline, Months 1, 3, 6, 12, and final assessment (up to Month 12)
Population: The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alogliptin + SU | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Baseline (n=830) | 8.03 percentage of glycosylated hemoglobin | Standard Deviation 1.348 |
| Alogliptin + SU | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Month 1 (n = 655) | -0.40 percentage of glycosylated hemoglobin | Standard Deviation 0.708 |
| Alogliptin + SU | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Month 3 (n = 710) | -0.66 percentage of glycosylated hemoglobin | Standard Deviation 1.117 |
| Alogliptin + SU | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Month 6 (n = 725) | -0.72 percentage of glycosylated hemoglobin | Standard Deviation 1.117 |
| Alogliptin + SU | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Month 12 (n = 670) | -0.64 percentage of glycosylated hemoglobin | Standard Deviation 1.106 |
| Alogliptin + SU | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Final Assessment (n = 830) | -0.65 percentage of glycosylated hemoglobin | Standard Deviation 1.145 |
Secondary
Percentage of Participants Achieving Objective Glycemic Control
The rate of achieving objective glycemic control in HbA1c level was calculated at baseline and final visit (last visit for a participant in the study, up to Month 12). Glycemic control was measured as \<8.0%, \<7.0%, and \<6.0% of glycosylated hemoglobin. The efficacy analysis was planned to be assessed in the total alogliptin arm irrespective of SU treatment.
Time frame: Baseline and final assessment (up to Month 12)
Population: The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alogliptin + SU | Percentage of Participants Achieving Objective Glycemic Control | <8.0 percent: Baseline | 56.3 percentage of participants |
| Alogliptin + SU | Percentage of Participants Achieving Objective Glycemic Control | <8.0%: Final Assessment | 75.4 percentage of participants |
| Alogliptin + SU | Percentage of Participants Achieving Objective Glycemic Control | <7.0%: Baseline | 19.3 percentage of participants |
| Alogliptin + SU | Percentage of Participants Achieving Objective Glycemic Control | <7.0%: Final Assessment | 43.0 percentage of participants |
| Alogliptin + SU | Percentage of Participants Achieving Objective Glycemic Control | <6.0%: Baseline | 1.7 percentage of participants |
| Alogliptin + SU | Percentage of Participants Achieving Objective Glycemic Control | <6.0%: Final Assessment | 4.6 percentage of participants |