Surveillance
Conditions
Brief summary
To examine the safety and efficacy of long-term combination therapy with alogliptin (Nesina) and biguanides in participants with type 2 diabetes mellitus who responded inadequately to treatment with biguanides 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 biguanides in participants with type 2 diabetes mellitus in the routine clinical setting. Participants diagnosed with type 2 diabetes mellitus who responded inadequately to treatment with biguanides in addition to diet therapy and exercise therapy will be enrolled. 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 biguanides in addition to diet therapy and exercise therapy
Exclusion criteria
* Participants contraindicated for Nesina 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 patients, or patients 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 + biguanides and alogliptin + other arm separately. |
| Number of Participants Reporting One or More Serious Adverse Drug Reactions | 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. An 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 + biguanides 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 biguanide treatment. |
| Percentage of Participants of 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 12 month or 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 biguanide 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 biguanide treatment. |
| Change From Baseline in Fasting Insulin Level | Baseline, 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 biguanide treatment. |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 207 investigative sites in Japan from 01 July 2011 to 31 December 2014.
Pre-assignment details
Participants with type 2 diabetes mellitus started treatment with alogliptin as per routine clinical practice were observed. As per protocol, participants were enrolled in 1 observational group at the start and were divided into 2 groups based on biguanide use for analysis of safety endpoints. Participant flow data was collected for overall arm.
Participants by arm
| Arm | Count |
|---|---|
| Alogliptin + Biguanides Alogliptin 25 milligram (mg), tablets, orally, once daily for up to 12 months in participants who received a biguanide 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. | 954 |
| Alogliptin + Other Alogliptin 25 mg, tablets, orally, once daily for up to 12 months in participants who did not receive a biguanide 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. | 109 |
| Total | 1,063 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 31 |
Baseline characteristics
| Characteristic | Alogliptin + Biguanides | Total | Alogliptin + Other |
|---|---|---|---|
| Age, Customized Greater than or equal to (>=) 65 years | 415 participants | 456 participants | 41 participants |
| Age, Customized Less than (<) 65 years | 539 participants | 607 participants | 68 participants |
| Body Mass Index >=25 kg/m^2 | 410 participants | 455 participants | 45 participants |
| Body Mass Index <25 kilogram per square meter (kg/m^2) | 345 participants | 380 participants | 35 participants |
| Body Mass Index Unknown | 199 participants | 228 participants | 29 participants |
| Breakdown of Complications of Heart Disease Angina pectoris | 49 participants | 52 participants | 3 participants |
| Breakdown of Complications of Heart Disease Cardiac failure | 19 participants | 20 participants | 1 participants |
| Breakdown of Complications of Heart Disease Myocardial infarction | 24 participants | 25 participants | 1 participants |
| Breakdown of Complications of Heart Disease Other | 24 participants | 26 participants | 2 participants |
| Breakdown of Complications of Liver Damage Chronic hepatitis | 15 participants | 20 participants | 5 participants |
| Breakdown of Complications of Liver Damage Hepatic cirrhosis | 2 participants | 3 participants | 1 participants |
| Breakdown of Complications of Liver Damage Hepatic steatosis | 158 participants | 173 participants | 15 participants |
| Breakdown of Complications of Liver Damage Hepatitis alcoholic | 23 participants | 28 participants | 5 participants |
| Breakdown of Complications of Liver Damage Other | 7 participants | 7 participants | 0 participants |
| Breakdown of Complications of Renal Damage Glomerulonephritis | 1 participants | 1 participants | 0 participants |
| Breakdown of Complications of Renal Damage Nephrotic syndrome | 1 participants | 1 participants | 0 participants |
| Breakdown of Complications of Renal Damage Other | 110 participants | 122 participants | 12 participants |
| Breakdown of Complications of Renal Damage Renal failure chronic | 2 participants | 2 participants | 0 participants |
| Breakdown of Complications of Stroke-related Disease Cerebral hemorrhage | 1 participants | 1 participants | 0 participants |
| Breakdown of Complications of Stroke-related Disease Cerebral infarction | 57 participants | 62 participants | 5 participants |
| Breakdown of diabetic complications Diabetic nephropathy | 110 participants | 122 participants | 12 participants |
| Breakdown of diabetic complications Diabetic neuropathy | 83 participants | 91 participants | 8 participants |
| Breakdown of diabetic complications Diabetic retinopathy | 91 participants | 101 participants | 10 participants |
| Complications of Allergic Disease Had complications | 66 participants | 73 participants | 7 participants |
| Complications of Allergic Disease Had no complications | 888 participants | 990 participants | 102 participants |
| Complications of Dyslipidemia Had complications | 623 participants | 692 participants | 69 participants |
| Complications of Dyslipidemia Had no complications | 331 participants | 371 participants | 40 participants |
| Complications of Heart Disease Had complications | 103 participants | 110 participants | 7 participants |
| Complications of Heart Disease Had no complications | 851 participants | 953 participants | 102 participants |
| Complications of Heart Failure Had complications | 19 participants | 20 participants | 1 participants |
| Complications of Heart Failure Had no complications | 935 participants | 1043 participants | 108 participants |
| Complications of Hypertension Had complications | 567 participants | 621 participants | 54 participants |
| Complications of Hypertension Had no complications | 387 participants | 442 participants | 55 participants |
| Complications of Hyperuricemia Had complications | 69 participants | 83 participants | 14 participants |
| Complications of Hyperuricemia Had no complications | 885 participants | 980 participants | 95 participants |
| Complications of Liver Damage Had complications | 203 participants | 223 participants | 20 participants |
| Complications of Liver Damage Had no complications | 751 participants | 840 participants | 89 participants |
| Complications of Malignant Tumor Had complications | 18 participants | 24 participants | 6 participants |
| Complications of Malignant Tumor Had no complications | 936 participants | 1039 participants | 103 participants |
| Complications of Renal Damage Had complications | 114 participants | 126 participants | 12 participants |
| Complications of Renal Damage Had No Complications | 840 participants | 937 participants | 97 participants |
| Complications of Stroke-related Disease Had complications | 58 participants | 63 participants | 5 participants |
| Complications of Stroke-related Disease Had no complications | 896 participants | 1000 participants | 104 participants |
| Degree of Hepatic Dysfunction Grade 1 | 81 participants | 94 participants | 13 participants |
| Degree of Hepatic Dysfunction Grade 2 | 21 participants | 22 participants | 1 participants |
| Degree of Hepatic Dysfunction Normal | 597 participants | 662 participants | 65 participants |
| Degree of Hepatic Dysfunction Unknown | 255 participants | 285 participants | 30 participants |
| Degree of Renal Dysfunction Mild | 359 participants | 409 participants | 50 participants |
| Degree of Renal Dysfunction Moderate | 135 participants | 148 participants | 13 participants |
| Degree of Renal Dysfunction Normal | 213 participants | 225 participants | 12 participants |
| Degree of Renal Dysfunction Severe | 3 participants | 3 participants | 0 participants |
| Degree of Renal Dysfunction Unknown | 244 participants | 278 participants | 34 participants |
| Diabetic complications Had complications | 206 participants | 226 participants | 20 participants |
| Diabetic complications Had No Complications | 748 participants | 837 participants | 89 participants |
| Glycosylated Hemoglobin (HbA1c) Level HbA1c <6.0 percent (%) | 12 participants | 17 participants | 5 participants |
| Glycosylated Hemoglobin (HbA1c) Level HbA1c >=6.0% to <7.0% | 177 participants | 193 participants | 16 participants |
| Glycosylated Hemoglobin (HbA1c) Level HbA1c >=7.0% to <8.0% | 381 participants | 424 participants | 43 participants |
| Glycosylated Hemoglobin (HbA1c) Level HbA1c >=8.0% | 341 participants | 376 participants | 35 participants |
| Glycosylated Hemoglobin (HbA1c) Level Unknown | 43 participants | 53 participants | 10 participants |
| Healthcare Category Inpatient | 2 participants | 3 participants | 1 participants |
| Healthcare Category Outpatient | 920 participants | 1022 participants | 102 participants |
| Healthcare Category Outpatient and inpatient | 32 participants | 38 participants | 6 participants |
| Health-related Complications Had complications | 862 participants | 953 participants | 91 participants |
| Health-related Complications Had no complications | 92 participants | 110 participants | 18 participants |
| History of Alcohol Consumption No | 573 participants | 633 participants | 60 participants |
| History of Alcohol Consumption Unknown | 150 participants | 173 participants | 23 participants |
| History of Alcohol Consumption Yes | 231 participants | 257 participants | 26 participants |
| History of Allergy Did not have allergy | 92 participants | 102 participants | 10 participants |
| History of Allergy Had allergy | 773 participants | 857 participants | 84 participants |
| History of Allergy Unknown | 89 participants | 104 participants | 15 participants |
| New York Heart Association (NYHA) Heart Failure Classification NYHA Class I | 13 participants | 13 participants | 0 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 IV | 1 participants | 2 participants | 1 participants |
| Other Complications Had complications | 315 participants | 353 participants | 38 participants |
| Other Complications Had no complications | 639 participants | 710 participants | 71 participants |
| Pregnancy Status Not pregnant | 388 participants | 425 participants | 37 participants |
| Pregnancy Status Pregnant | 0 participants | 0 participants | 0 participants |
| Presence of Medical History Did not have medical history | 694 participants | 762 participants | 68 participants |
| Presence of Medical History Had medical history | 150 participants | 180 participants | 30 participants |
| Presence of Medical History Unknown | 110 participants | 121 participants | 11 participants |
| Sex: Female, Male Female | 388 Participants | 425 Participants | 37 Participants |
| Sex: Female, Male Male | 566 Participants | 638 Participants | 72 Participants |
| Smoking Classification Current Smoker | 167 participants | 185 participants | 18 participants |
| Smoking Classification Ex-smoker | 162 participants | 177 participants | 15 participants |
| Smoking Classification Never Smoked | 442 participants | 487 participants | 45 participants |
| Smoking Classification Unknown | 183 participants | 214 participants | 31 participants |
| Time from Diagnosis of Type 2 Diabetes >=10 years | 254 participants | 281 participants | 27 participants |
| Time from Diagnosis of Type 2 Diabetes >=2 to <5 years | 169 participants | 189 participants | 20 participants |
| Time from Diagnosis of Type 2 Diabetes <2 years | 114 participants | 130 participants | 16 participants |
| Time from Diagnosis of Type 2 Diabetes >=5 to <10 years | 218 participants | 237 participants | 19 participants |
| Time from Diagnosis of Type 2 Diabetes Unknown | 199 participants | 226 participants | 27 participants |
| Waist Circumference <85 centimeter (cm) (Male) | 25 participants | 30 participants | 5 participants |
| Waist Circumference >=85 cm (Male) | 90 participants | 94 participants | 4 participants |
| Waist Circumference <90 cm (Female) | 37 participants | 41 participants | 4 participants |
| Waist Circumference >=90 cm (Female) | 33 participants | 36 participants | 3 participants |
| Waist Circumference Unknown (Female) | 318 participants | 348 participants | 30 participants |
| Waist Circumference Unknown (Male) | 451 participants | 514 participants | 63 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 954 | 2 / 109 |
| serious Total, serious adverse events | 4 / 954 | 0 / 109 |
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 + biguanides 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 + Biguanides | Number of Participants Reporting One or More Adverse Drug Reactions | 26 participants |
| Alogliptin + Other | Number of Participants Reporting One or More Adverse Drug Reactions | 2 participants |
Primary
Number of Participants Reporting One or More Serious Adverse Drug Reactions
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. An 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 + biguanides 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 + Biguanides | Number of Participants Reporting One or More Serious Adverse Drug Reactions | 4 participants |
| Alogliptin + Other | Number of Participants Reporting One or More Serious Adverse Drug Reactions | 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 biguanide 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 + Biguanides | Change From Baseline in Fasting Blood Glucose | Baseline (n = 253) | 151.8 milligram per deciliter (mg/dL) | Standard Deviation 48.68 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Blood Glucose | Change at Month 1 (n = 160) | -16.7 milligram per deciliter (mg/dL) | Standard Deviation 40.47 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Blood Glucose | Change at Month 3 (n = 198) | -17.1 milligram per deciliter (mg/dL) | Standard Deviation 47.05 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Blood Glucose | Change at Month 6 (n = 189) | -16.0 milligram per deciliter (mg/dL) | Standard Deviation 44.03 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Blood Glucose | Change at Month 12 (n = 186) | -19.1 milligram per deciliter (mg/dL) | Standard Deviation 40.04 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Blood Glucose | Change at final assessment (n = 253) | -17.2 milligram per deciliter (mg/dL) | Standard Deviation 44.25 |
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 biguanide 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 insulin data at baseline and post-baseline time points available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alogliptin + Biguanides | Change From Baseline in Fasting Insulin Level | Baseline (n = 32) | 9.00 microunits per milliliter | Standard Deviation 6.712 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Insulin Level | Change at Month 1 (n = 21) | 1.79 microunits per milliliter | Standard Deviation 5.485 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Insulin Level | Change at Month 3 (n = 18) | 2.21 microunits per milliliter | Standard Deviation 6.305 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Insulin Level | Change at Month 6 (n = 24) | 0.04 microunits per milliliter | Standard Deviation 4.913 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Insulin Level | Change at Month 12 (n = 19) | -1.21 microunits per milliliter | Standard Deviation 3.711 |
| Alogliptin + Biguanides | Change From Baseline in Fasting Insulin Level | Change at final assessment (n = 32) | -0.25 microunits per milliliter | Standard Deviation 5.286 |
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 biguanide 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 + Biguanides | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Baseline (n = 880) | 7.84 percentage of glycosylated hemoglobin | Standard Deviation 1.215 |
| Alogliptin + Biguanides | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Month 1 (n = 671) | -0.35 percentage of glycosylated hemoglobin | Standard Deviation 0.63 |
| Alogliptin + Biguanides | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Month 3 (n = 768) | -0.59 percentage of glycosylated hemoglobin | Standard Deviation 0.943 |
| Alogliptin + Biguanides | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Month 6 (n = 776) | -0.62 percentage of glycosylated hemoglobin | Standard Deviation 1.011 |
| Alogliptin + Biguanides | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Month 12 (n = 723) | -0.65 percentage of glycosylated hemoglobin | Standard Deviation 1.027 |
| Alogliptin + Biguanides | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change at Final Assessment (n = 880) | -0.58 percentage of glycosylated hemoglobin | Standard Deviation 1.066 |
Secondary
Percentage of Participants of Achieving Objective Glycemic Control
The rate of achieving objective glycemic control in HbA1c level, was calculated at 12 month or 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 biguanide 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 + Biguanides | Percentage of Participants of Achieving Objective Glycemic Control | <8.0% (Baseline) | 62.8 percentage of participants |
| Alogliptin + Biguanides | Percentage of Participants of Achieving Objective Glycemic Control | <8.0% (Final assessment [upto month 12]) | 80.5 percentage of participants |
| Alogliptin + Biguanides | Percentage of Participants of Achieving Objective Glycemic Control | <7.0% (Baseline) | 21.4 percentage of participants |
| Alogliptin + Biguanides | Percentage of Participants of Achieving Objective Glycemic Control | <7.0% (Final assessment [upto month 12]) | 47.2 percentage of participants |
| Alogliptin + Biguanides | Percentage of Participants of Achieving Objective Glycemic Control | <6.0% (Baseline) | 1.4 percentage of participants |
| Alogliptin + Biguanides | Percentage of Participants of Achieving Objective Glycemic Control | <6.0% (Final assessment [upto month 12]) | 5.2 percentage of participants |