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1.0 SYNOPSIS Survey title Objectives Survey population Nesina Tablets Special Drug Use Surveillance: Mild Type 2 Diabetes Mellitus To examine the safety and efficacy of long-term treatment with alogliptin (Nesina) in patients with mild type 2 diabetes mellitus in the routine clinical setting. This surveillance was conducted in patients with mild type 2 diabetes mellitus who met the following inclusion criteria and who did not meet the following exclusion criteria. The Precautions related to Indications section of the package insert for Nesina also had to be referenced. Inclusion criteria: Subjects had to meet the following criterion: Patients with HbA1c (JDS value) 7.0% at the time of enrollment (within 3 months before initiation of Nesina therapy) *Regardless of the use of antidiabetic medication Exclusion criteria: Subjects who met the following criterion were excluded: (1) Patients with severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus (2) Patients with severe infection, perioperative status, or serious trauma (3) Patients with a history of hypersensitivity to any ingredients of Nesina The usual adult dosage was 25 mg of alogliptin once daily orally. The Dosage and Precautions related to Dosage and Administration section of the Nesina administration package insert had to be referenced. 36 months from the first day of Nesina therapy. Follow-up duration However, if administration of Nesina was discontinued for certain reasons, the patient was to be withdrawn from observation in this surveillance at the point. Survey period August 3, 2011 to July 31, 2017 Patient enrollment August 3, 2011 to July 31, 2013 period Patient information for enrollment, patient background information, treatment details (details of Nesina use, details of other antidiabetic Key data collected medications, details of concomitant medications), test/observation parameters (laboratory test values, body weight, blood pressure), and adverse events [Planned] Number of patients 20,000 patients [Analyzed] 1
Safety conclusions Enrolled: 19,192 patients Case report forms (electronic) collected: 18,304 patients Evaluated for safety: 18,254 patients (including 16,561 patients with mild type 2 diabetes mellitus*) Evaluated for efficacy: 16,561 patients *: Defined as type 2 diabetic patients evaluated for safety who had HbA1c (NGSP value) 7.4% at baseline Overall, 483 adverse drug reactions or infections (hereinafter referred to as ADRs ) occurred in 441 patients, with an incidence of 2.42% (441/18,254 patients). Common ADRs (defined as those reported 20 events) were hypoglycaemia (43 events), constipation (33 events), rash (25 events), and dizziness (20 events). In the sub-population with mild type 2 diabetes mellitus, 458 ADRs occurred in 417 patients with an incidence of 2.52% (417/16,561 patients). Common ADRs (defined as those reported 20 events) were hypoglycaemia (40 events), constipation (33 events), and rash (25 events). As for the ADRs designated as the important identified risks, important potential risks, or important missing information with Nesina (hereinafter referred to as important identified or potential risks ), the most common event in the overall population in this surveillance was hypoglycaemia (PT: Hypoglycaemia; 43 events in 43 patients) (40 events in 40 patients with mild type 2 diabetes mellitus), followed by malignant tumor (PTs: Bile duct cancer, Bladder cancer, Bladder neoplasm, Colon cancer, Diffuse large B-cell lymphoma, Gastric cancer, Myelofibrosis, Neoplasm malignant, Oesophageal carcinoma, Ovarian cancer, Pancreatic carcinoma, Lung neoplasm malignant, Prostate cancer, Intraductal papillary mucinous neoplasm, Hepatic cancer, Hepatic cancer recurrent, Hepatocellular carcinoma; 21 events in 20 patients) (21 events in 20 patients with mild type 2 diabetes mellitus), angioedema (PTs: Eyelid oedema, Face oedema, Urticaria; 13 events in 13 patients) (12 events in 12 patients with mild type 2 diabetes mellitus; other than 1 event of eyelid oedema), hepatic function disorder/jaundice (PTs: Aspartate aminotransferase increased, Hepatic function abnormal, Liver disorder, Hepatic cancer, Hepatic cancer recurrent, Hepatocellular carcinoma; 12 events in 11 patients) (12 events in 11 patients with mild type 2 diabetes mellitus), cardiovascular risks (PTs: Acute myocardial infarction, Blood creatine phosphokinase increased, Cerebellar haemorrhage, Cerebral infarction, Cerebrovascular accident, Subdural haematoma; 10 events in 10 patients) (9 events in 9 patients with mild type 2 diabetes mellitus; other than 1 event of cerebellar haemorrhage), infection (PTs: Gastroenteritis, Peritonitis, Pneumonia, Anal 2
abscess; 5 events in 5 patients) (5 events in 5 patients with mild type 2 diabetes mellitus), acute pancreatitis (PT: Pancreatitis acute; 4 events in 4 patients) (4 events in 4 patients with mild type 2 diabetes mellitus), severe skin disorders including oculomucocutaneous syndrome (Stevens-Johnson syndrome) and erythema multiforme (PT: Erythema multiforme; 3 events in 3 patients) (3 events in 3 patients with mild type 2 diabetes mellitus), and rhabdomyolysis (PT: Rhabdomyolysis; 2 events in 2 patients) (2 events in 2 patients with mild type 2 diabetes mellitus). There were no ADRs involving intestinal obstruction, interstitial pneumonia, or pemphigoid, among the ADRs designated as the important identified or potential risks of Nesina. Serious ADRs were reported 65 events in 52 patients in the overall population in this surveillance with an incidence of 0.28% (52/18,254 patients). In the sub-population with mild type 2 diabetes mellitus, there were 62 serious ADRs in 49 patients with an incidence of 0.30% (49/16,561 patients). The causal relationship to Nesina was assessed as related for 15 serious ADRs in 7 patients, all in those with mild type 2 diabetes mellitus. Specifically these 15 serious ADRs were 2 events of pancreatitis acute, 2 events of hypoglycaemia, and 1 event each of marasmus, rhabdomyolysis, pyrexia, white blood cell count increased, C-reactive protein increased, fall, excoriation, contusion, subdural hygroma, headache, and subdural haematoma. Of these, the ADRs involving the important identified or potential risks were pancreatitis acute, hypoglycaemia, rhabdomyolysis, and subdural haematoma. The event outcome was resolved or resolving for all serious ADRs assessed as related to Nesina with the exception of the event of marasmus that had fatal outcome. The safety of Nesina in patients with renal dysfunction was analyzed with stratification according to the presence or absence of concurrent renal disorder. The incidence of ADRs was 2.33% (387/16,577 patients) in patients without concurrent renal disorder and 3.22% (54/1,677 patients) in patients with concurrent renal disorder in the overall population, and 2.41% (363/15,036 patients) and 3.54% (54/1,525 patients) respectively in the sub-population with mild type 2 diabetes mellitus. Thus, the incidence of ADRs was higher in patients with concurrent renal disorder than in patients without. Common ADRs (defined as those reported 5 events) in patients with concurrent renal disorder in the overall population were hypoglycaemia (7 events) and diabetic nephropathy (7 events), and were the same in patients with concurrent renal disorder in the subpopulation with mild type 2 diabetes mellitus. With stratification by severity of renal dysfunction (rated by physician; the same applies below) ( normal + mild vs. "moderate or higher [i.e., moderate + severe] ), the incidence of ADRs 3
in patients with normal + mild and moderate + severe renal dysfunction was 2.39% (420/17,579 patients) and 3.11% (21/675 patients) respectively in the overall population, and 2.48% (396/15,954 patients) and 3.46% (21/607 patients) respectively in the sub-population with mild type 2 diabetes mellitus. Thus, in both the overall population and the sub-population with mild type 2 diabetes mellitus, the incidence of ADRs did not differ between different strata of the severity of renal dysfunction. The ADRs that occurred 2 or more events in patients with moderate + severe renal dysfunction in the overall population were diabetic nephropathy (3 events) and constipation (2 events). By presence or absence of concomitant use of renally excreted drugs, the incidence of ADRs in patients without and with concomitant use of renally excreted drugs was 2.29% (240/10,465 patients) and 2.58% (201/7,789 patients) respectively in the overall population, and 2.40% (226/9,425 patients) and 2.68% (191/7,136 patients) respectively in the sub-population with mild type 2 diabetes mellitus. Thus, in both the overall population and the sub-population with mild type 2 diabetes mellitus, the incidence of ADRs did not differ between patients with and without concomitant use of renally excreted drugs. The safety of Nesina in patients with moderate or higher renal dysfunction was analyzed with stratification according to the average daily dose of Nesina. In the overall population, the incidence of ADRs was 3.23% (15/465 patients) in the 25 to >12.5 mg stratum, 2.13% (3/141 patients) in the 12.5 to >6.25 mg stratum, and 4.35% (3/69 patients) in the 6.25 mg stratum. In the sub-population with mild type 2 diabetes mellitus, the incidence of ADRs was 3.65% (15/411 patients) in the 25 to >12.5 mg stratum, 2.31% (3/130 patients) in the 12.5 to >6.25 mg stratum, and 4.55% (3/66 patients) in the 6.25 mg stratum. The only ADR that occurred 2 or more events in any stratum of Nesina s average daily dose was diabetic nephropathy (3 events) in the 25 to >12.5 mg stratum. The safety of Nesina in patients with hepatic dysfunction was analyzed with stratification according to the presence or absence of concurrent hepatic disorder. The incidence of ADRs was 2.40% (390/16,271 patients) in patients without concurrent hepatic disorder and 2.57% (51/1,983 patients) in patients with concurrent hepatic disorder in the overall population, and 2.50% (369/14,739 patients) and 2.63% (48/1,822 patients) respectively in the sub-population with mild type 2 diabetes mellitus. Thus, the incidence of ADRs did not differ between patients with and without concurrent hepatic disorder, in both the overall population and the sub-population with 4
mild type 2 diabetes mellitus. The safety of Nesina in elderly patients was analyzed with stratification by age category (<65 years vs. 65 years). The incidence of ADRs was 2.00% (141/7,038 patients) in patients aged <65 years and 2.67% (300/11,216 patients) in patients aged 65 years in the overall population, and 2.10% (132/6,281 patients) and 2.77% (285/10,280 patients) respectively in the sub-population with mild type 2 diabetes mellitus. Thus, the incidence of ADRs was higher in patients aged 65 years than in those aged <65 years, in both the overall population and the sub-population with mild type 2 diabetes mellitus. With stratification by age category (<75 years vs. 75 years), the incidence of ADRs was 2.28% (297/13,030 patients) in patients aged <75 years and 2.76% (144/5,224 patients) in patients aged 75 years, and 2.36% (277/11,760 patients) and 2.92% (140/4,801 patients) respectively in the sub-population with mild type 2 diabetes mellitus. Thus, the incidence of ADRs was higher in patients aged 75 years than in those aged <75 years, with a difference in the sub-population with mild type 2 diabetes mellitus. In terms of the effects on cardiovascular risks, the ADRs involving cardiovascular risks occurred 10 events with an incidence of 0.05% (10/18,254 patients) in the overall population, and 9 events with an incidence of 0.05% (9/16,561 patients) in the sub-population with mild type 2 diabetes mellitus. Specifically these ADRs involving cardiovascular risks were: 3 events of cerebral infarction, 2 events of cerebrovascular accident, 2 events of subdural haematoma, and 1 event each of acute myocardial infarction, blood creatine phosphokinase increased, and cerebellar haemorrhage (of these, 1 event of cerebellar haemorrhage was not in patients with mild type 2 diabetes mellitus). With stratification by presence or absence of concurrent cardiac disease, the incidence of ADRs was 2.37% (380/16,036 patients) in patients without concurrent cardiac disease and 2.75% (61/2,218 patients) in patients with concurrent cardiac disease in the overall population; and 2.47% (359/14,516 patients) and 2.84% (58/2,045 patients) respectively in the sub-population with mild type 2 diabetes mellitus. By presence or absence of concurrent stroke-related diseases, the incidence of ADRs was 2.41% (411/17,077 patients) in patients without concurrent stroke-related diseases and 2.55% (30/1,177 patients) in patients with concurrent stroke-related diseases in the overall population, and 2.51% (387/15,477 patients) and 2.69% (30/1,144 patients) respectively in the sub-population with mild type 2 diabetes mellitus. In both the overall population and the sub-population with mild type 2 diabetes mellitus, the incidence of ADRs did not differ between patients with and without 5
concurrent cardiac disease, or patients with and without concurrent stroke-related diseases. With stratification according to the presence or absence of concurrent cardiac failure and the severity of cardiac failure (NYHA class), the incidence of ADRs did not differ between different strata. In this surveillance, cardiovascular risk factors such as dyslipidaemia or hypertension were present in approximately 60% of the patients in either the overall population or the sub-population with mild type 2 diabetes mellitus. However, in terms of blood pressure (systolic and diastolic) and body weight, the mean values at final evaluation showed almost no changes from baseline. The mean values of lipid parameters except HDL-cholesterol (fasting triglyceride, total cholesterol, LDL-cholesterol, and non-hdl-cholesterol) decreased from baseline at all time points of evaluation. The mean values of HDL-cholesterol showed almost no changes from baseline. With stratification by sex, the incidence of ADRs was 2.21% (227/10,281 patients) in males and 2.68% (214/7,973 patients) in females in the overall population, and 2.26% (210/9,285 patients) and 2.84% (207/7,276 patients) respectively in the sub-population with mild type 2 diabetes mellitus, and was higher in females than in males. With stratification by the presence or absence of concomitant medication (antidiabetic medication) as well as specific concomitant medication (antidiabetic medication), the incidence of ADRs was approximately 2.5% in patients with concomitant use of antidiabetic medication other than insulin, in both the overall population and the sub-population with mild type 2 diabetes mellitus. In patients with concomitant use of insulin, the incidence of ADRs was 6.56% (8/122 patients) in the overall population and 6.48% (7/108 patients) in the sub-population with mild type 2 diabetes mellitus. The only ADR that occurred 2 or more events was hypoglycaemia, which occurred 2 events in the overall population. Efficacy conclusions The mean HbA1c (NGSP value; the same applies below) was 6.79±0.451% at baseline, decreased to 6.62±0.617% at 3 months of Nesina therapy, and was stable thereafter with 6.66±0.781% at final evaluation. The change from baseline at final evaluation was 0.14±0.777%. The percentage of patients with achievement of an HbA1c control goal of <7.0% and <6.0% was 58.0% and 5.2% respectively at baseline, and increased to 72.6% and 14.0% respectively at final evaluation. Stratified analysis by patient background factor was performed on the change in HbA1c. Except for baseline HbA1c <6.0% and concomitant antidiabetic medication with insulin, the HbA1c values did not substantially differ between different strata of any patient background 6
Discussion and overall conclusions factors and showed decrease. Stratified analysis by patient background factor was performed also on the HbA1c control goal achievement rate. The HbA1c control goal achievement rate improved from baseline at final evaluation in all strata of patient background factors other than baseline HbA1c <6.0% and concomitant antidiabetic medication with insulin. The efficacy of Nesina in patients with moderate or higher renal dysfunction was analyzed. With stratification by severity of renal dysfunction, the change in HbA1c at final evaluation was 0.14±0.773% in patients with normal + mild renal dysfunction and 0.09±0.875% in patients with moderate + severe renal dysfunction. The percentage of patients with achievement of an HbA1c control goal of <7.0% and <6.0% in patients with normal + mild renal dysfunction was 57.8% and 5.0% respectively at baseline, and increased to 72.6% and 13.7% respectively at final evaluation. In patients with moderate + severe renal dysfunction, the corresponding percentage was 64.3% and 9.9% respectively at baseline, and increased to 72.3% and 21.6% respectively at final evaluation. In patients with moderate or higher renal dysfunction, the change in HbA1c at final evaluation by average daily dose of Nesina was 0.10±0.907% in the 25 to >12.5 mg stratum, 0.04±0.890% in the 12.5 to >6.25 mg stratum, and 0.11±0.593% in the 6.25 mg stratum. The percentage of patients with achievement of an HbA1c control goal of <7.0% and <6.0% in the 25 to >12.5 mg stratum was 61.6% and 6.3% respectively at baseline, and increased to 71.1% and 19.6% respectively at final evaluation. In the 12.5 to >6.25 mg stratum, the corresponding percentage was 66.2% and 15.4% respectively at baseline, and increased to 71.5% and 24.4% respectively at final evaluation. In the 6.25 mg stratum, the corresponding percentage was 77.3% and 21.2% respectively at baseline, and increased to 82.0% and 29.5% respectively at final evaluation. This surveillance was conducted to examine the safety and efficacy of long-term Nesina therapy in patients with mild type 2 diabetes mellitus. The surveillance results raised no major concerns about the safety or efficacy of long-term Nesina therapy, as stated below. (1) Safety of long-term Nesina therapy The incidence of ADRs was 2.42% (441/18,254 patients) in the overall population and 2.52% (417/16,561 patients) in the sub-population with mild type 2 diabetes mellitus. The incidence of ADRs in the overall population or the sub-population with mild type 2 diabetes mellitus showed no substantial difference compared with the incidence in other specified drug-use surveys of Nesina in patients with type 2 diabetes mellitus (i.e., 1.47% with Nesina 7
monotherapy, 3.88% with Nesina + α-glucosidase inhibitor, 1.76% with Nesina + thiazolidine, 2.73% with Nesina + biguanide, 2.07% with Nesina + sulfonylurea). Analysis of ADRs by time to onset identified no delayed ADRs occurring with an increased incidence particularly beyond 1 year (336 days) of treatment. In terms of the safety of Nesina used in patients with renal dysfunction, the results of stratified analysis according to the presence or absence of concurrent renal disorder and severity of renal dysfunction showed that, in both the overall population and the sub-population with mild type 2 diabetes mellitus, the incidence of ADRs was higher in patients with concurrent renal disorder than in patients without concurrent renal disorder. However, the incidence of ADRs did not differ between different strata of the severity of renal dysfunction, in both the overall population and the sub-population with mild type 2 diabetes mellitus. In patients with moderate or higher renal dysfunction, the incidence of ADRs by average daily dose of Nesina showed no trend such as a higher incidence of ADRs at a higher dose. By presence or absence of concomitant use of renally excreted drugs, the incidence of ADRs did not differ between the different strata, in both the overall population and the sub-population with mild type 2 diabetes mellitus. Although the data indicate that patients with renal dysfunction are at higher risk for ADRs to Nesina, comparison with pre-approval data identified no new concerns. The current package insert already includes precautionary statement regarding the use in patients with renal dysfunction. In terms of the safety in patients with hepatic dysfunction, the results of stratified analysis according to the presence or absence of concurrent hepatic disorder showed that the incidence of ADRs did not differ between the different strata in both the overall population and the sub-population with mild type 2 diabetes mellitus. In terms of the safety of Nesina used in elderly patients, the results of stratified analysis by age category (<65 years vs. 65 years, or <75 years vs. 75 years) showed that the incidence of ADRs was higher in patients aged 65 years than in those aged <65 years in both the overall population and the sub-population with mild type 2 diabetes mellitus. In the sub-population with mild type 2 diabetes mellitus, the incidence of ADRs was higher also in patients aged 75 years than in those aged <75 years, but comparison with pre-approval data identified no new concerns. The current package insert already includes precautionary statement regarding the use in elderly patients. 8
In terms of the effects on cardiovascular risks, the ADRs involving cardiovascular risks occurred with an incidence of 0.05% in both the overall population and the sub-population with mild type 2 diabetes mellitus (specifically, 10/18,254 patients in the overall population and 9/16,561 patients in the sub-population with mild type 2 diabetes mellitus). In both the overall population and the sub-population with mild type 2 diabetes mellitus, the incidence of ADRs did not differ depending on the presence or absence of concurrent cardiac disease, presence or absence of concurrent cardiac failure, severity of cardiac failure (NYHA class), or presence or absence of concurrent stroke-related diseases. No new concerns were raised regarding cardiovascular risks. With stratification by the presence or absence of concomitant medication (antidiabetic medication) as well as specific concomitant medication (antidiabetic medication), the incidence of ADRs was approximately 2.5% in patients with concomitant use of antidiabetic medication other than insulin, in both the overall population and the sub-population with mild type 2 diabetes mellitus. In patients with concomitant use of insulin, the incidence of ADRs was approximately 6.5% in both the overall population and the sub-population with mild type 2 diabetes mellitus. Given the limited samples sizes of 122 patients who concomitantly used insulin in the overall population and 108 patients who had mild type 2 diabetes mellitus, the data from these populations would not allow assessment by simple comparison with the data from Nesina use in combination with sulfonylurea or biguanide that has a population size of 3,000 or more. The current package insert already includes precautionary statement regarding co-administration with insulin. With stratification by sex, the incidence of ADRs was higher in females than in males, in both the overall population and the sub-population with mild type 2 diabetes mellitus. However, no particular ADR had a marked difference in the incidence between males and females. (2) Efficacy of long-term Nesina therapy The mean HbA1c was 6.79±0.451% at baseline and 6.66±0.781% at final evaluation, with a change of 0.14±0.777% from baseline at final evaluation. The percentage of patients with achievement of an HbA1c control goal of <7.0% and <6.0% was 58.0% and 5.2% respectively at baseline, and increased to 72.6% and 14.0% respectively at final evaluation, indicating the usefulness of Nesina in long-term glycemic control of patients with mild type 2 diabetes mellitus as well. With stratification by severity of renal dysfunction into normal + mild 9
and moderate + severe, the change in HbA1c at final evaluation was similar at 0.14±0.773% in the normal + mild stratum and 0.09±0.875% in the moderate + severe stratum. The percentage of patients with achievement of an HbA1c control goal of <7.0% and <6.0% in patients with normal + mild renal dysfunction was 57.8% and 5.0% respectively at baseline and 72.6% and 13.7% respectively at final evaluation, and that in patients with moderate + severe dysfunction was 64.3% and 9.9% respectively at baseline and 72.3% and 21.6% respectively at final evaluation, all showing improvement from baseline. In patients with moderate or higher renal dysfunction, the change in HbA1c at final evaluation by average daily dose of Nesina was 0.10±0.907% in the 25 to >12.5 mg stratum, 0.04±0.890% in the 12.5 to >6.25 mg stratum, and 0.11±0.593% in the 6.25 mg stratum. The percentage of patients with achievement of an HbA1c control goal of <7.0% and <6.0% in the 25 to >12.5 mg stratum was 61.6% and 6.3% respectively at baseline and 71.1% and 19.6% respectively at final evaluation. In the 12.5 to >6.25 mg stratum, the corresponding percentage was 66.2% and 15.4% respectively at baseline and 71.5% and 24.4% respectively at final evaluation. In the 6.25 mg stratum, the corresponding percentage was 77.3% and 21.2% respectively at baseline and 82.0% and 29.5% respectively at final evaluation, all showing improvement from baseline. Stratified analysis by patient background and treatment factors showed that, other than baseline HbA1c <6.0% and concomitant antidiabetic medication with insulin, no factors appeared to have particular effect on the efficacy. In patients with baseline HbA1c <6.0%, no decrease in HbA1c was shown after administration of Nesina presumably because the control of HbA1c was already favorable at the start of Nesina therapy. In patients with concomitant antidiabetic medication with insulin, the effect greatly varied partly because of the limited sample size, and involvement of patient background factors not evaluated in this survey is also conceivable, but further assessment was difficult. In conclusion from the above data, regarding the efficacy of Nesina in patients with mild type 2 diabetes mellitus, the effect in improving HbA1c was stable and maintained irrespective of the severity of renal dysfunction and other factors, thereby confirming the usefulness of Nesina in long-term glycemic control. 10