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SYR-322 Page 1of 10 1. SYNOPSIS Study title: A phase III clinical study of SYR-322 combination therapy with insulin preparation Name of Sponsor: Takeda Pharmaceutical Company Limited Name of investigational product: SYR-322 Product name: Nesina tablet Investigator(s) and study site(s): Kenichi Imamura, Director, Internal Medicine, Imamura Clinic, and other study sites, a total of 37 study sites Publication: The contents of this clinical study have not been published. Study period: Phase III Date first subject signed informed consent form: 24 February 2012 Date last subject received the last dose: 29 September 2013 Objective: The efficacy and safety of SYR-322 25 mg tablet as an add-on to insulin therapy were studied in patients with type 2 diabetes with inadequate glycemic control despite treatment with insulin preparation in addition to diet and exercise therapy. Study design: This study was a multicenter, randomized, Phase III, parallel-group, comparative trial (Treatment Period I, double-blind; Treatment Period II, open-label) that examined the efficacy and safety of SYR-322 25 mg tablet as an add-on to insulin therapy in patients with type 2 diabetes with inadequate glycemic control despite treatment with insulin preparation in addition to diet and exercise therapy, with a control group of insulin plus placebo. The subjects who proceeded to the observation period after signing informed consent and were assessed eligible based on the inclusion and exclusion criteria were randomized and assigned to the SYR-322 25 mg add-on therapy (A/A Group) or insulin plus placebo group (P/A Group). Study drugs were allocated based on the type of insulin preparation as an allocation factor by dynamic allocation [pre-mixed (rapid-acting or short-acting insulin content not more than 30%), intermediate-acting, or long-acting]. As for SYR-322 therapy, one SYR-322 25 mg tablet or placebo tablet was orally administered once daily before breakfast in Treatment Period I, and one SYR-322 25 mg tablet was orally administered once daily before breakfast in Treatment Period II. In addition, insulin preparation was administered at fixed dose and regimen in the observation period and Treatment Period I, and the dose and regimen were allowed to be changed as needed in Treatment Period II. From the standpoint of subjects safety assurance, in accordance with the insulin preparation dose reduction and dose increase criteria described in the dose and regimen of insulin preparation, the daily dose of insulin preparation was allowed to be changed. The duration of the study was 58 weeks, including a 6-week observation period and a 52-week treatment period. The treatment period up to Week 12 was set as Treatment Period I (double-blind), and the treatment period between Week 12 and Week 52 was set as Treatment Period II (open-label). Subjects were instructed to make study visits at the initiation of the observation period (Week -6) and
SYR-322 Page 2of 10 4 weeks after the initiation of the observation period (Week -2), every 2 weeks from 4 weeks after the initiation of the observation period (Week -2) to Week 4, and every 4 weeks from Week 4 to the end of the treatment period (Week 52) (a total of 17 study visits). Number of subjects: (planned and analyzed) Planned Number of subjects evaluable for the primary endpoint: 70 subjects/group, a total of 140 subjects Number of randomized subjects: 84 subjects/group, a total of 168 subjects Analyzed P/A Group A/A Group Total All randomized subjects 89 90 179 Full analysis set (FAS) 89 90 179 Per protocol set (PPS) 71 75 146 Safety analysis set 89 90 179 Inclusion criteria: 1) Patients who had been diagnosed with type 2 diabetes. 2) Patients with fasting C-peptide of 0.6 ng/ml or more at the initiation of the observation period (Week -6) and 4 weeks after the initiation of the observation period (Week -2). 3) 10.0% at 4 weeks after the initiation of the observation period (Week -2). 4) Patients with the difference in HbA1c (JDS) between at the initiation of the observation period (Week -6) and 4 weeks after the initiation of the observation period (Week -2) within 10.0%* of the HbA1c (JDS) at the initiation of the observation period (Week -6). *Rounded to one decimal place. 5) Patients who had been on a fixed diet and exercise (if given) therapy since at least 6 weeks before the initiation of the observation period (Week -6). 6) Patients who had been on a basic diabetes treatment with insulin preparation units/day) since at least 6 weeks before the initiation of the observation period (Week -6)** at fixed dose and regimen of insulin preparation. **Patients on one of the following insulin monotherapy: pre-mixed (rapid-acting or short-acting insulin content not more than 30%), intermediate-acting, or long-acting]. 7) Patients who were deemed appropriate for a combination of insulin and another antidiabetic agent by the investigator or subinvestigator at the initiation of the observation period (Week -6). 8) For patients complicated with hypertension, those who had stable blood pressure control and were deemed to be not requiring dose alteration of the antihypertensive agent (including discontinuation or suspension) or addition of a new antihypertensive agent during the study period by the investigator or subinvestigator. 9) Regardless of gender, those who were at least 20 years of age at the time of informed consent. 10) For any woman of childbearing potential who had a nonsterilized male partner, those who agreed to regular practice of appropriate contraceptive from the time of informed consent throughout the study period. 11) Patients who were deemed to be capable of understanding and complying the protocol requirements by the investigator or subinvestigator. 12) Patients who were capable of signing and dating the informed consent form prior to the study procedure.
SYR-322 Page 3of 10 Exclusion criteria: 1) Patients with clinically apparent hepatic function disorder (e.g., AST and ALT at the initiation of the observation period (Week -6) not less than 2.5 times the upper limit of normal). 2) Patients with severe renal function disorder or end-stage renal failure [e.g., patients with serum creatinine level at the initiation of the observation period (Week -6) over 2.4 mg/dl(male), or over 2.0 mg/dl(female)]. 3) Patients with serious cardiac disease or cerebrovascular disorder, or patients with serious pancreatic/blood disease (e.g., patients requiring hospitalization and treatments). 4) Patients with systolic blood pressure of 180 mmhg and over or diastolic blood pressure of 110 mmhg and over during the observation period. 5) Patients who experienced hypoglycaemia within 6 weeks before the initiation of the observation period (Week -6) or during the observation period (at least twice per week). 6) Patients with malignant tumor. 7) Patients with a history of hypersensitivity to or allergy to DPP-4 inhibitors. 8) Patients with habitual drinking over 100 ml of alcohol per day on average. 9) Patients with a history of drug abuse (defined as illegal drug use) or alcohol dependence. 10) Patients who required treatment with excluded concomitant medication during the study period. 11) Patients with a history of SYR-322 or Nesina tablet therapy in a trial or as a therapeutic drug. 12) Patients who received study drugs (including study drugs for post-marketing trial) within 12 weeks before the initiation of the observation period. 13) Patients who were participating in another clinical study at the time of informed consent. 14) Pregnant women or nursing mothers. Women who planned to be pregnant from the time of informed consent to within 1 month after the end of study, or women who planned to become an egg donor during this period. 15) Employees of the study sites, their family, or those who are dependents of study site employees involved in the conduct of this study (e.g., spouse, parent, offspring, brother/sister), or those with a possibility to give consent under compulsion. 16) Patients with altered dose and regimen of insulin preparation during the observation period. 17) Patients with a history of hypersensitivity to or allergy to insulin preparations. 18) Patients who were in a condition which was a contraindication specified in the package insert of Nesina tablet or insulin preparations. 19) Patients who were hospitalized during the observation period or who were deemed to require hospitalization during the study period by the investigator or subinvestigator. 20) Other patients who were deemed to be inappropriate for the conduct of the study by the investigator or subinvestigator. Investigational product, dose and mode of administration, and lot number: (1) SYR-322 Dosage form Both SYR-322 25 mg tablet and placebo tablet were yellow, scored, film-coated tablets, and the appearance of SYR-322 25 mg tablet and SYR-322 placebo tablet was identical and indistinguishable from each other. Dose and regimen In Treatment Period I, one tablet of SYR-322 25 mg or placebo was orally administered once daily before breakfast. In Treatment Period II, one tablet of SYR-322 25 mg was orally administered once daily before breakfast. Administration of the study drug was started on the day after the end of the observation period
SYR-322 Page 4of 10 (Week 0). At specified study visits between Week 2 (Week 2) and the end of the treatment period (Week 52), subjects were instructed to make study visits without taking the study drug, and the study drug was administered after all tests/observations/evaluations specified for the visit were performed. At Week 12, subjects had to make a study visit without taking the study drug, and after all physical examination and tests scheduled for Week 12 were performed, the study drug for Treatment Period II was administered before the next meal. Lot No. Study drug Treatment period Lot No. Expiration date SYR-322 Treatment Period I DB641U041 January 2014 Treatment Period II Z641U042 January 2014 (2) Insulin preparation The existing marketed insulin preparations prescribed by the investigator or subinvestigator were used. Dose and regimen The unit of insulin preparation at the initiation of the observation period (Week -6) was set as the observation period, the dose and regimen were not to be altered. Patients administered one of the following insulin preparation throughout the study period without alteration: pre-mixed (the rapid-acting or short-acting insulin content not more than 30%), intermediate-acting, or long-acting. The dose and regimen for Treatment Period I and Treatment Period II were as follows: Treatment Period I: For insulin preparation, the dose and regimen at the initiation of the observation period (Week -6) were to be continued without alteration as a general rule. However, in accordance with the following dose reduction and dose increase criteria for insulin preparation, the dose units of insulin preparation were allowed to be changed. Even if changes in the insulin preparation units resulted in <8 units/day or >40 units/day, the study treatment was allowed to be continued. Treatment Period II: At the discretion of the investigator or subinvestigator, the dose and regimen of insulin preparation were allowed to be changed in reference to the Treatment Guide for Diabetes [1] as needed. Even if changes in the insulin preparation units resulted in <8 units/day, similarly to Treatment Period I, the study treatment was allowed to be continued. However, if changes in the insulin preparation units resulted in over 40 units/day continuously, the investigator or subinvestigator was required to determine whether the study was allowed to be continued or not, taking the safety of subjects into account. At scheduled study visits, patients were instructed to make study visits without taking insulin preparation, and after all tests/observations/evaluations specified for the visit were performed, insulin preparation was administered at a dose and regimen according to individual prescription.
SYR-322 Page 5of 10 Criteria for dose reduction and dose increase of insulin preparation to assure subjects safety in Treatment Period I If the following was applicable, the investigator or subinvestigator was to consider reduction and increase of the daily dose of insulin preparation. After dose reduction or dose increase, the reduced dose units or increased dose units was to be maintained. Dose reduction criterion: If any one of the following 1) and 2) was applicable, the daily dose of insulin preparation was allowed to be reduced from the daily dose units at the initiation of the observation period (Week -6) by a maximum of 4 units (regardless of the number of changes made). When a dose reduction by over 4 units/day was required, the study treatment was to be discontinued, and appropriate measures were to be taken. 1) When hypoglycemic symptoms were observed, and the investigator or subinvestigator considered that the subject required dose reduction of insulin preparation from the safety standpoint. 2) When the Self-Monitoring Blood Glucose level of <80 mg/dl was observed for at least 2 consecutive measurements, hypoglycemic symptoms were suspected, and the investigator or subinvestigator considered that the subject was at a high risk of hypoglyceamia. Dose increase criteria: When the Self-Monitoring Blood Glucose level of >200 mg/dl was observed for at least 2 consecutive measurements, and the investigator or subinvestigator considered that the patient required dose increase of insulin preparation from the safety standpoint, the daily dose of insulin preparation was allowed to be increased from the daily dose units at the initiation of the observation period (Week -6) by a maximum of 4 units (regardless of the number of changes made). When a dose increase by over 4 units/day was required, the study treatment was to be discontinued, and appropriate measures were to be taken. Criteria for dose reduction and dose increase of insulin preparation to assure subjects safety in Treatment Period II If the following was applicable, the investigator or subinvestigator was to consider reduction and increase of the daily dose of insulin preparation. After dose reduction or dose increase, the reduced dose units or increased dose units was to be maintained. Dose reduction criterion: If any one of the following 1) and 2) was applicable, reduction of daily dose units of insulin preparation was to be considered. 1) When hypoglycemic symptoms were observed, and the investigator or subinvestigator considered that the subject required dose reduction of insulin preparation from the safety standpoint. 2) When the Self-Monitoring Blood Glucose level of <80 mg/dl was observed for at least 2 consecutive measurements, hypoglycemic symptoms were suspected, and the investigator or subinvestigator considered that the subject was at a high risk of hypoglycemia. Dose increase criterion: When the Self-Monitoring Blood Glucose level of >180 mg/dl was observed for at least 2 consecutive measurements, and the investigator or subinvestigator considered that the subject required dose increase of insulin preparation from the safety standpoint, increase of the daily dose units of insulin preparation was to be considered.
SYR-322 Page 6of 10 Duration of evaluation: 58 weeks (a 6-week observation period and a 52-week treatment period) Evaluation variables: Efficacy Primary endpoint: Changes in HbA1c at the end of Treatment Period I (Week 12) (end of Treatment Period I - end of the observation period) Secondary endpoints: HbA1c, fasting blood glucose Other evaluation variables: Fasting C-peptide, fasting glucagon, glycoalbumin, 1,5-AG, body weight, daily dose (units) of insulin preparation Safety Secondary endpoints: Adverse events, vital signs, 12-lead ECG, clinical laboratory values Statistical methods: Primary endpoint and analytical method (primary analysis) The following analyses were performed for the FAS. The summary statistics (number of subjects, mean, standard deviation (SD), maximum, minimum, quartile) and two-sided 95% confidence interval (CI) of the mean were calculated by treatment group, the mean and SD for each group were presented in graphs, and the point estimates and two-sided 95% CI of the inter-group difference in the means (A/A Group - P/A Group) were calculated. Additionally, based on the analysis of covariance model with the changes in HbA1c at the end of Treatment Period I (Week 12) (end of Treatment Period I - end of the observation period) as a dependent variable, type of insulin preparation during the observation period [pre-mixed (the rapid-acting or short-acting insulin content with not more than 30%), intermediate-acting, or long-acting] as a block factor, HbA1c at the end of the observation period (Week 0) as covariate, and treatment group as an independent variable, the least square means (LS means), standard error (SE), and two-sided 95% CI of the LS means were calculated for each treatment group, the LS means and SE for each group were presented in graphs, and the point estimates and two-sided 95% CI of the inter-group difference in the LS means (A/A Group - P/A Group) were calculated. Further, a contrast test was applied using the above-mentioned analysis of covariance model to compare the treatment groups. SUMMARY-CONCLUSIONS: In this study, 179 subjects were randomized and all of them received the study drug in a double-blind manner. Of these subjects, 169 subjects proceeded to Treatment Period II, and 164 subjects completed Treatment Period II. Among 15 discontinued subjects, 10 subjects discontinued during Treatment Period I, and 5 subjects discontinued during Treatment Period II. EFFICACY RESULTS: (1) Primary endpoint In the primary analysis, the LS mean of changes in HbA1c at the end of Treatment Period I (Week 12) (end of Treatment Period I - end of the observation period), the primary endpoint, was -0.29% and -0.96% for P/A Group and A/A Group, respectively, and the point estimate (two-sided 95% CI) of the inter-group difference of the LS means (A/A Group - P/A Group) was -0.66 ([-0.824,
SYR-322 Page 7of 10-0.505])%. The results of the contrast test using the contrast coefficient (1, -1) versus treatment groups (A/A Group, P/A Group) verified the superiority of A/A Group over P/A Group (p<0.0001). In the secondary analysis, the same analysis as the primary analysis was performed for the PPS, yielding the same results as the primary analysis for the FAS, and the robustness of the results was confirmed. (2) Secondary endpoints 1) HbA1c The mean of change from baseline in HbA1c at the end of Treatment Period I (Week 12) (end of Treatment Period I - end of the observation period) for P/A Group and A/A Group was -0.31% and -0.97%, respectively, and the point estimate (two-sided 95% CI) of the inter-group difference (A/A Group - P/A Group) was -0.66 ([-0.828, -0.499])%. The mean of change from baseline in HbA1c at the end of the treatment period (Week 52) (end of the treatment period - end of the observation period) was -1.00% for P/A Group and -1.00% for A/A Group. The achievement rates for HbA1c <5.8%, <6.5%, and <7.0% at the end of Treatment Period I (Week 12) were 0.0%, 2.2%, and 19.1%, respectively, for P/A Group, and 3.3%, 17.8%, and 50.0%, respectively, for A/A Group. The achievement rates for HbA1c <5.8%, <6.5%, and <7.0% at the end of the treatment period (Week 52) were 3.4%, 23.6%, and 52.8%, respectively, for P/A Group, and 1.1%, 24.4%, and 54.4%, respectively, for A/A Group. 2) Fasting blood glucose The mean of change from baseline in fasting blood glucose at the end of Treatment Period I (Week 12) (end of Treatment Period I - end of the observation period) was -9.4 mg/dl and -20.1 mg/dl for P/A Group and A/A Group, respectively, and the point estimate (two-sided 95% CI) of the inter-group difference (A/A Group - P/A Group) was -10.7 ([-21.49, 0.14]) mg/dl. The mean of change from baseline in fasting blood glucose at the end of the treatment period (Week 52) (end of the treatment period - end of the observation period) was -14.0 mg/dl and -20.9 mg/dl for P/A Group and A/A Group, respectively. (3) Other evaluation variables The mean of change from baseline in fasting C-peptide at Week 12 (Week 12 - end of the observation period) for P/A Group and A/A Group was 0.01 ng/ml and 0.07 ng/ml, respectively, and the mean of change from baseline in fasting C-peptide at the end of the treatment period (Week 52) (end of the treatment period - end of the observation period) for P/A Group and A/A Group was 0.16 ng/ml and 0.00 ng/ml, respectively. The mean of change from baseline in fasting glucagon at Week 12 (Week 12 - end of the observation period) for P/A Group and A/A Group was 2.3 pg/ml and -0.9 pg/ml, respectively, and the mean of change from baseline in fasting glucagon at the end of the treatment period (Week 52) (end of the treatment period - end of the observation period) for P/A Group and A/A Group was 18.3 pg/ml and 14.8 pg/ml, respectively. The mean of change from baseline in glycoalbumin at Week 12 (Week 12 - end of the observation period) for P/A Group and A/A Group was -0.81% and -3.47%, respectively, and the mean of change from baseline in glycoalbumin at the end of the treatment period (Week 52) (end of the treatment period - end of the observation period) for P/A Group and A/A Group was -3.65% and
SYR-322 Page 8of 10-3.96%, respectively. The mean of change from baseline in 1,5-AG at Week 12 (Week 12 - end of the observation period) for P/A Group and A/A Group was 0.60 mean of change from baseline in 1,5-AG at the end of the treatment period (Week 52) (end of the treatment period - end of the observation period) for P/A Group and A/A Group was 3.13 and 3.09 The mean of change from baseline in body weight at Week 12 (Week 12 - end of the observation period) for P/A Group and A/A Group was 0.06 kg and 0.04 kg, respectively, and the mean of change from baseline in body weight at the end of the treatment period (Week 52) (end of the treatment period - end of the observation period) for P/A Group and A/A Group was 0.47 kg and 0.29 kg, respectively. The change status (increase, reduction, and unchanged) of the daily dose (units) of insulin preparation at Week 12 was 9.5%, 6.0%, and 84.5%, respectively, for P/A Group, and 3.5%, 10.6%, and 85.9%, respectively, for A/A Group. The change status (increase, reduction, and unchanged) of the daily dose (units) of insulin preparation at the end of the treatment period (Week 52) was 18.0%, 24.7%, and 57.3%, respectively, for P/A Group, and 35.6%, 14.4%, and 50.0%, respectively, for A/A Group. One subject each in P/A Group and A/A Group discontinued insulin preparation during Treatment Period II. SAFETY RESULTS: The incidence of adverse events (AEs) during the treatment period (Treatment Period I and Treatment Period II) for P/A Group and A/A Group was 86.5% (77/89 subjects) and 88.9% (80/90 subjects), respectively. The incidence of drug-related AEs during the treatment period (Treatment Period I and Treatment Period II) for P/A Group and A/A Group was 27.0% (24/89 subjects) and 28.9% (26/90 subjects), respectively. Of these AEs, the event reported in at least 2 subjects was hypoglycaemia alone. The incidence of AEs by severity during the treatment period (Treatment Period I and Treatment Period II) was 62.9% (56/89 subjects) for mild, 20.2% (18/89 subjects) for moderate, and 3.4% (3/89 subjects) for severe in P/A Group, and was 62.2% (56/90 subjects) for mild, 26.7% (24/90 subjects) for moderate, and 0.0% (0/90 subject) for severe in A/A Group. The incidence of drug-related AEs by severity was 24.7% (22/89 subjects) for mild, 1.1% (1/89 subject) for moderate and 1.1% (1/89 subject) for severe in P/A Group, and was 25.6% (23/90 subjects) for mild, 3.3% (3/90 subjects) for moderate and 0.0% (0/90 subject) for severe in A/A Group. The examination on the time of onset revealed that the incidence of AEs showed no increase or decrease with longer duration of treatment during the treatment period (Treatment Period I and Treatment Period II). The incidence of AEs in Days 1 to 84, corresponding to Treatment Period I, was slightly higher in A/A Group compared to that in P/A Group, while examination by PT revealed no marked difference between the treatment groups. No death was reported during the study period. The incidence of serious SAEs during the treatment period (Treatment Period I and Treatment Period II) for P/A Group and A/A Group was 5.6% (5/89 subjects) and 3.3% (3/90 subjects), respectively. The incidence of AEs resulted in treatment discontinuation (including treatment suspension)
SYR-322 Page 9of 10 during the treatment period (Treatment Period I and Treatment Period II) was 6.7% (6/89 subjects) for P/A Group, and 4.4% (4/90 subjects) for A/A Group. As AEs of special interest (specified AEs) during the treatment period (Treatment Period I and Treatment Period II), serious hypoglycemia and pancreatitis acute were specified, but neither one of these events was reported. The incidence of hypoglycemia reported as an AE during the treatment period (Treatment Period I and Treatment Period II) for P/A Group and A/A Group was 42.7% (38/89 subjects) and 34.4% (31/90 subjects), respectively. The incidence of hypoglycaemia assessed as drug-related for P/A Group and A/A Group was 23.6% (21/89 subjects) and 21.1% (19/90 subjects), respectively. As for laboratory test results, all parameters showed a small difference between pre- and post-treatment, without clinically meaningful changes. No clinically significant change or finding was found in vital signs or 12-lead ECG findings. CONCLUSION: The changes in HbA1c at the end of Treatment Period I (Week 12) (end of Treatment Period I - end of the observation period) (LS mean) verified the superiority of A/A Group over P/A Group (p<0.0001). In the mean of change from baseline in HbA1c during Treatment Period I, greater reductions were observed in A/A Group than P/A Group at all visits. For Treatment Period II, no major difference between the treatment groups was found at most of the visits. Co-administration of SYR-322 and insulin preparation showed no safety concerns and was well tolerated throughout the treatment period (Treatment Period I and Treatment Period II). Date of the report: 10 January 2014