abcd Clinical Study for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis which is part of the clinical study report had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of.
Page 3 of 437 2014 International GmbH or one or more of its affiliated companies 2. SYNOPSIS 1 of 8 2014 International GmbH or one or more of its affiliated companies. All rights reserved. Title of trial: Principal/Coordinating Investigator: Trial sites: Publication (reference): Clinical phase: Objectives: Methodology: No. of subjects: planned: Enrolled: 40 An open-label 8-week adjunctive-to-insulin and renal mechanistic pilot trial of BI 10773 in type 1 diabetes mellitus (the ATIRMA trial) MD, CM, PhD, FRCP(C) Cherney DZI, Perkins BA, Soleymanlou N, et al. Cardiovasc Diabetol 2014.13(28):1-18. Cherney DZ, Perkins BA, Soleymanlou N, et al. Circulation. 2014 Feb 4;129(5):587-97. Epub ahead of print: 2013 Dec 13. Perkins BA, Cherney DZI, Partridge H, et al. Diabetes Care 2014. Epub ahead of print: 4 Mar 2014 II There were two separate objectives in this trial: The primary objective was to determine the impact of 8 weeks of treatment with empagliflozin (25 mg QD) on renal hyperfiltration in patients with type 1 diabetes mellitus (T1DM) under conditions of controlled euglycaemia and hyperglycaemia. The secondary objective was to characterize the safety and efficacy of empagliflozin (25 mg QD) in patients with T1DM on insulin pump or multiple daily injections (MDI) therapy. Open-label, single centre mechanistic pilot study to characterize: 1) the impact of empagliflozin on glomerular filtration rate (GFR) and 2) the safety and efficacy of empagliflozin-treatment as adjunctive-to-insulin therapy in T1DM. Entered: 30
Page 4 of 437 2014 International GmbH or one or more of its affiliated companies 2 of 8 2014 International GmbH or one or more of its affiliated companies. All rights reserved. actual: Enrolled: 52 Diagnosis and main criteria for inclusion: Test product: dose: mode of admin.: batch no.: Reference therapy: dose: mode of admin.: Entered: 44 subjects were entered in the 2 week open-label placebo run-in period; 42 subjects were dosed in the 8 week open-label empagliflozin treatment period; 40 subjects completed the empagliflozin treatment period and were analysed (for primary endpoint). Patients 18 years with T1DM and with a glycated hemoglobin (HbA 1C ) of 6.5% to 11.0% and on basal insulin. Patients must have had an estimated GFR 60 ml/min/1.73m2 at screening. 25 mg 25 mg once daily oral 909473A (placebo used as run-in medication for 2 weeks before empagliflozin treatment) oral batch no.: 88627 Duration of treatment: Criteria for evaluation: Efficacy / clinical pharmacology: 8 week empagliflozin treatment period following a 2 week placebo run-in period The primary exploratory renal endpoint was the change in GFR after treatment with empagliflozin under controlled conditions of euglycaemia and hyperglycaemia. There were no key secondary endpoints in this trial. Other exploratory endpoints: There were 4 exploratory categories of renal endpoints: 1) change in renal hemodynamic function; 2) change in systemic hemodynamic function (mean arterial pressure and arterial stiffness); 3) change in circulating levels of mediators involved in the Renin-Angiotensin-Aldosterone System (RAAS) activation and markers of sympathetic activity; and 4) change in urinary nitric oxide, prostanoids, and albumin excretion. In addition there were 14 exploratory categories of diabetes mellitus endpoints.
Page 5 of 437 2014 International GmbH or one or more of its affiliated companies 3 of 8 2014 International GmbH or one or more of its affiliated companies. All rights reserved. Safety: Statistical methods: SUMMARY CONCLUSIONS: Efficacy / clinical pharmacology results: Adverse events (AEs), protocol-specified significant AEs, hypoglycaemic events, and change from baseline in the following: frequency of asymptomatic hypoglycaemia, weight, waist circumference, clinical laboratory values, and vital signs. In the primary analysis, paired t-tests were performed to test the difference in the GFR response between baseline and after treatment of empagliflozin (25 mg QD) within the hyperfilterer patients under separate conditions of controlled euglycaemia and hyperglycaemia. This analysis was also performed within the non-hyperfilterer patients and within all patients (both hyperfilterers and non-hyperfilterers). Analysis of variance (ANOVA) was performed on the primary endpoint to assess the difference between hyperfilterer versus non-hyperfilterer patients under separate conditions of controlled euglycaemia and hyperglycaemia. Between-group and within-group comparisons were also performed for other exploratory endpoints. An analysis was performed on the per-protocol set for renal (PPS_RENAL). Descriptive inferential statistics were used to summarise and evaluate the other diabetes-related endpoints. Analyses were performed on the per-protocol set for type 1 diabetes mellitus (PPS_T1DM). Descriptive statistics were used to summarise and evaluate safety endpoints. A total of 52 patients were enrolled, 44 patients were entered in a 2-week placebo run-in period, 2 patients discontinued during the run-in period, 42 patients were entered and dosed in an 8-week empagliflozin treatment period and 2 patients discontinued early from the treatment period due to AEs. Hence, 40 patients completed the 8 week empagliflozin treatment period and the 2 week follow-up period. All these 40 patients also completed the baseline and end of treatment renal assessments performed under clamped euglycaemic (plasma glucose of 4-6 mmol/l) and hyperglycaemic (plasma glucose of 9-11 mmol/l) conditions. The mean age (SD) of participants was 24.1 (5.0) years and the majority were white (83.3%) and had never smoked (85.7%). Overall, there were similar percentages of males and females in the study population. There were 13 patients in the non-hyperfilterer group (defined by a GFR of <135 ml/min/1.73 m2) and 29 in the hyperfilterer group (GFR of 135 ml/min/1.73 m2). The mean GFR (SD) at baseline was 116.9 (11.1) ml/min/1.73 m2 for the nonhyperfilterer group and 172.6 (22.9) ml/min/1.73 m2 for the hyperfilterer group as assessed by inulin-clearance under euglycaemic conditions. At screening, over 90% of the patients had been diagnosed with type 1 diabetes for more than
Page 6 of 437 2014 International GmbH or one or more of its affiliated companies 4 of 8 2014 International GmbH or one or more of its affiliated companies. All rights reserved. 5 years. The highest baseline HbA1c value was 9.6% with a baseline mean (SD) of 8.0 (0.9)%; 81% of patients had an HbA1c of 9.0%. Insulin delivery was by pump in 66.7% of patients, and by multiple daily injections in 33.3%. The GFR showed a statistically significant (p<0.0001) mean (SE) change after week 8 treatment in the hyperfilterer group of -33.4 (6.2) ml/min/1.73 m2 from a baseline of 172.2 ml/min/1.73 m2 under euglycaemia and -44.5 (7.1) ml/min/1.73 m2 from a baseline of 186.4 ml/min/1.73 m2 under hyperglycaemia. In contrast, the mean GFR did not change significantly in nonhyperfilterer patients at end of treatment (see summary table below). For between group comparisons, the mean difference (SE) in the change from baseline in GFR between the two groups under euglycaemia was statistically significant: 42.4 (9.90) ml/min/1.73 m2 (95% CI: 22.4, 62.5) (p=0.0001). Under hyperglycaemia, a statistically significant mean difference (SE) in the change from baseline in GFR between the two groups was observed, 42.1 (11.55) ml/min/1.73 m2 (95% CI: 18.7, 65.4) (p=0.0008). Primary endpoint: GFR change from baseline after 8 weeks of treatment with empagliflozin under euglycaemia and hyperglycaemia clamps in hyperfilterers (n=27) and non-hyperfilterers (n=13) Mean at Baseline Mean at Week 8 Mean Change from Baseline Standard Error p-value* Euglycaemia clamp Hyperfilterers 172.2 138.8-33.4 6.2 <0.0001 Non-Hyperfilterers 116.9 126.0 9.0 5.9 0.1524 Hyperglycaemia clamp Hyperfilterers 186.4 141.9-44.5 7.1 <0.0001 Non-Hyperfilterers 136.1 133.7-2.4 7.7 0.7585 *Paired t tests were performed to test the difference between baseline and end of treatment. Summary of important findings based on other exploratory renal and diabetes endpoints: Changes in other exploratory renal hemodynamic parameters such as effective renal plasma flow (ERPF) and renal blood flow (RBF) in hyperfilterers and nonhyperfilterers were similar to GFR. In addition to changes in renal hemodynamic function, changes in other important exploratory endpoints at week 8 were also noted. A mean change (SE) in systolic blood pressure (SBP) of
Page 7 of 437 2014 International GmbH or one or more of its affiliated companies 5 of 8 2014 International GmbH or one or more of its affiliated companies. All rights reserved. -2.7 (1.1) mmhg from a baseline mean of 111.2 mmhg was observed in all patients under euglycaemia. SBP was decreased despite a slight increase in circulating levels of angiotensin II and aldosterone. Circulating nitric oxide (NO) levels under clamped euglycaemic and hyperglycaemic conditions decreased significantly in hyperfilterers at end of treatment. A change in urine volume, based on a 24-hour collection, was also observed at end of treatment relative to baseline, both in non-hyperfilterer (approximately +14%) and, particularly, in hyperfilterer patients (approximately +56%). In general, arterial stiffness markers were supportive of decreased vascular stiffness at end of treatment relative to baseline; based on analyses of augmentation indices of the radial, carotid, and derived aortic pulse waveforms plus carotid to radial and carotid to femoral pulse wave velocities (PWVs). Empagliflozin, was also evaluated for its potential efficacy on glycaemia and rates of hypoglycaemia in patients with T1DM as an adjunctive to insulin therapy. After 8 weeks of treatment with empagliflozin, a clinically significant mean (SE) increase in urinary glucose excretion (UGE) of 114.6 (9.2) g/day was observed from baseline value of 18.9 g/day. Based on the 40 patients who completed 8 weeks of treatment with empagliflozin, the mean change (SE) in HbA1c from baseline to end of treatment was -0.40 (0.08)% from a mean baseline HbA1c (SD) of 8.03 (0.91)%. The mean change (SE) in fasting plasma glucose (FPG) from a baseline mean (SD) of 10.01 (4.87) mmol/l was -1.39 (0.73) mmol/l. Symptomatic hypoglycaemia (defined by a blood glucose value of <3.0 mmol/l based on Home Blood Glucose Monitoring [HBGM]), declined from a mean of 0.12 events per day in the 2 week placebo run-in period to 0.04 events per day in the last 2 weeks of the treatment period. The mean change (SE) in total daily insulin dose at end of treatment was approximately -8.9 (1.7) units/day from a baseline mean (SD) of approximately 54.7 (20.4) units/day primarily driven by a reduction in basal insulin. Decreased total insulin requirements were observed, despite patient-reported increased carbohydrate intake during the same periods; mean change (SE) of 53.78 (14.56) grams per day from a mean (SD) baseline value of 176.82 (121.09) grams/day. It was also observed that the majority of patients were considered as responders to empagliflozin treatment (30 out of the 40 completed patients or 75% of the treated population), based on predefined responder criteria that were based on changes in glycaemia, rates of hypoglycaemia and insulin needs. Pharmacokinetic results: Mean (SD) trough concentrations were 56.9 (33.0), 49.8 (16.9), and 47.5 (25.6) nmol/l on days 29, 50, and 57, respectively of the empagliflozin treatment
Page 8 of 437 2014 International GmbH or one or more of its affiliated companies 6 of 8 2014 International GmbH or one or more of its affiliated companies. All rights reserved. period indicating that steady-state concentrations of empagliflozin were maintained during the course of the study. Safety results: Safety data were analysed descriptively for all 42 patients who took at least one dose of empagliflozin (Treated set). The mean duration (SD) of exposure was 54.5 (11.9) days. The range of exposure was 3 to 73 days. Adverse events Overall, the most frequently reported AE was hypoglycemia (95.2% of patients). The percentage of patients with other relevant reported AEs (>10% frequency) were: 78.6% with pollakiura; 73.8% with thirst; 26.2% with nasopharyngitis; 23.8% with headache; 16.7% dry mouth or nausea; 14.3% with genitourinary tract infection, or dizziness or vomiting; and 11.9% for abdominal pain. Adverse events of severe intensity were reported in 16.7% of patients. Drug-related AEs per investigator judgement were reported in 34 out of the 42 treated patients (81.0%); the most frequently ( 2 patients) AEs were: pollakiura (78.6%; 33 patients), thirst (73.8%; 31 patients), dry mouth (16.7%; 7 patients), genitourinary tract infection (9.5%; 4 patients) and vaginal infection (4.8%; 2 patients). Three SAEs were reported that resulted in 3 patients being hospitalized, 2 of them due to diabetic ketoacidosis (DKA) and one of them due to gastroenteritis. Two of the 3 SAEs led to premature discontinuation of 2 patients within the first few days of treatment with empagliflozin; one patient discontinued due to severe DKA in conjunction with the non-serious event of severe gastroenteritis predating the DKA event, and the other discontinued due severe DKA due to insulin pump failure. None of these events were considered related to empagliflozin treatment. No deaths were reported during the trial and no patients experienced protocol-defined significant AEs of decreased renal function or hepatic injury. Symptomatic hypoglycaemia was reported in similar proportions of patients in the placebo run-in and treatment periods: 88.1% in the placebo run-in period and 90.5% in the empagliflozin treatment period. Only 1 patient in the placebo run-in period and 1 patient in the empagliflozin treatment period required assistance for a symptomatic episode per investigator judgment. These patients could not get to an oral carbohydrate rescue by themselves due to their symptoms and required assistance from a partner or a family member who brought them oral carbohydrate rescue treatment. Patients were able to ingest the carbohydrate rescue by themselves and no emergency medical services or glucagon was required for either of these events. Both events were not considered to be a serious or a significant AE.
Page 9 of 437 2014 International GmbH or one or more of its affiliated companies 7 of 8 2014 International GmbH or one or more of its affiliated companies. All rights reserved. When comparing the 2 week baseline period to the last 2 weeks of treatment period, the average number of hypoglycaemic episodes per patient per day decreased after empagliflozin treatment (0.30 event/day/patient at baseline relative to 0.18 event/day/patient at end of treatment as reported by HBGM). Relevant clinical laboratory tests, vital signs and anthropometric measurements Generally, mean changes from baseline (week -2) to the mean last value on treatment (week 7) were not clinically relevant for hematology, differentials, electrolytes, enzymes, substrates, plasma proteins or urinalysis assessments. Mean change (SD) in the haematocrit value was +0.014 (0.023) L/L at end of treatment relative to a baseline value of 0.423 (0.041) L/L. Total cholesterol, HDL cholesterol, and LDL cholesterol did not change in a clinically relevant manner. Triglycerides increased from a mean (SD) of 0.79 (0.38) mmol/l at baseline to a mean (SD) of 0.97 (0.49) mmol/l at week 7 and urea increased from a mean (SD) baseline value of 4.8 (1.6) mmol/l to 6.1 (1.9) mmol/l at week 7. Changes in triglyceride and urea were not considered to be clinically relevant. Similar to decreased systolic blood pressure observed at end of treatment relative to baseline as assessed by vital sign measurements, the mean (SD) for pulse rate was also decreased after 8 weeks of treatment with empagliflozin by 2.40 (11.34) from a baseline mean (SD) value of 74.60 (13.01). Mean change (SD) in body weight at week 8 was -2.67 (2.68) kg from a mean (SD) of 72.80 (12.50) at baseline and mean change in waist circumference followed the same trend, -3.79 (3.06) cm at week 8 relative to a baseline value of 83.05 (8.56) cm.
Page 10 of 437 2014 International GmbH or one or more of its affiliated companies 8 of 8 2014 International GmbH or one or more of its affiliated companies. All rights reserved. Conclusions: A 25 mg dose of empagliflozin QD, over 8-weeks in patients with T1DM, significantly reduced GFR, the primary endpoint of this exploratory study, in patients with renal hyperfiltration under both euglycaemic and hyperglycemic clamp conditions. In contrast, no clinically-relevant changes were observed in renal function in patients with normal kidney function. Empagliflozin treatment also reduced arterial stiffness, blood pressure, waist circumference and body weight. In addition, improvements in glycaemic control in conjunction with reductions in rates of patient-reported hypoglycaemia and insulin requirements were observed after treatment. The safety profile of empagliflozin as adjunctive treatment to insulin for 8 weeks in T1DM did not show any unexpected AE trends in this small population. Three SAEs were reported that resulted in 3 patients being hospitalized, 2 of them due to DKA and one of them due to gastroenteritis. Two of the 3 SAEs led to premature discontinuation of 2 patients within the first few days of treatment with empagliflozin; one patient discontinued due to severe DKA in conjunction with the non-serious event of severe gastroenteritis predating the DKA event, and the other discontinued due severe DKA due to insulin pump failure. In both DKA cases, per investigator recommendations on the first day of treatment with empagliflozin, total insulin was substantially reduced. No clinically relevant changes were observed with vital signs or safety laboratory assessments. Randomized controlled clinical trials assessing the efficacy and safety of adjunctive empagliflozin to insulin treatment in patients diagnosed with T1DM are warranted to further validate the glycaemia findings observed in this exploratory study.
BI trial number 1245.46 Trial - Appendix c02539594 Trial - Appendix The appended tables on the following pages supplement the trial results presented in the Trial. They complement the results for the primary endpoint of the trial. Results for Change from baseline in GFR after 8 weeks of treatment (primary endpoint) presented in Table 15.2.1: 1 AE Summary Table Table 15.3.2: 1
Page 193 of 440 2014 International GmbH or one or more of its affiliated companies Table 15.2.1: 1 Change from baseline in GFR [ml/min/1.73 m^2], within group comparisons PPS_Renal Change from baseline Mean Mean Baseline Week 8 Mean Standard Error p value Clamping condition/group (N) Euglycaemia All patients (40) 154.3 134.7 19.6 5.6 0.0011 Hyperfilterers (27) 172.2 138.8 33.4 6.2 <.0001 Non Hyperfilterers (13) 116.9 126.0 9.0 5.9 0.1524 Hyperglycaemia All patients (40) 170.0 139.2 30.8 6.2 <.0001 Hyperfilterers (27) 186.4 141.9 44.5 7.1 <.0001 Non Hyperfilterers (13) 136.1 133.7 2.4 7.7 0.7585 Paired t tests were performed to test the difference between baseline and end of treatment. Source data: Appendix 16.1.9.2, Statdoc 6.1, Appendix 16.2, Listing 3.1, 6.1.1 ctr\renal_w_1.sas 14JAN2014
Page 318 of 440 2014 International GmbH or one or more of its affiliated companies Table 15.3.2: 1 Adverse event overall summary treated set Empagliflozin N (%) Number of patients 42 (100.0) Patients with any AE 42 (100.0) Patients with severe AEs 7 ( 16.7) Patients with investigator defined drug related 34 ( 81.0) AEs Patients with other significant AEs (according to 1 ( 2.4) ICH E3) Patients with AEs leading to discontinuation of 2 ( 4.8) trial drug Patients with significant AEs (pre specified 0 ( 0.0) events) Patients with serious AEs 3 ( 7.1) Fatal 0 ( 0.0) Imm life threatening 0 ( 0.0) Disability/incap. 0 ( 0.0) Req.hospitalisation 3 ( 7.1) Prol.hospitalisation 0 ( 0.0) Congenital anomaly 0 ( 0.0) Other 0 ( 0.0) A patient may be counted in more than one seriousness criterion. Percentages are calculated using total number of patients per treatment as the denominator. MedDRA version used for reporting: 16.0 Source data: Appendix 16.2, Listing 7.2.1, 7.2.2, 7.2.3 ctr\ae1.sas 16JAN2014