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Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 1 Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride both in combination with metformin Product: Substance: EudraCT Number: Sponsor: Victoza® Liraglutide EudraCT nr 2010-022695-31 Karolinska Institutet, Södersjukhuset AB Coordinating Investigator: Johan Jendle Principal Investigators: Thomas Nyström, Johan Jendle, Åke Sjöholm, Leif Bojö, Bo Nilsson, Lars-Åke Brodin 2 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 1(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 3 Table of Contents 4 1 ADMINISTRATIVE INFORMATION ..................................................................................................7 5 2 BACKGROUND INFORMATION ......................................................................................................9 6 7 2.1 3 TRIAL RATIONALE .........................................................................................................................9 ENDPOINTS ................................................................................................................................... 10 8 3.1 PRIMARY ENDPOINTS ................................................................................................................. 10 9 3.2 SECONDARY ENDPOINTS ........................................................................................................... 10 10 4 DESIGN .......................................................................................................................................... 10 11 4.1 OUTLINE ................................................................................................................................... 10 12 4.2 ASSESSMENTS AND PROCEDURES.............................................................................................. 11 13 4.3 SCHEDULE OF INVESTIGATIONAL EVENTS.................................... 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BOOKMARK NOT DEFINED. 14 5 SELECTION AND WITHDRAWAL OF SUBJECTS ...................................................................... 10 15 5.1 INCLUSION CRITERIA .................................................................................................................. 12 16 5.2 EXCLUSION CRITERIA ................................................................................................................ 13 17 5.3 CRITERIA FOR W ITHDRAWAL ...................................................................................................... 14 18 5.4 SUBJECT LOG............................................................................................................................ 14 19 6 TREATMENT .................................................................................................................................. 14 20 6.1 DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS.......................................................... 14 21 6.2 PACKAGING, LABELLING, STORAGE AND HANDLING OF INVESTIGATIONAL MEDICINAL PRODUCTS... 14 22 6.3 TREATMENT ASSIGNMENT .......................................................................................................... 15 23 6.4 CONCOMITANT MEDICATION ....................................................................................................... 16 24 6.5 COMPLIANCE TO TREATMENT ..................................................................................................... 16 25 6.6 PRODUCT ACCOUNTABILITY AND DESTRUCTION .......................................................................... 16 26 6.7 CONTINUATION OF TREATMENT .................................................................................................. 16 27 7 ASSESSMENT OF EFFICACY AND SAFETY .............................................................................. 16 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 2(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 28 7.1 CLINICAL EFFICACY ASSESSMENTS ............................................................................................ 16 29 7.2 LABORATORY EFFICACY ASSESSMENTS...................................................................................... 19 30 7.3 LABORATORY SAFETY ASSESSMENTS ......................................................................................... 20 31 8 PROCEEDINGS FOR ADVERSE EVENTS ................................................................................... 21 32 8.1 DEFINITION OF ADVERSE EVENTS ............................................................................................... 21 33 8.2 ASSESSMENT OF ADVERSE EVENTS ........................................................................................... 22 34 8.3 METHODS FOR ELICITING ADVERSE EVENTS ............................................................................... 22 35 8.4 REPORTING OF ADVERSE EVENTS .............................................................................................. 22 36 8.5 FOLLOW-UP OF ADVERSE EVENTS .............................................................................................. 23 37 9 STATISTICS AND DATA MANAGEMENT .................................................................................... 24 38 9.1 DATA MANAGEMENT .................................................................................................................. 24 39 9.2 DETERMINATION OF SAMPLE SIZE .............................................................................................. 24 40 10 41 42 QUALITY CONTROL AND QUALITY ASSURANCE.................................................................... 25 10.1 11 MONITORING ............................................................................................................................. 25 ETHICS ........................................................................................................................................... 25 43 11.1 ETHICAL CONDUCT OF THE TRIAL ............................................................................................... 25 44 11.2 SUBJECT INFORMATION AND INFORMED CONSENT....................................................................... 26 45 12 46 DATA HANDLING AND RECORD KEEPING ............................................................................... 26 12.1 CASE REPORT FORMS ............................................................................................................... 26 47 13 FINANCING AND INSURANCE ..................................................................................................... 26 48 14 PUBLICATION POLICY ................................................................................................................. 26 49 15 SUPPLEMENTS ............................................................................................................................. 27 50 15.1 AMENDMENTS ........................................................................................................................... 27 51 15.2 PERSONNEL INFORMATION ......................................................................................................... 27 52 16 REFERENCES ............................................................................................................................... 28 53 17 APPENDICES................................................................................................................................. 30 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 3(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 54 17.1 SCHEDULE OF INVESTIGATIONAL EVENTS.................................................................................... 30 55 17.2 SPC GLIMEPIRIDE 30 56 17.3 SPC LIRAGLUTIDE 30 57 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 4(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 58 Protocol Summary PROTOCOL IDENTITY AND OBJECTIVES EudraCT Number: 2010022695-31 Protocol Title: Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride both in combination with metformin Trial Objectives: To investigate whether liraglutide 1.8 mg QD improves left ventricle longitudinal functional reserve. An 18 week, open, assessor-blinded and activecontrolled, parallel-group trial. INVESTIGATIONAL MEDICINAL PRODUCTS (IMP) Liraglutide Test Product: Solution for injection in prefilled pen Pharmaceutical Form: Subcutaneous (s.c) Route of Administration: Test Product: Pharmaceutical Form: Route of Administration: Glimepiride Tablet Oral (p.o) METHODOLOGY Trial Design: Open, assessor-blinded and activecontrolled, parallel-group trial, in combination with metformin 1.8 mg liraglutide QD vs. glimepiride 4 mg QD in total 18 weeks Increase in left ventricle longitudinal function and/or functional reserve during rest and after exercise Improvement in left ventricle longitudinal functional reserve, as measured by tissue Doppler echocardiography Dose/Duration: Primary Endpoint: Efficacy Parameters: Safety Parameters: POPULATION OF TRIAL SUBJECTS Description of Trial Subjects: Number of Subjects: Type 2 diabetes subjects with an HbA1c above 60 mmol/mol Eighty (80) TRIAL TIMETABLE First Subject In: Last Subject In: Last Subject Out: 2011 2011 2012 59 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 5(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 60 Abbreviations Abbreviation AE ADR CRF IB ICH IEC IMP MPA SADR SAE SPC SUSAR Explanation Adverse Event Adverse Drug Reaction Case Report Form Investigator’s Brochure International Conference of Harmonisation Independent Ethics Committee Investigational Medicinal Products Medicinal Product Agency Serious Adverse Drug Reaction Serious Adverse Event Summary of Product Characteristics Suspected Unexpected Serious Adverse Reaction 61 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 6(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 62 1 Administrative Information 63 Thomas Nyström MD, PhD 64 Karolinska Institutet, Department of Clinical Science and Education Division of Internal 65 Medicine Södersjukhuset AB, Stockholm, Sweden. 66 SE-118 83 Stockholm, Sweden 67 68 Åke Sjöholm MD, PhD 69 Karolinska Institutet, Department of Clinical Science and Education Division of Internal 70 Medicine Södersjukhuset AB, Stockholm, Sweden. 71 SE-118 83 Stockholm, Sweden 72 73 Cristina Häll BMA 74 Karolinska Institutet, Department of Clinical Science and Education Division of Internal 75 Medicine Södersjukhuset AB, Stockholm, Sweden. 76 SE-118 83 Stockholm, Sweden 77 78 Johan Jendle MD, PhD 79 Endocrine and Diabetes Center 80 Karlstad Central Hospital 81 SE-65185 Karlstad, Sweden 82 83 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 7(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 84 Bo Nilsson MD, PhD 85 Department of Clinical Physiology 86 Karlstad Central Hospital 87 SE-651 82 Karlstad, Sweden 88 89 Leif Bojö MD, PhD 90 Department of Clinical Physiology 91 Karlstad Central Hospital 92 SE-651 82 Karlstad, Sweden 93 94 Lars-Åke Brodin MD, PhD 95 School of Technology and Health 96 Royal Institute of Technology 97 Alfred Nobels Allé 98 SE-14152 Huddinge, Sweden 99 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 8(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 100 2 Background Information 101 102 103 104 105 106 107 108 109 110 111 112 113 Heart disease, often presenting as cardiomyopathy, is the leading cause of death among patients with diabetes mellitus [1]. Heart failure in diabetic patients might be due to metabolic disturbances even in the absence of ischemia, e.g. heart failure and cardiomyopathy may be accompanied by the development of insulin resistance, both in whole-body and myocardial glucose uptake disturbances [2]. The spectrum of diabetic heart disease involves a progression from the normal heart, to subclinical left ventricular (LV) diastolic and systolic dysfunction, followed by clinically overt symptomatic heart failure. Notably, sub-clinical LV dysfunction is common in patients with diabetes [3], and the detection of sub-clinical LV dysfunction in these patients may provide an approach for identifying high-risk individuals who may benefit from earlier and more active intervention to prevent heart failure [4]. Although overt LV diastolic and systolic dysfunction can be readily identified by conventional diagnostic techniques including echocardiography, the initial stage of myocardial dysfunction may be concealed by various compensatory mechanisms. 114 115 116 117 118 119 120 121 122 Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with insulinotropic properties [5]. Apart from the glycemic actions, cardiovascular effects by GLP-1 have recently been reviewed [6]. Receptors for GLP-1 are expressed in the rodent and human heart and acute activation of GLP-1 signalling has been shown to influence e.g. heart rate and blood pressure [6]. In a knock-out mouse model, GLP-1R-/- mice exhibited a defective cardiovascular contractile response together with left ventricular hypertrophy [7]. GLP-1 improves severe left ventricular heart failure in humans suffering from a myocardial infarction [8]. Hence, it has been demonstrated that GLP-1 exerts direct functional effects through both GLP-1 receptor dependent and independent pathways in the heart [9]. 123 124 125 126 127 128 129 Native GLP-1 is an extremely short acting peptide, with a half-time breakdown of 1-2 minutes, a feature that makes it unsuitable as a drug treatment for type 2 diabetes. To this end, several longacting GLP-1 analogues, drugs for treating type 2 diabetes, have been tested for this purpose. The analogue liraglutide exerts its effects via the native GLP-1 receptor, localized not only on the pancreatic β-cells, but also in the human heart. Interestingly, liraglutide has been demonstrated to have beneficial effect on heart function in mice [10]. Taken together, recent data shows that GLP-1 and its stable analogue liraglutide exert beneficial cardiovascular effects. 130 2.1 Trial Rationale 131 132 133 134 135 136 137 138 Acutely beneficial cardiovascular effects of GLP-1 on the heart have recently been demonstrated. Therefore the rational for this study is to investigate liraglutide effect on the heart in type 2 diabetic subjects. The 18 week treatment period is expected to be sufficient to evaluate the efficacy and safety of the treatment to be studied. Also, the comparator was chosen due to the fact that glimepiride 4 mg QD has an equal anti-diabetic effects in terms of lowering plasma glucose as for liraglutide 1.8 mg QD , during a 18 week period [11]. In order to obtain the necessary power in the trial, 80 subjects are expected to complete the trial (further described under Determination of sample size, section 9.2). 139 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 9(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 140 141 3 Endpoints 142 143 144 145 Subjects achieving an absolute increase in left ventricle longitudinal function and/or functional reserve during rest and/or after exercise of 0.7 cm/s, i.e., ΔE’ [1-(1/E’base)] or ΔS’ [1-(1/S’base)] after 18 weeks of liraglutide + metformin, compared with glimepiride + metformin, using tissue Doppler echocardiography. 146 3.2 Secondary Endpoints 147 148 The changes from baseline for 18 weeks of liraglutide + metformin compared with glimepiride + metformin treatment will improve or affect; 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 3.1 Primary Endpoints Global LV function (echocardiography) expressed as ejection fraction (EF) Exercise ECG, including working capacity 24-hour blood pressure Energy delivering from the carotid artery N-terminal pro b-type natriuretic peptide (NT-proBNP) levels in serum over time and symptoms of dyspnea or fatigue as assessed by patient and clinician using established scoring systems. Gene expression (Affymetrix) Plasma markers of inflammation i.e. hsCRP, IL-6, TNF-α and PAI-1 Plasma markers of endothelial activation i.e. E-selectin, VCAM-1, ICAM-1 and plasma levels of nitrate/nitrite Lipids HbA1c Body weight Adverse events in terms of hypoglycaemia Quality of life (SF 36) Blood test (venipuncture) 166 167 4 Design 168 169 170 171 The present trial is a two centre, open, assessor-blinded and active-controlled, parallel-group trial, in combination with metformin. The trial will compare the treatment with liraglutide 1.8 mg (s.c) QD + metformin up to 1 g BID, with that of glimepiride 4 mg QD (comparator) + metformin up to 1 g BID, on LV function in subjects with type 2 diabetes. 172 173 174 175 176 Patients are asked to participate in the study and after informed and written consent has been obtained, subjects will be screened based on the inclusion and exclusion criteria. If needed, subjects will have metformin up-titrated to a maximal daily dose of 2g, or the highest tolerated dose in the run-in period. Total trial duration for the individual subject will be 18 ± 4 weeks. A population of 80 type 2 diabetic subjects will be investigated (Figure 1). 4.1 Outline Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 10(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride Fig 1. Liraglutide 1.8 mg QD + Metformin 1 g BID Glimepiride 4 mg QD + Metformin 1 g BID Visit 1 2* 3 4 5 6 Week -4 0 2 10 18 20 *Liraglutide and Glimepiride will be uptitrated according to protocol section 6 Run-in period Treatment Follow up 177 178 4.2 Assessments and Procedures 179 180 181 182 The subjects will attend a screening visit (Visit 1) in order to assess their eligibility. If found eligible, the subjects will return at Visit 2 within approximately 4 weeks, after Visit 1, with an up-titration with metformin 1 g BID or the maximal tolerated dosage of metformin (Run-in period). 183 At Visit 2 patients will be tested for; 184 185 186 187 188 189 190 191 Heart function at rest and during an exercise ECG Stress Test with tissue Doppler echocardiography 24-hour blood pressure Antropometric assessment Symptoms of dyspnea or fatigue (scoring system, classified as NYHA). Quality of life (SF 36) Blood test (venipuncture) U-HCG (in fertilized women) 192 193 194 195 Subsequently thereafter, subjects will during visit 2 be randomized to receive either liraglutide 1.8 mg s.c. (initial dose of 0.6 mg with an up-titration of 0.6 mg every week, final dose 1.8 mg QD) or glimepiride 4 mg p.o (initial dose of 2 mg, with an up-titration of 1 mg every week, final dose 4 mg QD). 196 197 198 At Visit 2, subjects will be supplied with a glucose meter (Abbot Contour) and instruction on use of the device including regular calibration according to the manufacturer’s instruction. Subject will also be provided with written instruction. The glucose meter use test strips calibrated to Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 11(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 199 200 201 plasma values. Therefore all glucose measurements performed with drawn capillary blood are automatically calibrated to plasma equivalent glucose values, which will be shown on the display and are the values to be used. 202 203 204 205 Subjects will be instructed on how to record the results of the self measured plasma glucose (SMPG) values in the meter. Subjects will then ask to monitor a 7 point profile glucose curve consecutively in three days before visit 3, at visit 4 and at the end of treatment (visit 5) and at the end of the trial (visit 6). SMBG values will be transferred via a computerized system (Diasend®). 206 Visit 3. Telephone visit. Self-reporting glucose measurements. 207 Visit 4. Telephone visit. Self-reporting glucose measurements. 208 At week 18 (Visit 5), subjects will be re-tested for: 209 210 211 212 213 214 215 216 Heart function at rest and during an exercise ECG Stress Test with tissue Doppler echocardiography 24-hour blood pressure Antropometric assessment Symptoms of dyspnea or fatigue (scoring system, classified as NYHA). Quality of life (SF 36) Blood test (venipuncture) U-HCG (in fertilized women) 217 218 219 The physician will decide what treatment patients will be continued on Visit 6. Follow up and reevaluate the anti-diabetic treatment.At all contacts Investigators will ask subject for signs or symptoms of an AE. 220 4.3 Schedule of Investigational Events 221 222 223 Procedures for the scheduled visits and phone contacts are described in the section above and in the flowchart (Schedule of Investigational Events, Appendix 17. 1). Each subject will be followed approximately 18 ± 4 weeks after randomisation. 224 225 5 Selection and Withdrawal of Subjects 226 227 228 229 230 231 232 233 234 1 Type 2 diabetes. 2 Heart Failure, visualized with echocardiography, one of the following (2.1, 2.2 or 2.3). 2.1 Ejection Fraction ≤ 50%. 2.2 Decreased systolic velocity (four chamber view) where two, out of four segments (Septum, Lateral, Inferior and Anterior Wall) has a relative decrease in velocity of 20% compared to a normal population. 2.3 Evidence of diastolic dysfunction as shown by abnormal left ventricular relaxation, filling, diastolic distensibility or stiffness. An E/E’ ratio (ratio of early diastolic velocities of mitral inflow derived Doppler imaging and myocardial movement derived by tissue Doppler 5.1 Inclusion Criteria Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 12(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 3 4 5 6 imaging) >15 is considered diagnostic of diastolic dysfunction and an E/E′ ratio < 8 as diagnostic of the absence of diastolic heart failure. An increased left atrial size (>49 ml/ m2) and an increased left ventricular mass (>122 g/m2 in women and >149 g/m2 in men) are considered sufficient evidence of diastolic dysfunction when the E/E′ ratio is inconclusive. HbA1c (accordingly to IFCC) 60 mmol/mol – 95 mmol/mol. If antihypertensive treatment, the medication has to be stable, no change, for the last 1 month. Male and female subjects, 18-70 years of age. Signed informed consent form. 5.2 Exclusion Criteria 1. Type 1 diabetes (autoantibody positive). 2. Any history of receiving GLP-1 analogues or dipeptidyl peptidase inhibitors (DPP-IV inhibitor) or glimeperid. 3. Previous treatment with glitazones within 6 months. 4. Previous treatment with other sulphonylurea within 3 months. 5. Previous treatment with insulin (any regimen) within 1 month. 6. Known severe heart failure, classified as NYHA 3-4. 7. Significant ischemic heart disease (defined as angina-limited exercise or unstable angina); documented acute myocardial infarction (MI) within the previous 8 weeks. 8. Active myocarditis; malfunctioning artificial heart valve. 9. Atria fibrillation or flutter 10. History of ventricular tachycardia within 3 months before study entry; second- or thirddegree atrioventricular block. 11. Implanted pacemaker. 12. Supine systolic blood pressure <85 mm Hg or >200 mm Hg. 13. Primary renal impairment (creatinine clearance < 30 ml/min), or creatinine clearance < 60 ml/min if treated with metformin. 14. Uncorrected hypokalemia or hyperkalemia (potassium <3.5 mmol/l or >5.5 mmol/l). 15. Significant anemia (Hb < 90 g/l) 16. Treatment with another investigational agent within 30 days before study entry, judged by the investigator. 17. Severe gastrointestinal disease, including gastroparesis. As judged by the investigator. 18. Body mass index (BMI) > 40 kg/m2. 19. Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Patients with intraepithelial squamous cell carcinoma of the skin treated with topical 5FU and subjects with basal cell skin cancer are allowed to enter the trial. 20. Females of child bearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive measures as required by local law or practice). 21. Current drug and alcohol abuse. 22. History of acute or chronic pancreatitis 23. Subjects considered by the investigator to be unsuitable for the study. Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 13(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 279 5.3 Criteria for Withdrawal 280 281 282 The subjects may withdraw at will at any time. The subjects may be withdrawn from the trial at the discretion of the Investigator due to safety concerns or if judged non-compliant with trial procedures. Subjects randomised in error must be withdrawn from the trial 283 A subject must be withdrawn if the following applies: 284 285 286 1. Pregnancy or intention of becoming pregnant 2. Participation in other trials throughout the trial 3. Serious heart failure or a cardiovascular event 287 5.4 Subject Log 288 289 All subjects in the screening process will be documented in a medical chart accordingly to their inclusion criteria or exclusion criteria. 290 6 Treatment 291 292 293 294 295 296 All subjects have been instructed to up-titrate metformin to 1 g BID, or maximal tolerated dose of metformin, before randomisation (run-in period). At randomisation (Visit 2) subjects will be randomised into one of the two treatment groups; liraglutide 1.8 mg (s.c) QD (initial dose of 0.6 mg with an up-titration of 0.6 mg every week, final dose 1.8 mg) or glimepiride 4 mg (p.o) QD (initial dose of 2 mg, with an up-titration of 1 mg every week, final dose 4 mg), both in combination with metformin 1 g BID. 297 Subjects will be instructed to take metformin meanwhile the breakfast and the dinner meal. 298 299 Subjects will be instructed to take glimepiride before the breakfast meal and liraglutide at the same time point every day. 300 6.1 Description of Investigational Medicinal Products 301 302 Liraglutide will be available as a solution for injection at a concentration of 6.0 mg/ml, supplied in a 3 mL pre-filled disposable pen. 303 304 Glimepiride will be available as tablet for oral administration, each tablet containing 1 mg, 2 mg or 4 mg of glimepiride. 305 6.2 Packaging, Labelling, Storage and Handling of Investigational Medicinal Products 306 307 308 The trial products will be packed and labelled by an external clinical supply contractor, which can be done since both trial products are commercially available. Labelling will be in accordance with Annex 13, local law and trial requirements. 309 Each investigator site will be supplied with sufficient trial products for the trial. Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 14(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 310 311 Trial product will be packed in dispensing units and will be distributed to the sites according to enrolment and randomisation. 312 313 314 315 The trial products will be dispensed to each subject at Visit 2, as required according to treatment group. The randomisation procedure will allocate trial product Dispensing Unit Number (DUN) to the subject at the dispensing visit. The correct DUN must be dispensed to the subject at the dispensing visit. 316 317 Instruction to the subject on how to use the trial liraglutide pre-filled disposable pen should be provide by the Investigator at Visit 2. 318 319 The trial products should be stored in accordance with the storage conditions as stated in the Summary of Product Characteristics for each product, see Appendices 17.2 and 17.3. 320 321 322 The Investigator must ensure availability of proper storage conditions, and record and evaluate the temperature (at least every working day). Storage facilities should be checked frequently. A log to document the temperature must be kept. 323 Storage and in-use conditions: 324 Liraglutide 325 326 327 Not in use: The liraglutide pre-filled pen must be stored in a refrigerator at a temperature between +2°C and + 8°C. Keep away from the cooling element. Do not freeze and do not use if it has been frozen. 328 329 In-use: After first opening the liraglutide pre-filled pen can be stored for one month at temperatures below +30°C or in a refrigerator between +2°C and +8°C. 330 Do not freeze and do not use if it has been frozen. 331 332 The pen must be protected from all sources of light, and the pen cap should be kept on when the pen is not in use. The liraglutide should not be used if it does not appear clear and colourless. 333 Glimepiride 334 Store at temperatures below +30°C. Store in original package. Sensitive to damp. 335 336 In case of incorrect storage, the site staff should inform the Principal Investigator without delay. The trial products must be set on-hold until notified by Principal Investigator. 337 No trial product should be dispensed to any person not enrolled in the trial. 338 6.3 Treatment Assignment 339 The study is an open, assessor-blinded and active-controlled, parallel-group trial. Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 15(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 340 341 342 343 Randomisation will be carried out in a (1:1) manner using an interactive voice/web response system (IV/WRS) to randomise subjects into the treatment groups: Liraglutide QD or Glimepiride QD 344 both in combination with metformin. 345 6.4 Concomitant Medication 346 347 Type 2 diabetic patients with metformin, as a single oral anti-diabetic drug, or diet controlled, will be eligible for the study. 348 All other new medications in the study period will be documented in the CRF. 349 6.5 Compliance to Treatment 350 351 352 Subject compliance will be assessed by monitoring of drug accountability. The unused amount of trial product will be assessed against the dispensed amount and, in case of discrepancies, the subjects must be asked. 353 6.6 Product Accountability and Destruction 354 355 The person delegated by the Investigator must keep track of all received, used, partly used and unused trial products, and if possible all empty packaging, This shall be properly documented. 356 357 358 Used, partly used and unused trial products and empty packaging must be stored separately from non-allocated trial products. Used, partly used and unused trial products must be stored until the monitor has performed drug accountability. 359 360 The monitor is responsible for arranging destruction of trial products. The destruction will be performed in accordance with local legislation and recorded on a destruction form. 361 6.7 Continuation of Treatment 362 363 364 After the study end subjects will be referred to theirs ordinary general practitioner (GP). All subjects will be offered to contact Investigator regarding questions of the study and their treatment for diabetes. 365 366 7 Assessment of Efficacy and Safety 367 368 Accordingly to 20.1 Schedule of Investigational Events subjects will be investigated at two centres, Stockholm South General Hospital and Karlstad Central Hospital, respectively. 7.1 Clinical Efficacy Assessments Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 16(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 369 7.1.1 370 371 372 Systolic and diastolic pressure and pulse will be recorded in the patient’s both arms while the subject is sitting in an upright position, after a 15 min rest. For blood pressure at Visit 2 and Visit 5, three measurements need to be performed and all three values should be entered into the CRF. 373 7.1.2 374 375 An ambulatory 24-hour blood pressure recording will be performed using an ABPM-05 system (Meditech Ltd, Budapest, Hungary). 376 7.1.3 377 378 379 380 381 382 383 384 385 386 387 Transthoracic echocardiography will be performed, with the subject in a lying position, using a Vivid 9 system (GE, Vingmed Ultrasound, Horten, Norway) with a 3,5 MHz phased-array transducer, Cine-loops including at least 3 consecutive heart beats will be saved and transmitted to a work station (EchoPAC-PC version 60; GE Medical systems) for off-line analysis. Parasternal long- and short axis views, apical long axis, 2- and 4-chamber views are obtained. Measurements of cardiac dimensions are made in accordance with recommendations of the American Society of Echocardiography Committee [12]. The diastolic mitral inflow velocities are recorded by pulsed wave Doppler from the apical 4-chamber view with the sample volume located at the tips of the mitral leaflets. Blood flow velocities during early diastole, and during atrial contraction, will be obtained. From apical views, Tissue Velocity Imaging (TVI) will be performed and loops are saved for analysis of long-axes contraction and relaxation velocities. 388 7.1.4 389 390 391 392 393 The carotid artery measurements will be performed, with the subject in a lying position, using a Vivid 9 system (GE, Vingmed Ultrasound, Horten, Norway) with a high-resolution 10 MHz transducer. Artery diameter and blood flow during at least 3 consecutive pulse waves will be saved and transmitted to a work station (EchoPAC-PC version 60; GE Medical systems) for offline analysis. 394 7.1.5 395 396 397 398 399 A bicycle exercise stress test, following a standard protocol, will be performed using a Case 5 system (GE Medical Systems, WI, USA) immediately after the work. A stepwise increase of 20 W in working-load capacity will be changed every other minute. Subjects’ will be asked to finish the work accordingly to the Borg scale 14-15. The electrocardiogram (ECG) will be monitored with a 12 lead ECG devices. 400 7.1.6 401 402 403 Adverse Events will be recorded at each visit in accordance with the procedures described in section 8. Any clinically significant worsening since baseline of a previous finding must be reported as an AE. Blood pressure 24 hours blood pressure Tissue Doppler Echocardiography Carotid artery energy delivering Exercise ECG Stress Test and Tissue Doppler Echocardiography Adverse events Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 17(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 404 7.1.7 405 406 407 Blood glucose should always be measured when there is a suspicion of a hypoglycaemic episode. All plasma glucose values ≤ 3.9 mmol/l when hypoglycaemic symptoms have occurred will be recorded by the subjects in the diaries and transcribed into the CRF. 408 409 A hypoglycaemic episode will be defined as treatment emergent if the onset of the episode is on or after first day of trial product. The recording should include: 410 411 412 413 414 415 416 417 418 419 420 421 Hypoglycaemic episodes Date Time of hypoglycaemic episode Time of last liraglutide/glimepiride dose prior to episode Amount of last liraglutide/glimepiride dose prior to episode Time of last main meal prior to episode Whether the episode was symptomatic Whether the episode was in relation to exercise Whether hypoglycaemic re-occurred in the 24-hrs after initial recovery If yes, approximately number of hours since the first hypoglycaemic episode Whether the subject was able to treat him/herself, whether he/she recovered with oral administration of carbohydrates The plasma glucose level before treating the episode 422 423 Hypoglycaemic episodes will be defined as nocturnal if the time of onset is between 00:01 (included) and 05:59 am (included). 424 425 Documentation of hypoglycaemia by data from the Glucometer being downloaded at the next visit using Diasend®. 426 427 428 A hypoglycaemic episode form must be filled in for all hypoglycaemic episodes. If the hypoglycaemic episodes fulfil the criteria of a serious AE, a hypoglycaemic episode Form, an AE form and a Safety Information Form must be filled in. 429 ADA definitions and classification of hypoglycaemia will be applicable: 430 431 Severe hypoglycaemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagons, or other resuscitative actions. 432 433 Documented hypoglycaemia: an episode during which typical symptoms of hypoglycaemia are accompanied by measured plasma glucose concentration ≤ 3.9 mmol/l. 434 435 Asymptomatic hypoglycaemia: an episode not accompanied by typical symptoms hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/l. Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 18(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride Physical examination 436 7.1.8 437 Physical examination will include: 438 439 440 441 442 Head, ears, nose, throat, neck Lungs Cardiovascular system Gastrointestinal system Vital signs 443 444 In the case of an abnormal clinical significant finding, the Investigator must comment in the subject notes. 445 Any clinically significant worsening from baseline must be reported as an AE. 446 7.2 Laboratory Efficacy Assessments 447 448 449 450 451 452 For laboratory analysis of efficacy parameters a total of approximately 100 ml blood will be drawn during the 18 weeks of the trial. The laboratory analyses will be performed by a central laboratory unless otherwise specified. Description of assays methods, laboratory supplies and procedures for obtaining samples, handling and storage of samples and information on who will perform the assessments, will be described in a trial specific laboratory manual provided by a central laboratory. 453 454 455 Laboratory samples can be drawn on a day other than the day the visit is performed as long as it is within the visit window stated in the flowchart. For some of the samples drawn during the trial it is required for the sensitivity of the analysis that the subject is fasting. 456 Samples will be coded such that the subject identity will remain anonymous. 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 Blood samples will be drawn for the efficacy assessments to determine levels of following: HbA1c Fasting plasma glucose Lipids – Subject must be fasting o Total Cholesterol o HDL Cholesterol o LDL Cholesterol o Triglycerides Plasma markers of inflammation o hsCRP o IL-6 o TNF-α o PAI-1 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 19(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 473 474 475 476 477 478 479 480 481 482 483 Plasma markers of endothelial activation o E-selectin o VCAM-1 o ICAM-1 o Plasma levels of nitrate/nitrite Brain natriuretic peptide (NT-proBNP) Whole blood for Gene Expression (Affymetrix) Proteomics 484 7.3 Laboratory Safety Assessments 485 486 487 488 489 490 For laboratory analysis of safety parameters a total of approximately 16 ml blood will be drawn during the 18 weeks of the trial. The laboratory analyses will be performed by a central laboratory unless otherwise specified. Description of assays methods, laboratory supplies and procedures for obtaining samples, handling and storage of samples and information on who will perform the assessments, will be described in a trial specific laboratory manual provided by a central laboratory. 491 492 493 494 Laboratory samples can be drawn on a day other than the day the visit is performed as long as it is within the visit window stated in the flowchart. For some of the samples drawn during the trial it is required for the sensitivity of the analysis that the subject is fasting. Samples will be coded such that the subject identity will remain anonymous. 495 496 497 498 499 500 Laboratory results will be sent by the central laboratory to the Investigator on an ongoing basis. Data from the analysis will be included in the clinical trial report and the trial database. All laboratory printouts must be dated and signed by the Investigator on the day of evaluation. If a result is outside the normal range, the investigator must judge whether the abnormality is clinically significant. If considering clinically significant the results must be reported as an AE according to section 8, Proceedings for Adverse Events. 501 502 503 504 505 506 507 508 509 510 511 512 513 Blood samples will be drawn for safety assessments to determine levels of following: Haematology o Erythrocytes o Haematocrit o Haemoglobine o Leucocytes o Thrombocytes Biochemistry o Creatinine o ALAT (Alanine aminotransferase) o ASAT (Aspartate aminotransferase) o Alkaline phosphate (AP) o Sodium Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 20(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 514 515 516 517 518 519 520 521 522 523 524 525 526 o o o o o o Potassium Calcium Calcitonin (TBD might be a demand) Albumin Amylas Bilirubin (total) Pregnancy test will be performed as a urine sample (U-HCG) for females of childbearing potential, at visit 1 and visit 5. For those of childbearing potentials the required use of contraceptives will be discussed. Urine samples o Albumin/creatinine ratio by urine spot 527 528 529 8 Proceedings for Adverse Events 530 531 532 533 534 An Adverse Event (AE) is any untoward medical occurrence in a subject administered Investigational Medicinal Products (IMP) and which does not necessarily have a causal relationship with this product. An AE can be any unfavourable and unintended sign, abnormal laboratory finding, symptom or disease temporally associated with the use of IMP, whether or not related to the product. 535 8.1.2 536 537 538 539 Each AE is to be classified by the investigator as related or not related to the IMP. An Adverse Reaction (AR) is a noxious and unintended medical response to a medical product related to any dose. For an AE to be an AR the suspected association between the product and the unwanted medical condition should be at least a reasonable possibility. 540 8.1.3 541 542 543 544 545 546 547 548 549 550 551 552 Each AE is to be classified by the investigator as serious or non-serious. Seriousness is not defined by a medical term; it is a result or an outcome. An AE is defined as a Serious Adverse Event (SAE) if it: results in death is life-threatening requires inpatient hospitalisation or prolongation of existing hospitalisation results in persistent or significant disability/incapacity results in a congenital anomaly/birth defect Important medical events that may not result in death, be life-threatening, or require hospitalisation may be considered an SAR when, based upon appropriate medical judgement, they may jeopardise the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition 8.1 Definition of Adverse Events 8.1.1 Definition of Adverse Events Definition of Adverse Reactions Definition of Serious Adverse Events Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 21(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 553 554 555 556 557 558 559 Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or development of drug dependency or drug abuse. 560 8.1.4 561 562 563 564 565 Each SAE that is at least possibly related to IMP is to be classified by the investigator as expected or unexpected. A SAE that is at least possibly related to IMP, and unexpected, is defined as a Suspected Unexpected Serious Adverse Reaction (SUSAR). It is expected if it is already known from earlier trials or is mentioned in relevant documents (SPC, summary of product characteristics). 566 567 8.2 Assessment of Adverse Events 8.2.1 Assessment of Intensity 568 Each AE is to be classified by the investigator as mild, moderate or severe. 569 Mild: Acceptable. The subject is awareness of symptoms or signs, but they are easy tolerated. 570 Moderate: Disturbing. The AE is discomfort enough to interfere with usual daily activity. 571 Severe: Unacceptable. The subject is incapacity to work or to do usual daily activities. 572 8.2.2 573 Unlikely: The event is most likely related to aetiology other than the IMP. 574 Possible: A causal relationship is conceivable and cannot be dismissed. 575 Probably: Good reason and sufficient documentation to assume a causal relationship. 576 8.3 Methods for Eliciting Adverse Events 577 578 All adverse effects regardless of relationship to study drug or protocol procedure will be recorded in the adverse event CRF, including date and time of symptoms. 579 580 The Investigator should record the diagnosis, if available. If no diagnosis is available then the Investigator should record each sign and symptom as Individual SAEs. 581 582 8.4 Reporting of Adverse Events 8.4.1 Reporting of Adverse Events 583 All AEs will be recorded on a separate AE form in the CRF. Definition of Suspected Unexpected Serious Adverse Reactions Assessment of Causality Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 22(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 584 8.4.2 585 586 587 588 589 590 In addition will SAEs also be reported by the investigator to the sponsor on a separate SAE form within 24 hours after the SAE have been communicated to the investigator. Follow-up information describing the outcome of the SAE and action taken will be reported as soon as it is available. The original SAE form must be filed with the CRF. The sponsor shall report all cases of death to the MPA within 7 days, and if necessary complete the report to the MPA within 8 days and all cases of death to the Independent Ethics Committee (IEC). 591 8.4.3 592 593 594 595 The sponsor must report all SUSARs that resulted in death or was life threatening to the authority through the EudraVigilance database and to the IEC within 7 days, and if necessary complete the report within the following 8 days. Other SUSAR should be reported within 15 days. In addition will the sponsor report all SUSAR to all Principal Investigators involved in trials with the IMP. 596 8.5 Follow-up of Adverse Events 597 598 599 600 Follow-up information (corrections, new or additional information) should be reported within the timeline of obtaining knowledge of the information for SAEs, and if previously non-serious AEs become SAEs to the Sponsor. The Investigator must ensure that the worst case severity and seriousness is kept consistent. 601 602 603 604 During and following a subject’s participation in a clinical trial, the Investigator/institution should ensure that adequate medical care is provided to the subjects for any AE(s), including clinically significant laboratory values related to the trial. The investigator should inform the subject when medical care is needed for AE(s) of which the Investigator becomes aware. 605 606 The follow up information should only include new (updated and/or additional) information that reflects the situation at the time of the Investigator’s signature. 607 8.6 Pregnancy 608 609 Subjects must be instructed to notify the Investigator immediately if they or their partner become pregnant during the trial. 610 611 612 613 614 615 616 The Investigator must report any pregnancy reported during the trial except for pregnancies occurring in the screening period. Trial subjects will give consent on enrolment that the Investigator will document any pregnancy during the trial, and that she will be asked to provide information about her pregnancy, delivery and the health of her infant until age one month. If the pregnancy results in an abnormal outcome, such as congenital anomalies, foetal death, spontaneous abortion, or SAEs in the neonate then this should be regarded as an SAE with the same reporting requirements and timelines as for SAE. 617 618 If an SAE occurs in relation to a pregnancy, either to the mother or the newborn, then follow the same reporting requirements and timelines as for SAE. Reporting of Serious Adverse Events Reporting of Suspected Unexpected Serious Adverse reactions Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 23(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 619 620 9 Statistics and Data Management 621 622 623 624 625 626 A case report form (CRF) will be obtained and completed for each included patient. Investigators will ensure completion and review of the CRF. Investigators have personal responsibility for the accuracy and authenticity of all clinical and laboratory data that are entered into the CRF. Also, electronic charts will be transferred to paper charts and stored for each included patient. CRFs, including paper charts, will be in locked in a safe place. However, in case of emergency, CRFs will be made readily available. 627 9.2 Determination of Sample Size 628 629 630 631 632 633 634 635 636 637 638 The primary endpoint is defined as an improvement of LV longitudinal contraction measured with tissue Doppler echocardiography at rest and at ECG Stress Test. Longitudinal diastolic function reserve index = ∆E´[1-(1/ E´base)] and Longitudinal systolic function reserve index = ∆S´[1-(1/ S´base)]. Patients with an absolute increase in ∆E´[1-(1/ E´base)] = cm/s or ∆S´[1-(1/ S´base)] cm/s of 0.7 cm/s, i.e., a 15 % in relative increase in cm/s from an assumed mean value of 6 cm/s) [13,14]. This assumption is estimated in accordance with previous human data [3, 4]. In that case we need to investigate 68 patients to demonstrate a mean absolute difference of 0.7 cm/s with an alpha error of 5 % and a beta error of 80 %, in an open labelled parallel trial. This calculation is done with a standard deviation for the method assumed to be 1.0 cm/s (absolute). We estimate that some subject will drop-out, therefore we will investigate 80 subjects (40 in each group). See attached figures. These figures (A and B), below. 639 640 641 A) With the proposed sample size of 34 and 34 for the two groups, the study will have power of 81.2% to 9.1 Data Management yield a statistically significant result. This computation assumes that the mean difference is -0.7 (corresponding to means of 6.0 versus 6.7) and the common within-group standard deviation is 1.0. 642 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 24(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 643 644 645 B) The precision estimated here is the median precision. Precision will vary as a function of the observed standard deviation (as well as sample size), and in any single study will be narrower or wider than this estimate. 646 647 648 10 Quality Control and Quality Assurance 649 650 651 652 653 During the course of the trial, the Monitor will visit the trial site to ensure that the protocol has been adhered to, that all issues have been recorded, perform source data verification, monitor drug accountability etc. The study will be monitored by a boarded monitor (Christina Häll, Metabollab Södersjukhuset). All adverse effects regardless of relationship to study drug or protocol procedure will be recorded in the adverse event CRF. 654 655 656 657 658 The monitor must be given direct access to source documents (original documents, data and records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) and report(s) that are important to the evaluation of the clinical trial. In order to that, a written consent from patient should be fulfilled. In addition the monitor should be available for discussions by telephone. 659 660 An investigator Source Document Verification Agreement will be completed and signed for each site in order to describe where source data for each data item can be found. 661 The monitor will ensure that the CRFs are completed by site staff. 662 663 11 Ethics 664 665 666 The protocol will be reviewed and approved by an IEC. The trial will be performed in accordance with the protocol guidelines in full accordance with Good Clinical Practice and applicable local regulatory requirements and laws. The investigator must insure that each trial 10.1 Monitoring 11.1 Ethical Conduct of the Trial Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 25(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 667 668 669 670 subject is fully informed about the nature and the objectives of the trial and possible risks associated with participation. The investigator will obtain written informed consent from each subject before any trial-specific activity is performed. The investigator will retain the original of each subject’s signed consent form. 671 11.2 Subject Information and Informed Consent 672 673 674 In obtaining and documenting informed consent, the Investigator must comply with applicable regulatory requirement and adhere to the ICH GCP and the requirements in the Declaration of the Helsinki 675 676 Prior to any trial related activity, the Investigator must give the subject oral and written information about the trial in a form that the subject can read and understand. 677 678 679 A voluntary, signed and personally dated, including time, informed consent must be obtained from the subject before any trial related activity. The subject must be provided with a copy of his/her signed informed consent. 680 681 682 The responsibility for obtaining informed consent must remain with that of a medically qualified person and cannot be delegated to a non-medical qualified person. The written informed consent must be signed and personally dated, by the person who obtained the informed consent. 683 684 685 If information becomes available that may be relevant to the subject’s willingness to continue participating in the trial, the Investigator must inform the subject in a timely manner, and a revised written informed consent must be obtained. 686 687 Once a subject’s participation in the trial has ended no additional care different from what is normally provided according to subjects medical condition is required. 688 689 12 Data Handling and Record Keeping 690 691 692 693 694 A case report form (CRF) will be obtained and completed for each included patient. Investigators will ensure completion and review of the CRF. Investigators have personal responsibility for the accuracy and authenticity of all clinical and laboratory data that are entered into the CRF. CRFs, including paper charts, will be stored in locked and secure place. However, in case of emergency, CRFs will be made readily available. 695 13 Financing and Insurance 696 697 Separate financially protocol will be set up. Subjects are insured accordingly to the Swedish patient insurance scheme and the Swedish Drug Insurance Scheme. 698 14 Publication Policy 699 The results of the trial will be published by the investigators in an international scientific journal. 12.1 Case Report Forms Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 26(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 700 701 15 Supplements 702 Before the Investigator starts the trial, the following documents must be available: 703 704 705 706 707 15.1 Amendments Regulatory approval and/or notification as required (independent ethics committee and the Medical Products Agency – Sweden) Signed and dated agreement on the final protocol Curricula vitae of the Investigator and Sub-Investigator(s) (current, dated and signed and/or supported by an official regulatory document) 708 15.2 Personnel Information 709 710 711 The Investigator is accountable for the conduct of the trial. If any tasks are delegated, the Investigator should maintain a list of appropriately qualified persons to whom he/she has delegated specified significant trial-related duties 712 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 27(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 713 16 References 714 715 [1] Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes: Part I: general concepts. Circulation. 2002 Apr 9;105(14):1727-33. 716 717 [2] Taegtmeyer H. Cardiac metabolism as a target for the treatment of heart failure. Circulation. 2004 Aug 24;110(8):894-6. 718 719 720 [3] Zabalgoitia M, Ismaeil MF, Anderson L, Maklady FA. Prevalence of diastolic dysfunction in normotensive, asymptomatic patients with well-controlled type 2 diabetes mellitus. The American journal of cardiology. 2001 Feb 1;87(3):320-3. 721 722 723 724 [4] Ha JW, Lee HC, Kang ES, Ahn CM, Kim JM, Ahn JA, et al. Abnormal left ventricular longitudinal functional reserve in patients with diabetes mellitus: implication for detecting subclinical myocardial dysfunction using exercise tissue Doppler echocardiography. Heart (British Cardiac Society). 2007 Dec;93(12):1571-6. 725 726 727 [5] Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006 Nov 11;368(9548):1696-705. 728 729 730 [6] Nyström T. The Potential Beneficial Role of Glucagon-like Peptide-1 in Endothelial Dysfunction and Heart Failure Associated with Insulin Resistance. Horm Metab Res. 2008 Sep;40(9):593-606. 731 732 733 [7] Gros R, You X, Baggio LL, Kabir MG, Sadi AM, Mungrue IN, et al. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology. 2003 Jun;144(6):2242-52. 734 735 736 [8] Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004 Mar 2;109(8):962-5. 737 738 739 740 [9] Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008 May 6;117(18):2340-50. 741 742 743 [10] Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009 Apr;58(4):975-83. Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 28(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 744 745 746 747 [11] Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring M, Matthews DR; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32: 84–90 748 749 750 751 [12] Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography´s Guidelines and Standards Committee and the Chamber Quantification Writing Group. J Am Soc Echocardiogr 2005;18:1440-63. 752 753 754 [13] Kukulski T, Voigt JU, Wilkenshoff UM, Strotmann JM,Wranne B, Hatle L, Sutherland GR. Comparison of Regional Myocardial Velocity Information Derived by Pulsed and Color Doppler Techniques: Echocardiography 2000 17,639-651 755 756 [14] Bibra H and Sutton MS. Diastolic dysfunction in diabetes and the metabolic syndrome: promising potential for diagnosis and prognosis Diabetologia 2010 53:1033–1045 757 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 29(30) Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment versus glimepiride 758 Appendices 759 16.1 Schedule of Investigational Events Visit 1 Screening Week -4 to -1 Informed consent X Inclusion/exclusion criteria X Visit 2 Visit 3 Week 0 Week 2 Week 10 Week 18 Dispensation of trial drug X Echocardiogram (Tissue Doppler) X X Exercise ECG X X Blood chemistry X X Body weight/length X X Waist and hip circumferences X X Quality of life (scoring) X X 24-hour blood pressure X X Vital signs X X X Week 20 X X X 760 17.2 Summary of Product Characteristics Glimepiride 762 17.3 Summary of Product Characteristics Liraglutide 764 Protocol No: EudraCT nr 2010022695-31 Date: 20110204 Version: 7.5 Visit 6 Randomisation (Telephone) (Telephone) End of treatment End of trial X AE/SAE 763 Visit 5 Randomisation Pregnancy test 761 Visit 4 30(30) X X X