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Integrated Clinical Study Protocol No. BAY 1021189 / 15371 06 JUL 2014 Version 2.0 Page: 1 of 95 Integrated Clinical Study Protocol No. BAY 1021189 / 15371 06 JUL 2014 Version 2.0 Page: 1 of 95 Study title: A randomized parallel-group, placebo-controlled, double-blind, multi- center dose finding phase II trial exploring the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the oral sGC stimulator BAY 1021189 over 12 weeks in patients with worsening heart failure and reduced ejection fraction (HFrEF) - SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with REDUCED EF (SOCRATES-REDUCED) For this study, the protocol and subsequent protocol amendments were released as follows: Original protocol, Version 1.0, dated 16 JUL 2013 Amendment 01, dated 16 SEP 2013 (local amendment valid for Japan only) Amendment 02, (global amendment described in Section 13.1) (forming current integrated protocol Version 2.0, dated 06 JUL 2014) This document integrates the original protocol and all global amendments. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Integrated Clinical Study Protocol No. BAY 1021189 / 15371 06 JUL 2014 Version 2.0 Page: 2 of 95 Title page Study title: A randomized parallel-group, placebo-controlled, double-blind, multi- center dose finding phase II trial exploring the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the oral sGC stimulator BAY 1021189 over 12 weeks in patients with worsening heart failure and reduced ejection fraction (HFrEF) - SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with REDUCED EF (SOCRATES-REDUCED) Short title: Phase IIb safety and efficacy study of four dose regimens of BAY 1021189 in patients with worsening HF and reduced EF (SOCRATES-REDUCED) Test drug: BAY 1021189 Study purpose: Safety, efficacy, pharmacokinetics Clinical study phase: IIb Date: 06 JUL 2014 EudraCT no.: 2013-002287-11 Version no.: 2.0 Study no.: BAY 1021189 / 15371 Sponsor: Bayer HealthCare AG, D-51368 Leverkusen, Germany Sponsor’s medical expert: Eliana Samano, MD Bayer S.A Av. Domingos Jorge, 1100 - São Paulo - Brazil Phone: +55-11-5694-4007 The study will be conducted in compliance with the protocol, International Conference on Harmonization –Good Clinical Practice (ICH-GCP) and any applicable regulatory requirements. Confidential The information provided in this document is strictly confidential and is intended solely for the guidance of the clinical investigation. Reproduction or disclosure of this document - whether in part or in full - to parties not associated with the clinical investigation, or its use for any other purpose, without the prior written consent of the sponsor is not permitted. Throughout this document, symbols indicating proprietary names (, TM) may not be displayed. Hence, the appearance of product names without these symbols does not imply that these names are not protected. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Downloaded From: https://jamanetwork.com/ on 10/02/2021 Integrated Clinical Study Protocol No. BAY 1021189 / 15371 06 JUL 2014 Version 2.0 Page: 4 of 95 Signature of principal investigator The signatory agrees to the content of the final clinical study protocol as presented. Name: Date: Signature: Signed copies of this signature page are stored in the sponsor’s study file and in the respective center’s investigator site file. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Integrated Clinical Study Protocol No. BAY 1021189 / 15371 06 JUL 2014 Version 2.0 Page: 5 of 95 Synopsis--amended Title A randomized parallel-group, placebo-controlled, double-blind, multi-center dose finding phase II trial exploring the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the oral sGC stimulator BAY 1021189 over 12 weeks in patients with worsening heart failure and reduced ejection fraction (HFrEF) Short title Phase IIb safety and efficacy study of four dose regimens of BAY 1021189 in patients with HFrEF suffering from worsening chronic HF (SOCRATES- REDUCED) Clinical study phase IIb Study objective(s) To find the optimal dose of the oral soluble guanylate cyclase (sGC) stimulator BAY 1021189 for Phase III that can be given in addition to standard therapy for heart failure with reduced EF (HFrEF) by characterizing the safety, tolerability, pharmacodynamic effects, and pharmacokinetics, and detecting a significant dose-response relationship in the primary endpoint change in NT-ProBNP at 12 weeks in patients with worsening chronic heart failure with reduced ejection fraction (HFrEF). Test drug(s) BAY 1021189 immediate-release (IR) tablet Name of active ingredient BAY 1021189 Dose(s) 1.25 mg once daily 2.5 mg once daily 5 mg once daily 10 mg once daily Route of administration Oral Duration of treatment 12 weeks Reference drug(s) Placebo Name of active ingredient N/A Dose(s) N/A Route of administration Oral coated tablet Duration of treatment 12 weeks Indication Heart failure (HF) with reduced ejection fraction (HFrEF) Main inclusion criterion Worsening chronic heart failure (WCHF) requiring hospitalization (or intravenous [IV] diuretic treatment for HF without hospitalization) with initiation of study treatment after clinical stabilization Downloaded From: https://jamanetwork.com/ on 10/02/2021 Integrated Clinical Study Protocol No. BAY 1021189 / 15371 06 JUL 2014 Version 2.0 Page: 6 of 95 Diagnosis 1. History of chronic HF: NYHA class II-IV and standard HF therapy ≥30 days before hospitalization1 2. Worsening HF at hospitalization1 a. N-terminal pro brain natriuretic peptide (NT-proBNP) ≥1000 or BNP ≥300 if in sinus rhythm, or NT-proBNP ≥1600 or BNP ≥500 pg/mL in atrial fibrillation in local routine labs, and b. Symptoms and signs of congestion (clinical or radiographic signs in routine chest x-ray demonstrating pleural effusion, pulmonary congestion, or cardiomegaly) 3. Clinical stabilization defined by a. no IV vasodilator for >24h and no IV diuretic for >12h before randomization and b. Systolic blood pressure (SBP) ≥110 and <160 mmHg and resting heart rate (HR) ≥50 and <100 beats per minute (bpm) at randomization 4. Left ventricular ejection fraction (LVEF) <45% by echocardiography at randomization 1 or IV diuretic treatment for HF without hospitalization Key exclusion criteria 1. IV inotropes at any time between hospitalization and randomization1 2. Concurrent or anticipated nitrate use (all routes, incl. prn) for the treatment of ischemic heart disease or HFrEF 3. Cardiac comorbidity o Specific HF etiologies, incl. hypertrophic cardiomyopathy with left ventricular (LV ) outflow tract obstruction; pericardial disease; infiltrative or inflammatory myocardial disease; valvular heart disease with severe aortic or primary2 mitral regurgitation, moderate or severe aortic stenosis, any mitral stenosis requiring surgical repair, or active endocarditis; or o Acute coronary syndrome (ACS), including unstable angina, Non-ST elevation myocardial infarction (NSTEMI) or ST elevation myocardial infarction (STEMI), or coronary artery bypass grafting (CABG) within 60 days prior to randomization; or o Current indication for percutaneous coronary intervention (PCI) or CABG (at the time of randomization)3; or o Significant cardiac ischemia in a stress test within a year of enrollment without revascularization since; or 1 Clarified via Amendment 2 2 Clarified via Amendment 2 3 Clarified via Amendment 2 Downloaded From: https://jamanetwork.com/ on 10/02/2021 Integrated Clinical Study Protocol No. BAY 1021189 / 15371 06 JUL 2014 Version 2.0 Page: 7 of 95 o Symptomatic carotid stenosis, or TIA or stroke within 30 days prior to randomization; or o New initiation of cardiac resynchronization therapy (CRT) within 60 days prior to randomization; or o Listing for heart transplantation and/or anticipated/implanted ventricular assist device; or o Complex congenital heart disease 4. Non-cardiac comorbidity at the time of randomization o Glomerular filtration rate <30 mL/min/1.73 m2 calculated by MDRD; or o Hepatic insufficiency Child-Pugh B or C; or o Body mass index (BMI) >454 kg/m²; or o Malignancy or other non-cardiac condition limiting life expectancy to <1 year; or o Severe pulmonary disease with either requirement of continuous home oxygen or bronchial artery embolization for massive hemoptysis 5. Previous (within 30 days of randomization) or concomitant participation in another clinical study with investigational medicinal5 product(s). 6. Close affiliation with the investigational site; e.g., a close relative of the investigator, dependent person (e.g., employee or student of the investigational site).6 7. Previous assignment to treatment during this study.7 Study design Prospective, randomized, placebo-controlled, double-blind, 5 parallel arm global multi-center dose finding phase II trial 4 BMI exclusion changed from 40 to 45kg/m2 via Amendment 2 5 Clarified via Amendment 2 6 Added via Amendment 2 7 Added via Amendment 2 Downloaded From: https://jamanetwork.com/ on 10/02/2021 Integrated Clinical Study Protocol No. BAY 1021189 / 15371 06 JUL 2014 Version 2.0 Page: 8 of 95 Methodology Subjects will be randomized to either 1. Placebo and sham titration 2. 1.25 mg and sham titration 3. 2.5 mg and sham titration 4. 2.5 mg, which will be up-titrated to 5 mg after 14 days 5. 2.5 mg, which will be up-titrated to 5 mg after 14 days and to 10 mg after 28 days Titration steps at 14 and 28 days include sham titrations in groups 1, 2, and 3, and in group 4 after 28 days. Titration in all groups will depend on systolic blood pressure
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