Study Synopsis for Feasibility

Transcription

1 Study Cde D1699C00001 Study Synpsis fr Feasibility An Internatinal, Multicenter, Randmised, Duble-Blind, Placeb-Cntrlled Study t Evaluate the Effect f Dapagliflzin n the Incidence f Wrsening Heart Failure r Cardivascular Death in Patients with Chrnic Heart Failure with Reduced Ejectin Fractin

2 1. INTRODUCTION 1.1 Backgrund Despite advances in the management f chrnic heart failure (HF), the prevalence and incidence f HF cntinues t increase glbally. An estimated 38 millin peple are affected wrldwide (Braunwald 2015) with ver 1 millin hspitalizatins annually in bth the United States and Eurpe (Ambrsy et al 2014). Recently, in patients with type 2 diabetes and high CV risk, the SGLT-2 inhibitr, empagliflzin, markedly reduced mrtality frm any cause including cardivascular as well as hspitalizatin frm HF cmpared with placeb added t SOC (Zinman et al 2015). In a secndary analysis f HF utcmes, empagliflzin reduced the risk f hspitalizatin fr HF r cardivascular death by 34% (Fitchett et al 2016). There is a strng scientific ratinale fr beneficial effects f SGLT2 inhibitin als in patients with HF but withut diabetes. Patients with HF have similar pathphysilgical and clinical picture with increased fluid/sdium verlad regardless f the underlying disease and presence r absence f diabetes. SGLT2 inhibitin addresses these abnrmalities thrugh metablic-independent mechanisms and, indeed, the reductin n CV and renal events with empagliflzin cannt be explained by imprved glycemic cntrl (Rajasekeran et al 2016). The ptential fr beneficial effects in patients with HF that are independent f glucse lwering mechanisms has yet t be investigated. Dapagliflzin (Frxiga ), a highly selective SGLT2 inhibitr, prduces many favrable cardivascular and metablic effects that may be beneficial in patients with heart failure. In additin t lwering glucse, dapagliflzin induces a diuresis and natriuresis, thereby reducing bth prelad and afterlad and lwering bld pressure. Other pssible beneficial cardivascular effects f dapagliflzin include nn-smtic weight lss frm glucse wasting and reductin in albuminuria and plasma uric acid. In a pst-hc analysis frm the pled database frm the dapagliflzin develpment prgram, patients with a histry f T2D and cncmitant heart failure (171 patients received dapagliflzin 10 mg and 149 patients received placeb), had a significant reductin in weight, bld pressure and HbA1c, in line with the previus develpment prgram. Dapagliflzin 10 mg was well tlerated and vlume depletin and hypglycemia AEs were balanced between the grups (Ksibrd, pster, ADA, 2015). The clinical experience in healthy vlunteers at high multiple dses als shws that, due t the mechanism f actin, dapagliflzin des nt induce hypglycemia in nn-diabetics. The main bjective f the present study is t demnstrate that dapagliflzin will reduce the incidence f the cmpsite endpint CV death r wrsening heart failure event when added t standard f care treatment (SOC) in patients with established ( 1 mnth) HFrEF. 2. STUDY OBJECTIVES 2.1 Primary bjectives T determine, as a superirity assessment, whether treatment with dapagliflzin 5 mg and 10 mg (pled dses), when added t standard f care, will reduce the incidence f the cmpsite endpint f CV death r wrsening heart failure event (ne requiring hspitalizatin fr heart failure* r an urgent, unplanned, visit fr wrsening f heart failure**) 2 (7)

3 *HF hspitalizatin is defined as an event that meets all the fllwing criteria: 1. The patient is admitted t the hspital with a primary diagnsis f HF and has a length f stay that extends fr at least 24 hurs. 2. The patient exhibits at least ne new r wrsening symptm f HF such as dyspnea, decreased exercise tlerance r fatigue. 3. The patient has bjective evidence f new r wrsening HF including at least 2 physical examinatin finding indicative f HF OR 1 physical examinatin finding and 1 bjective labratry finding (btained within 24 hurs f admissin) fr HF. Examples f physical findings include peripheral edema, pulmnary rales, increased jugular venus pressure, an S3 gallp, r clinically significant weight gain thught secndary t fluid retentin. Examples f labratry evidence fr new r wrsening HF include increased natruiretic peptide cncentratins cnsistent with decmpensated HF, radilgical evidence f pulmnary cngestin, invasive r nninvasive diagnstic evidence f clinically significant elevatins f left r right sided ventricular filling pressures r lw cardiac utput. 4. Initiatin r intensificatin f treatment specifically fr heart failure including augmentatin f ral diuretic therapy, initiatin f intravenus diuretic r vasactive therapy, mechanical r surgical interventins t prvide circulatry supprt r remve fluid. **An Urgent HF visit is defined as an event that meets all f the fllwing criteria: 1. The patient has an urgent unscheduled ffice r emergency department visit fr a primary diagnsis f HF but des nt meet the criteria fr HF hspitalizatin 2. Signs and symptms fr HF are present and meet the criteria listed under HF hspitalizatin. 3. Initiatin r intensificatin f treatment specifically fr HF accrding t the criteria listed under hspitalizatin fr HF with the exceptin f ral diuretic therapy which will nt be sufficient. 2.2 Secndary bjectives T cmpare the effect f treatment f dapagliflzin versus placeb On an expanded cmpsite utcme reflecting wrsening f HF. This utcme includes all cmpnents f the primary cmpsite endpint plus wrsening heart failure symptms/signs leading t sustained augmentatin f existing ral therapy, r additin f a new ral treatment, specifically given fr wrsening HF. On time t death frm any cause. On the Kansas City Cardimypathy Questinnaire (KCCQ) clinical summary scre fr heart failure symptms and physical limitatins. On the incidence f renal cmpsite endpint f wrsening renal functin utcme 3. STUDY PLANS AND PROCEDURES (ASSESSMENTS) 3.1 Study Descriptin This is an event-driven, randmized, duble-blind, duble-dummy, placeb-cntrlled parallelgrup, internatinal multi-centre study in patients with chrnic HFrEF, evaluating the effect f dapagliflzin 5 mg and 10 mg versus placeb, given nce daily in additin t SOC, fr the preventin f CV death r wrsening heart failure event. Apprximately 4000 patients at centres in mre than 20 cuntries will be randmized in prprtins f 1:1:2, i.e. apprximately 1000:1000:2000 patients t respective treatment grup (see study flwchart). The anticipated duratin f the study is apprximately 3 years, including an anticipated enrlment perid f 2 years and a fllw-up perid f 1 year. Clseut f the trial will cmmence when a predetermined number f adjudicated CV events required t test the study hypthesis is reached. 3 (7)

4 The target ppulatin includes male and female patients with a dcumented established diagnsis f HFrEF 1 mnth. The Executive cmmittee f the study will cntinuusly mnitr the recruitment in the study as the intent is t enrl as typical crss-sectin f patients with HFrEF as pssible and t include representative prprtins f diabetic and nn-diabetic patients. The study medicatin (dapagliflzin r placeb), will be added t existing prescribed stable backgrund heart failure therapy (e.g. ACE inhibitr/arni r ARB, beta blcker, MRA unless cntraindicated r untlerated, fr at least 4 weeks befre study entry) as cnsidered apprpriate by the investigatr and in accrdance with guidelines and reginal standards f care fr heart failure. 3.2 Study Flwchart E = Enrlment, R = Randmizatin, TC=Telephne Cntact, PACD=Primary Analysis Censring Date, SCV=Study Clsure Visit Table 1 Study Plan and timing f Prcedures Activity Enrlm ent Randmi zatin TC Site visits TC Site visit PTDV a SCV b Visit number ,8 etc. PTDV SCV Day (±3) >every 3 rd mnth (Alternating site visits r TCs (±14) 6 wks Signed Infrmed Cnsent Frm Demgraphy Medical histry Inclusin/exclusin criteria 4 (7)

5 Activity Enrlm ent Randmi zatin TC Site visits TC Site visit PTDV a SCV b Visit number ,8 etc. PTDV SCV Day (±3) >every 3 rd mnth (Alternating site visits r TCs (±14) 6 wks General Physical examinatin Targeted physical examinatin (fcus n sign fr heart failure and vlume status) Vital signs (BP, pulse and bdy weight) Electrcardigram (ECG) Height Cncmitant medicatin Pregnancy testing c Assessment f left ventricular functin d Labratry assessments e egfr assessment f HbA1c f NT- prbnp f New Yrk Heart Assciatin (NYHA) Functinal Classificatin Kansas City Cardimypathy Questinnaire (KCCQ) g EQ-5D questinnaire g SAE, DAE, and ptential DKA h Ptential endpint events Dispense/Cllect study medicatin IP cmpliance reminder Sample fr bimarker research, if applicable i a) Patients wh prematurely and permanently discntinue treatment with IP shuld return fr a Premature Treatment Discntinuatin Visit (PTDV), which will be dne as sn as pssible but n later than 7 days after last IP dse. Patients wh discntinue treatment prematurely still need t attend a mdified SCV, where nly parts f assessments at that visit are made, i.e. check fr ptential study endpints, assessment f any SAE, Discntinuatin f investigatinal prduct due t Adverse Event (DAE), ptential DKA, and anti-diabetes and CV medicatin b) The Study Clsure Visit (SCV) may be a telephne cntact in exceptinal cases. c) Only applicable fr wmen f childbearing ptential (see exclusin criteria n.13). d) LV assessments nly assessed if n assessment has been perfrmed within 6 mnths prir t enrlment. 5 (7)

6 e) Labratry assessment will be dne at a central labratry. These assessments will include ptassium, sdium, creatinine and haematcrit, In additin, Hb and liver enzymes will be taken at the enrlment visit assessment. f) egfr, HBA1c and NTprBNP will be assessed at a central labratry. g) The QL frms will be filled ut by the patient prir t any ther site activities at site visits. h) SAEs will be cllected frm the time f infrmed cnsent thrughut the study until and incl. the SCV. Endpint events, DAEs and ptential DKAs will be cllected frm randmisatin thrughut the study until and incl. the SCV. i) Bld and urine samples fr ptential future bimarker research will be cllected that may be analysed at the discretin f the spnsr. The bimarker sampling is ptinal and subject t separate apprval/cnsent by the patient at Visit 1. General remark t Table 1: Plasma sampels fr Ppulatin Pharmackinetics will als be cnsidered frm a smaller prprtin f patients. This will be determined and elabrated during the develpment f the Clinical Study Prtcl. 4. SUBJECT SELECTION 4.1 Ppulatin Inclusin Fr inclusin in the study subjects shuld fulfil the fllwing criteria: 1. Prvisin f written infrmed cnsent prir t any study specific prcedures 2. Male r female, aged 18 years at the time f cnsent 3. Established diagnsis f HFrEF (>1 mnth), with NYHA class II-IV with a LVEF<40% (echcardigram, radinuclide ventriculgram r cardiac MRI fr assessment f LV functin) within the last 6 mnths prir t sceening (Visit 1). If there is mre than ne measurement f LVEF the value frm the mst recent measurement shuld be used in assessing eligibility. Patients underging crnary revascularizatin (PCI r CABG), valve repair/replacement r implantatin f a cardiac resynchrnizatin therapy device (CRT) must have a measurement f LVEF at least 3 mnths after the interventin in rder t be eligible. Patients withut a recent assessment f LV functin will underg a lcal echcardigram at the time f Visit 1) 4. NT-prBNP >600 pg/ml r, if hspitalized fr heart failure within the previus 12 mnths, NT-prBNP 400 pg per milliliter at Visit 1. If cncmitant atrial fibrillatin at Visit 1, NT-prBNP must be >1000 pg/ml at Visit 1 (irrespective f histry f heart failure hspitalizatin) 5. Stable guideline-recmmended dse f ACE inhibitr, ARB r sacubitril/valsartan, and a beta-blcker, unless cntraindicated r nt tlerated (and mineralcrticid receptr antagnist (MRA) if cnsidered apprpriate by the patient s treating physician) fr at least 4 weeks befre Visit 1 6. egfr 30 ml/min/1.73 m2 at Visit 1 (CKD-EPI frmula) Exclusin Subjects shuld nt enter the study if any f the fllwing exclusin criteria are fulfilled: 1. Receiving therapy with an SGLT2 inhibitr within 12 weeks prir t Visit 1 r previus intlerance f a SGLT2 inhibitr 2. Type 1 diabetes mellitus 3. Histry f diabetic ketacidsis (DKA) requiring medical interventin (eg, emergency rm visit and/r hspitalizatin) within 4 weeks prir t the Visit 1 4. Symptmatic hyptensin r systlic BP <95 mmhg 5. Current acute decmpensated heart failure r hspitalizatin due t decmpensated heart failure less than 4 weeks prir t Visit 1 6 (7)

7 6. Mycardial infarctin, strke, transient ischemic attack, r crnary revascularizatin (PCI r CABG) r valvular repair/replacement within 8 weeks f screening r expected t underg crnary revascularizatin (PCI r CABG) r valvular repair/replacement after randmizatin 7. Implantatin f a cardiac resynchrnizatin therapy device (CRT) within 12 weeks prir t Visit 1 r intent t implant a CRT device 8. Previus cardiac transplantatin r implantatin f a ventricular assistance device (VAD) r similar device, r implantatin expected after randmizatin 9. HF due t restrictive cardimypathy, active mycarditis, cnstrictive pericarditis, hypertrphic (bstructive) cardimypathy r uncrrected primary valvular disease 10. Symptmatic bradycardia r secnd r third degree heart blck withut a pacemaker 11. Any cnditin utside the cardivascular study area with a life expectancy f less than 2 years based n investigatr s judgement 12. Severe hepatic disease, including chrnic active hepatitis. 4.2 Cncmitant and ther treatments Heart failure medicatins and ther cardivascular medicatins Patients shuld be n standard backgrund therapies fr HF accrding t lcal guidelines. Standard evidence based treatments will include either an ACE inhibitr, ARB r sacubitril/valsartan in cmbinatin with a beta-blcker, as well as an MRA where apprpriate unless cntraindicated r nt tlerated. Mst patients will als require a diuretic, generally a lp diuretic such as fursemide, t cntrl symptms. Patients shuld remain n stable dses f medicatins which will allw assessment f incremental dapagliflzin effect. Hwever, if the patient s cnditin warrants a change in any f these standard evidence based medicatins, it will be allwed at the discretin f the study investigatr. If patients require dse adjustment f backgrund therapy t avid signs/symptms f vlume depletin, diuretic shuld be decreased prir t adjusting ther medicatins. 5. REFERENCES 1) Ambrsy et al 2014; Ambrsy AP, Gherghiade M, Chincel O, Mentz R J, Butler J. Glbal perspectives in hspitalized heart failure: reginal and ethnic variatin in patient characeteristics, management and utcmes. J Am Cll Cardil 2014; 63: ) Braunwald 2015; Braunwald E. the war against heart failure: the Lancet lecture. Lancet 2015; 385: ) Fitchett et al 2016; Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S et al. Heart failure utcmes with empagliflzin in patients with type 2 diabetes at high cardivascular risk: results f the EMPA-REG OUTCOME trial. Eur Heart J di: \eurheartj\ehv728 [Epub ahead f print]. 4) Ksibrd et al 2015; Ksibrd M, Gause-NilssnvI, J u J, Snessn C, Jhnssn E. Efficacy and safety f dapagliflzin in patients with type 2 diabetes mellitus and Cncmitant Heart Failure. Pster 1211-P at American Diabetes Assciatin; Bstn, MA, June 5 9, ) Rajasekeran et al 2016; Rajasekeran H, Lytvyn Y and Cherney DZI. Sdium glucse ctransprter 2 inhibitin and cardivascular risk reductin in patients with type 2 diabetes: the emerging rle f natriuresis. Kidney Internatinal 2016; 89: ) Zinman et al 2015; Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E et al. Empagliflzin, cardivascular utcmes, and mrtality in type 2 diabetes. N Engl J Med 2015; 373: (7)