Clinical Study Synopsis

Transcription

1 Clinical Study Synpsis This Clinical Study Synpsis is prvided fr patients and healthcare prfessinals t increase the transparency f Bayer's clinical research. This dcument is nt intended t replace the advice f a healthcare prfessinal and shuld nt be cnsidered as a recmmendatin. Patients shuld always seek medical advice befre making any decisins n their treatment. Healthcare Prfessinals shuld always refer t the specific labelling infrmatin apprved fr the patient's cuntry r regin. Data in this dcument r n the related website shuld nt be cnsidered as prescribing advice. The study listed may include apprved and nn-apprved frmulatins r treatment regimens. Data may differ frm published r presented data and are a reflectin f the limited infrmatin prvided here. The results frm a single trial need t be cnsidered in the cntext f the ttality f the available clinical research results fr a drug. The results frm a single study may nt reflect the verall results fr a drug. The fllwing infrmatin is the prperty f Bayer HealthCare. Reprductin f all r part f this reprt is strictly prhibited withut prir written permissin frm Bayer HealthCare. Cmmercial use f the infrmatin is nly pssible with the written permissin f the prprietr and is subject t a license fee. Please nte that the General Cnditins f Use and the Privacy Statement f bayerhealthcare.cm apply t the cntents f this file.

2 Study Spnsr: Study Number: Study Phase: IIb Clinical Trial Results Synpsis Study Design Descriptin Bayer HealthCare Pharmaceuticals Inc. NCT EudraCT number: Official Study Title: A placeb cntrlled, randmized, duble-blind, fixed-dse, multicenter, phase IIb study t investigate the efficacy and tlerability f lw dse BAY (25 µg/h, 10 µg/h) given intravenusly t subjects with acute decmpensated chrnic cngestive heart failure (ADHF) Therapeutic Area: Cardilgy/Cagulatin Test Prduct Name f Test Prduct: Name f Active Ingredient: Dse and Mde f Administratin: Cinaciguat (BAY ) Cinaciguat 10 µg/h r 25 µg/h administered as cntinuus intravenus (IV) infusin Reference Therapy/Placeb Reference Therapy: Matching placeb Dse and Mde f Administratin: Matching placeb was administered as cntinuus IV infusin Duratin f Treatment: Treatment was given fr at least 24 hurs and up t 48 hurs. Studied Perid: Date f first subjects first visit: 15 MAR 2010 Date f last subjects last visit: 05 NOV 2010 Premature Study Suspensin / Terminatin: Yes This study was terminated n 01 Mar 2011, in view f (i) the incnclusive risk-benefit balance fr the 10 µg/h and 25 µg/h dses and (ii) recruitment difficulties experienced by the study sites. Substantial Study Prtcl Amendments: Amendment n. 1, dated 14 SEP 2010, was enacted fr the fllwing substantial changes: Inclusin criteria: The fllwing changes were made: The requirement that a subject shuld have systlic bld pressure f 120 mmhg and heart rate f <100 beats per minute at inclusin in the study was mdified, and the subjects were required t have these values during the runin phase and at baseline. In additin, the criterin was als expanded t indicate that the shck index (heart Page 1 f 7

3 rate/systlic bld pressure) shuld be <1. Exclusin criteria: The exclusin criteria related t the specific prhibited medicatins was mdified t: restrict the use f IV vasdilating drugs and IV natriuretic peptides revise the exclusin regarding the use f any IV intrpic agent (e.g., dbutamine, levsimendan) frm within the last 3 hurs prir t the study drug infusin t exclude any IV catechlamines r levsimendan within the last 30 days prir t study drug infusin prhibit the use f PDE-5 inhibitrs. Safety variables: The fllwing changes were made: The safety variable "Length f in-hspital stay fr the initial admissin" was added as an additinal safety variable/endpint in the hpes f shwing an imprvement in the length f hspitalizatin with BAY cmpared with placeb. The definitin f a treatment-emergent adverse event (TEAE) was changed frm thse starting r wrsening within 24 hurs f start f the study drug infusin t thse starting r wrsening within tw calendar days f starting the infusin. Events f special interest: The events ventricular tachycardia and ventricular extrasystles were identified as events f special interest. These were changed t prvide a brader term, any ventricular arrhythmia (encmpassing bth ventricular tachycardia and ventricular extrasystles) that were cnsidered by the investigatr as medically imprtant. Assessment perids: The run-in perid f 24 hurs frm the admissin f the subjects t the hspital was changed such that the run-in perid n lnger had a time limit f 24 hurs and encmpassed the entire time frm hspital admissin t randmizatin in the study. Specific restrictins regarding the use f sme drugs during the run-in perid were mdified/added t reflect the changes made t the exclusin criteria and the use f prir and cncmitant therapy. Infrmatin regarding restricted therapy during the treatment was clarified/expanded t include prhibitin f IV vasdilatrs, IV natriuretic peptides, ral r tpical nitrates, and nn-invasive ventilatin during the infusin perid. A statement was added that these drugs culd be used as rescue medicatin nce the infusin had been stpped. The statement regarding the use f IV diuretics during the treatment was mdified t allw any diuretic. Hemdynamic measurements: The statement "The right heart thermdilutin methd will be used fr cntinuus hemdynamic measurements" was remved t allw the study sites t use their rutine prcedures. Page 2 f 7

4 Study Center(s): Planned: Apprximately 60 centers wrldwide. Actual: At the time f study terminatin, tw sites in Germany had screened the subjects, and tw sites had randmized a ttal f five subjects. Methdlgy: This study cnsisted f three grups: tw grups receiving different dses f cinaciguat (10 µg r 25 µg) and a placeb grup. Eligible subjects received an IV infusin f either ne f the tw dses f cinaciguat r matching placeb fr a minimum f 24 hurs and a maximum f 48 hurs. Subjects were evaluated at run-in phase (time frm hspital admissin t randmizatin f subjects), baseline (defined as: as clse t the start f study drug infusin as pssible), at varius time pints during the study drug infusin, within the immediate hurs after the stp f study drug infusin, at hspital discharge, and at 30 days after the stp f the infusin (fllw-up visit). Assessments included hemdynamic measurements, bld pressure, heart rate, adverse events (AEs), and the need fr cncmitant medicatins. The subjective well-being f the subject was assessed by the EurQl Visual Analgue Scale (VAS) and Kansas City Cardimypathy Questinnaire (KCCQ). Fr determining systemic expsure t IV infusin, bld samples were taken at several time pints during the infusin and at 1 and 2 hurs after the stp f the study drug infusin. Bld samples fr bimarker analysis were cllected befre infusin, at 24 hurs, at the end f the infusin, at hspital discharge, and at the 30-day fllw-up visit. Indicatin / Main Inclusin Criteria: Indicatin: Acute decmpensated chrnic cngestive heart failure (ADHF) Main inclusin criteria: Subjects with ADHF New Yrk Heart Assciatin functinal class III-IV, either ischemic r nn-ischemic, requiring hspitalizatin and with clinical indicatin fr parenteral pharmactherapy and invasive hemdynamic mnitring (i.e., in-dwelling pulmnary artery catheter [Swan-Ganz]) and pulmnary capillary wedge pressure [PCWP] 20 mmhg with cardiac index (CI) 2.5 at run-in and baseline Subjects aged 18 years and abve Male and nn-pregnant, nn-lactating female subjects r wmen withut childbearing ptential defined as pstmenpausal wmen aged 55 years r lder, wmen with bilateral tubal ligatin, wmen with bilateral varectmy, and wmen with a hysterectmy Subjects must have had a clinical diagnsis f cngestive heart failure (CHF) made at least 3 mnths prir t enrllment Page 3 f 7

5 Study Objectives: Primary: Subjects must have experienced wrsening f bth dyspnea and clinical evidence f vlume verlad leading t hspitalizatin at the time f entry int the study T investigate the safety and efficacy f a fixed dse ver at least 24 hurs and up t 48 hurs f intravenus cinaciguat (25 µg/h, 10 µg/h) in subjects with ADHF with the need fr parenteral pharmactherapy and invasive hemdynamic mnitring (i.e., in-dwelling pulmnary artery catheter [Swan-Ganz]) and pulmnary capillary wedge pressure (PCWP) 20 mmhg with cardiac index (CI) 2.5. Evaluatin Criteria: Secndary: T evaluate the ptential effects f the tw fixed dses f cinaciguat (10 µg/h, 25 µg/h) and placeb given intravenusly n QT/QTc prlngatin. Efficacy (Primary): The primary efficacy utcme measure was the change in PCWP frm baseline t 8 hurs after the start f the infusin (r last bservatin carried frward [LOCF]). Efficacy (Secndary): Explratry efficacy utcme measures included: Change in PCWP frm baseline t 48 hurs after the start f infusin Cardiac index at varius time pints up t the fllw-up visits (including at 8 hurs and 48 hurs after the start f the infusin) Right arterial pressure (RAP) at varius time pints up t the fllw-up visits (including at 8 hurs and 48 hurs after the start f the infusin) Other hemdynamic parameters including pulmnary artery pressure (PAP), mean arterial pressure, cardiac utput, systemic vascular resistance, and pulmnary vascular resistance at varius time pints up t the fllw-up visit Change in PCWP frm baseline t maximal effect Respnder rate (i.e., prprtin f subjects experiencing a PCWP reductin f 4 mmhg) Change in verall health status thrugh EurQl VAS frm baseline t 24 hurs and 48 hurs after the start f the infusin, and up t the fllw-up visit Change in verall health status thrugh KCCQ scres frm baseline t the fllw-up visit Physician's assessment at different time pints during the treatment phase Safety: Page 4 f 7

6 Safety assessments included: Change in heart rate frm baseline t different time pints up t the fllw-up visit Change in systlic and diastlic bld pressure frm baseline t different time pints up t the fllw-up visit Frequency f TEAEs; treatment-emergent serius adverse events (SAEs); and deaths during the study Evaluatin f renal and cardiac functin thrugh assessments f different bimarkers at different time pints up t the fllw-up visit Labratry parameters at different time pints up t the fllw-up visit Electrcardigram (ECG) assessments at different time pints up t the fllw-up visit In-hspital mrtality Length f in-hspital stay fr the initial admissin Days in hspital (frm first admissin until the fllw-up visit) Re-hspitalizatin until the fllw-up visit 30-days mrtality Pharmackinetics: Statistical Methds: Ppulatin: Bld samples were cllected peridically during the treatment perid, at the end f the study drug infusin, and during the fllw-up visit t determine the plasma cncentratins f cinaciguat. A randmized subject was cnsidered valid fr the safety ppulatin if he/she had received any study drug. A subject was cnsidered valid fr the intent-t-treat (ITT) ppulatin if he/she was cnsidered valid fr the safety ppulatin and had at least ne valid efficacy measurement (primary r secndary) at bth baseline (if required) and pst-baseline. A per prtcl (PP) ppulatin was planned in the riginal study prtcl. Hwever, because the study was prematurely terminated and cmprised f nly fur treated subjects, n PP analysis set was defined. Efficacy (Primary): N statistical analyses were perfrmed, and n descriptive statistics were prepared because f the small number f subjects enrlled in the study. Efficacy (Secndary): N statistical analyses were perfrmed, and n descriptive statistics Page 5 f 7

7 were prepared because f the small number f subjects enrlled in the study. Safety: Safety results were described individually fr each subject due t the small number f subjects enrlled in the study. N statistical analyses were perfrmed. Pharmackinetics: Plasma cncentratin f cinaciguat was reprted fr all the enrlled subjects t determine whether the cncentratin was abve r belw the lwer limit f quantificatin (LLOQ). N statistical analyses were perfrmed. Number f Subjects: Planned: A ttal f 60 subjects were t be randmized, 20 subjects per treatment grup, r a ttal f 60 subjects valid fr the prtcl. Results Summary Subject Dispsitin and Baseline Actual: Seven subjects were screened; five subjects were randmized; and fur subjects were treated (placeb grup n = 1; 10 µg/h grup n = 2; 25 µg/h grup n = 1). Study Results Of the five randmized subjects, fur subjects were treated (placeb grup n = 1; 10 µg/h grup n = 2; 25 µg/h grup n = 1), and ne subject did nt receive the study treatment. In this study, three subjects were males, and ne subject was female; all subjects were Caucasian. The age f the subjects ranged frm 58 t 75 years. Only ne subject (25 µg/h) cmpleted the treatment phase. The three ther subjects discntinued the treatment phase because f insufficient therapeutic effect. Results Summary Efficacy This study was prematurely terminated; therefre, n inferential efficacy analyses were cnducted, and n summary statistics fr the efficacy variables were prepared. Results Summary Safety Tw subjects (ne subject each in the 10 µg/h grup and 25 µg/h grup) reprted AEs, all f which were either mild r mderate in severity. Adverse events cnsidered related t the study drug were nausea and decreased bld pressure. N SAEs r deaths were reprted. Clinically significant changes in serum creatinine, creatinine clearance, and ultrasensitive trpnin I (UsTnI) were nt evaluated. Tw subjects had high serum creatinine at baseline; bth f these subjects had a histry f chrnic renal failure. In bth the cases, serum creatinine remained high and similar t baseline at 24 hurs. All fur treated subjects had high serum creatinine and lw egfr at the fllw-up visit. Tw subjects (10 µg/h grup) experienced elevated UsTnI nly at the fllw-up visit. A third subject (25 µg/h grup) had elevated UsTnI values at all time pints assessed (including Page 6 f 7

8 baseline). Fr the mst part f the study, vital signs remained relatively stable and within the expected ranges thrughut the treatment, and at 1 and 2 hurs pst-treatment in all subjects. One subject (10 µg/h grup) experienced a TEAE f decreased bld pressure that was cnsidered t be related t the study drug. The event reslved upn withdrawal f the study drug withut remedial drug therapy. The mst cmmn ECG findings included rhythm and rate disrders which were reprted in three subjects. Results Summary Pharmackinetics N appreciable difference in the plasma cncentratins f cinaciguat was bserved in the subjects wh received 10 µg/h and in the subject wh received 25 µg/h. The single subject wh received 25 µg/h had detectable cncentratins at 1 and 2 hurs pst-treatment, while cncentratins were belw the LLOQ at 2 hurs pst-treatment in bth the subjects treated with 10 µg/h f the study drug. Cnclusin(s) In this study, due t the small number f subjects, n definitive cnclusins culd be drawn regarding the efficacy r safety f cinaciguat at the dses tested. Publicatin(s): Nne Date f Clinical Study Reprt: 10 MAY 2013 Date Created r Date Last Updated : 16 APR 2013 Page 7 f 7