Endpoints in Heart Failure Clinical Trials: Challenges and Potential Resolutions

Transcription

1 Endpoints in Heart Failure Clinical Trials: Challenges and Potential Resolutions 1

2 Introductions Ø Olga Milo, MD Medical Director Ø Momentum Research, Inc. Ø Ø Mark Shapiro, MBA Vice President, Clinical Development Ø Clinipace Worldwide Ø 2016 Clinipace Worldwide

3 Introduction Ø Chronic heart failure (HF) affects 2% of the population and is the 4 th leading cause of adult hospitalizations in the U.S. Ø HF is the most frequent cause of hospitalization in patients > 65 years Ø Primary objectives in the treatment of patients with HF are to improve quality of life (QOL) and increase survival 3

4 Characteristics of Endpoints The selection of endpoints for HF clinical trials is challenging Ø They carry important implications for regulatory agencies and patients Ø Endpoints must be: Ø Easy to diagnose (easy to identify, no evaluator judgment needed) Ø Free of measurement error (reliable with repeated measure) Ø Internal validity (directly linked to property of interest) Ø External validity (ability to generalize to a wider population) 4

5 Objectives and Endpoints by Phase Phase Objective Efficacy/Endpoint Phase I Safety evaluation Patient tolerance Phase II Identify efficacy endpoints and doses for Phase III Phase III Efficacy and safety Evaluate for general use None "Exploratory Primary Secondary Primary - Indication Secondary - may be described in the label Phase IV Expand efficacy & Safety Expand patient reported outcomes 5

6 Hard vs Soft Endpoints Ø Hard endpoints Ø Well- defined in study protocol Ø Definitive with respect to the disease process Ø Require no subjectivity 6

7 Hard Endpoints in HF Studies Mortality as a hard endpoint Ø Easy to measure Ø Unbiased Ø Important event for the patient 7

8 Reduction in Mortality & Standard of Care Recent advances in HF pharmacological & device therapies significantly improved morbidity and mortality in patients with HF and reduced EF Ø Angiotensin- converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) Ø Beta- blockers Ø Mineralocorticoid receptor antagonists (MRAs) Ø Entresto (sacubitril/valsartan) - angiotensin receptor neprilysin inhibitor (ARNI) Ø Device- based approaches Ø Cardiac resynchronization therapy (CRT) Ø Implantable cardioverter defibrillator therapy (AICD) 8

9 Reduction in Mortality in Patients with Reduced EF Major drugs prescribed for HF % DECREASE IN MORTALITY Angiotensin receptor blocker ACE inhibitor Beta blocker Mineralocorticoid antagonist Entresto 20% on top of enalapril Based on results of SOLVD, CHARM- Alternative, COPERNICUS, CIBIS- II, MERIT- HF, RALES and EMPHASIS 9

10 Hard Endpoints in HF Studies Other hard endpoints Ø Adjusted all- cause mortality Ø Cause- specific mortality Ø LOS of Index HF hospitalization Ø Rate of re- hospitalization 10

11 Hard vs Soft Endpoints Ø Hard Endpoints Ø Well- defined in study protocol Ø Definitive with respect to the disease process Ø Require no subjectivity Ø Soft Endpoints Ø Do not relate strongly to the disease process Ø Require subjective assessments by investigators and/or patients Some endpoints fall between these two classifications 11

12 Soft Endpoints in HF Studies In order to test the effect of the treatment in earlier stages, reduction in the progress of the disease and improvement in functional status are the goals Ø Soft EP in HF Ø Functional status Ø Quality of life Ø Worsening of HF Ø Objective evaluation of functional capacity 12

13 True/Direct vs Surrogate Endpoints Ø True or Direct Endpoints Ø Clinically meaningful events that directly measure how a patient feels, functions or survives Ø Represent or characterize the clinical outcome of interest Ø Objective: survival, disease exacerbation, clinical event (e.g. MI, stroke), etc. Ø Subjective: symptom score, health- related quality of life (validated instrument), etc. Ø Surrogate Endpoints Ø Laboratory measure or a physical sign intended to be used as a substitute for a clinically meaningful endpoint Ø Usually tracks the progress or extent of the disease Ø Investigators choose a surrogate endpoint when the definitive endpoint is inaccessible due to cost, time or difficulty of measurement 13

14 Endpoints in Heart Failure Trials The choice of endpoint is further influenced by the target patient population (e.g. chronic (A) vs. acute (B) heart failure) and treatment objective (e.g. reduction of morbidity and/or mortality vs. symptomatic improvement) Source: Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document. Zannad F1, Garcia AA, Anker SD, et al. JJ. Eur J Heart Fail Oct;15(10): doi: /eurjhf/hft095. Epub 2013 Jun Clinipace Worldwide 14

15 Composite Endpoints A composite endpoint should: Ø Provide reliable and precise estimates of efficacy and safety Ø Be clinically meaningful or relevant to physicians, patients and care providers in terms of characterizing disease progression, stabilization or reversal Ø Meaningfully characterize the burden of disease for patients Ø Yield information that could be used in conjunction with other data to determine societal valuation of new therapies or interventions Ø Improve the efficiency of clinical trials while maintaining high validity and quality Source: Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency Stefan D. Anker, Stefan Schroeder, Dan Atar, et al. European Journal of Heart Failure (2016) 18,

16 Arena of Endpoints in HF Trials Ø Became increasingly recognizable that AHF captures a heterogeneous group of patients Ø Some of the traditional EPs that measured parameters related to the overemphasized role of fluid retention in HF are no longer our goals: Ø Fluid loss measures Ø Weight change Ø Edema Ø Hemodynamic measures 16

17 Dyspnea as an Endpoint As the AHF is marked by common symptoms of shortness of breath and congestion signs, prompting urgent medical attention, these patients often were recruited into AHF trials where dyspnea improvement was one of the pre- specified EPs (ADHERE Registry. 3rd Qtr 2003 National Benchmark Report) 17

18 Dyspnea and HF Ø As a result, dyspnea have been commonly used in AHF studies as a primary EP alone or in combination with other measures Ø Regulators request that the instrument for assessing dyspnea should ideally be well validated, clinically justified and defined a priori Ø Accordingly, investigators are free to use any method of assessing dyspnea that is clinically justified and prospectively defined, since none are validated 18

19 Acute Heart Failure Clinical Trials Methods, timing and results of dyspnea measurement Trial Year Patients Endpoint Who measured When When Measured Instrument VERITAS (1760) a Yes (primary) Patient After admission 0, 3, 6, and 24 h (AUC) VAS 3timepoints RITZ Yes (primary) Patient After admission 0, 3, 6, and 24 h 7 point Likert scale RITZ Yes (co- primary w CIrdiac index) Patient After admission 0, 6, and 24 h 7 point Likert scale OPTIME- CHF Yes b (secondary) Patient After admission 0, 3 days, discharge composite score VMAC Yes (co- primary with PCWP) Patient After admission 0, 3, 6, and 24 h 7 point Likert scale EVEREST 2007 A=2048, B=2085 Yes (secondary) Patient After admission Inpatient day 1 7 point scale SURVIVE Yes (secondary) Patient REVIVE Yes (secondary) Patient After admission After admission 24 h 7 point Scale 6 h 7 point Scale 19

20 Dyspnea Assessment Instruments Type of Scale Five- point Likert scale 10 cm- visual analog scale Seven- point Likert scale Scale Intervals 1=not short of breath 2=mildly short of breath 3=moderately short of breath 4=severely short of breath 5=very severely short of breath 1 cm increments, anchored by I am not breathless at all to I am the most breathless I have ever been Patients were asked to compare how they felt when they were first asked regarding dyspnea. Scores ranged from markedly worse, moderately worse, mildly worse, no change, mildly better, moderately better, to markedly better. Definition of Clinical Significance 1 point change 3 cm change Only patients who responded moderately or markedly improved 20

21 Pang & Cleland Proposal Ø European Heart Journal (2008) 29, Ø A proposal to standardize dyspnea measurement in clinical trials of acute heart failure syndromes: the need for a uniform approach Ø Peter S. Pang, John G.F. Cleland, John R. Teerlink, Sean P. Collins, Christopher J. Lindsell, George Sopko, W. Frank Peacock, Gregg C. Fonarow, Amer Z. Aldeen, J. Douglas Kirk, Alan B. Storrow, Miguel Tavares, Alexandre Mebazaa, Edmond Roland, Barry M. Massie, Alan S. Maisel, Michel Komajda, Gerasimos Filippatos, Mihai Gheorghiade 21

22 Dyspnea Severity Score Ø Consider the PDA used in conjunction with a 5- point Likert scale, with one being the greatest severity of patients self- reported dyspnea Ø Two numbers can be reported from this study Ø One from the Likert Ø The other based on the final step on the PDA that the patient completed Ø These can be combined to yield a final Dyspnea Severity Score (DSS) PDA 5- point Likert scale DSS Sitting upright (>60 ) with O2 (minimum 2L NC)) Worst possible shortness of breath 1 Severely short of breath 2 Moderately short of breath 3 Mildly short of breath 4 Not at all short of breath 5 Sitting upright (>60 ), no O2 Worst possible shortness of breath 6 Severely short of breath 7 Moderately short of breath 8 Mildly short of breath 9 Not at all short of breath 10 Supine (<20 head elevation), no O2 Worst possible shortness of breath 11 Walking 50 m as fast as possible (post walk assessment) Six minute walk test (post- 6 min walk assessment) Severely short of breath 12 Moderately short of breath 13 Mildly short of breath 14 Not at all short of breath 15 Worst possible shortness of breath 16 Severely short of breath 17 Moderately short of breath 18 Mildly short of breath 19 Not at all short of breath 20 Worst possible shortness of breath 21 Severely short of breath 22 Moderately short of breath 23 Mildly short of breath 24 Not at all short of breath 25 22

23 Evaluation of Provocative Dyspnea Severity Score in AHF Ø The acute heart failure (AHF) Syndromes International Working Group proposed that Dyspnea be assessed under standardized, incrementally provocative maneuvers Ø investigators sought to assess the feasibility and statistical characteristics of a novel provocative dyspnea severity score (pds) versus the traditional dyspnea visual analog scale (DVAS) in an AHF trial 23

24 Effect of Provocative Maneuvers on Dyspnea Severity Ø Correlation of DVAS and pds with HF severity Ø At enrollment, neither DVAS nor pds were correlated with the NT- probnp level (p > 0.6 for both) Ø Change in dyspnea scores over time Ø pds and DVAS each increased over time, indicating dyspnea improvement Ø Feasibility of provocative measures in AHF Ø Provocation was feasible in only 62% of eligible patients at enrollment Ø While exercise provocation did induce more severe dyspnea in 29% of patients, feasibility was too low to allow incorporation into a clinical trial endpoint The statistical characteristics of a pds based on feasible provocation measures do not support its potential as a robust dyspnea assessment tool in AHF 24

25 Determinants of Dyspnea in CHF Ø Journal of Cardiac Failure Vol.22 No Ø Dyspnea is a hallmark symptom of heart failure Ø Associated with impaired functional capacity and quality of life Ø The experience of dyspnea is multifactorial Ø May originate from different sources Ø Study set out to examine the relative importance of potential contributors to dyspnea (i.e., disease severity, inflammation and psychologic distress) in a large prospective cohort of chronic HF patients 25

26 Determinants of Dyspnea in CHF Results: Ø Somatic symptoms of depression and anxiety are the strongest determinants of the subjective report of dyspnea in patients with chronic HF Ø In addition to the psychologic determinants, BMI, age and comorbid COPD were the only other significant predictors of dyspnea complaints in the fully adjusted model Ø Systemic inflammatory markers were not significantly associated with levels of dyspnea 26

27 Why it is Problematic to Use Dyspnea as an EP? Ø Ø Ø Ø Ø For each scale, there are unique clinical factors associated with dyspnea improvement Ø Suggests that individual scales may capture different aspects of the patient s reported symptoms Ø While investigators prefer a single, best scale, use of multiple current scales may be required, as a single scale may not accurately represent all AHF patients Lack of validated instruments Relatively rapid improvement irrespective of therapy for AHF, even using standard of care therapy alone Poor correlation with HF severity (Natriuretic peptides) Can be significantly affected by patient s psychologic determinants, BMI, age and comorbidities (COPD) As a result, a comprehensive, validated patient- reported outcome of dyspnea improvement remains a critical unmet need in AHF research 27

28 Symptoms and Quality-of-Life Questionnaires Ø Majority of patients in HF studies do not contribute to a mortality primary endpoint, yet have important QOL issues Ø Quality- of- life (QOL) questionnaires Ø Minnesota Living with Heart Failure questionnaire (MLwHF) Ø Kansas City Questionnaire (KCCQ) Ø EuroQol (EQ- 5D) Ø Chronic Heart Failure Assessment Tool Ø Cardiac Health Profile congestive heart failure Ø Chronic Heart Failure Questionnaire (CHFQ) Ø Left Ventricular Disease Questionnaire (LVDQ) Ø Quality of Life in Severe Heart Failure Questionnaire 28

29 NYHA & INTERMACS Scores Ø Most direct approach to the evaluation of HF is to inquire about symptoms Ø Changes in NYHA functional class traditionally have been incorporated into EP of the large HF studies Ø However, it suffers from several limitations: Ø Reflects patients status from physician perspectives and not from patients Ø Requires solicitation Ø Limited validity and reproducibility 29

30 NYHA Classes New York Heart Association ( NYHA) Classes 30

31 INTERMACS Interagency Registry Level Level 1 Level 2 Level 3 Level 4 Level 5 Level 6 Level 7 Description Critical cardiogenic shock ( crashing and burning ) Progressive decline on inotropic support Stable but inotrope dependent Resting symptoms on home oral therapy Exertion intolerant Exertion limited Advanced NYHA class III

32 Worsening of HF as an EP Although there is no consensus definition of WHF, typically it is defined as: Ø Ø Ø Ø Failure to improve (persistent or worsening of HF signs and symptoms) Intensification of HF therapy Mechanical cardiac (IABP, LVAD) or respiratory (mechanical ventilation) support Need for re- initiation or intensification of IV diuretic therapy, Vasoactive drugs 32

33 Objective Evaluation of Functional Capacity: 6 MWT American Thoracic Society Am J Respir Crit Care Med Vol 166. pp , 2002 ATS Statement: Guidelines for the Six- Minute Walk Test Ø 6 minute walk test is the simplest of all functional testing in cardiac evaluation Ø Though walking is a routine daily motion, it is essentially a hemo- dynamic stress for the heart, especially for an ailing heart Ø Even though it appears simplest of all investigations, there are strict guidelines 33

34 6MWT Ø Easy to perform Ø Safe Ø Submaximal Ø Safe paced Ø Reliable, valid and reproducible Ø Learning and ceiling effect Ø Can be limited by patient s general health conditions Ø How much improvement or decline in the distance is clinically important? Ø The mean improvement of m was reported significant to indicate a change in functional status Ø Minimal clinically significant deference was found to be 54m 34

35 Surrogate Endpoints in HF Trials Ø HF is the final common endpoint of several processes. Once initiated, cardiovascular disease progresses through structural remodeling of the heart and blood vessels Ø Factors that contribute to this include: Ø Activation of various neurohormones Ø Growth factors Ø Cytokines Ø Markers of this biological process (left ventricular remodeling) and factors that contribute to it (e.g., neurohormones) may be viewed as surrogates of the progression of the disease 35

36 Surrogate Endpoints in HF Trials: Neurohormones and Biomarkers Ø Biomarkers of Congestion (BNP and probnp) Ø Biomarkers of Myocardial Injury (Troponins) Ø Renal function Ø Novel markers Ø ST- 2 Ø Galectin- 3 Ø Growth hormone differentiation factor (GDF- 15) 36

37 Imaging Studies as Surrogate EPs in HF Ø Rt & LV function and dimensions Ø Measures of Dyssynchrony Ø Measures of Diastolic dysfunction Ø LV mass and Left atrial size Ø Myocardial tissue Doppler imaging and myocardial motion Ø Measures of myocardial viability and fibrosis 37

38 Conclusion Ø Selecting primary endpoints for clinical trials is critical Ø Has imperative implications for: Ø Effectiveness Ø Economic value Ø Translation into clinical practice Ø Standardizing response variables, in order to measure the impact of interventions on the various domains of possible benefit, should therefore be a goal 38

39 Q&A