Challenges and Potential Resolutions€¦ · ©"2016"Clinipace"Worldwide" Endpoints in Heart...

Endpoints in Heart Failure Clinical Trials:

Challenges and Potential Resolutions

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© 2016 Clinipace Worldwide

Ø Olga Milo, MD Ø Medical DirectorØ Momentum Research, Inc.

Ø Mark Shapiro, MBAØ Vice President, Clinical DevelopmentØ Clinipace Worldwide

Introductions


Introduction

Ø Chronic heart failure (HF) affects 2% of the population and is the 4thleading 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

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The selection of endpoints for HF clinical trials is challengingØ 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)

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Characteristics of Endpoints


Objectives and Endpoints by Phase

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Phase Objective Efficacy/Endpoint

Phase I • Safety evaluation• Patient tolerance

• None

Phase II • Identify efficacy endpointsand doses for Phase III

• "Exploratory”• Primary Secondary

Phase III • Efficacy and safety• Evaluate for general use

• Primary -‐ Indication• Secondary -‐ may be

described in the label

Phase IV • Expand efficacy & Safety • Expand patient reported outcomes


“Hard” vs “Soft” Endpoints

Ø“Hard” endpointsØWell-‐defined in study protocolØDefinitive with respect to the disease process

ØRequire no subjectivity

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Mortality as a “ hard” endpointØ Easy to measureØ UnbiasedØ Important event for the patient

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Hard Endpoints in HF Studies


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-‐blockersØ Mineralocorticoid receptor antagonists (MRAs)Ø Entresto (sacubitril/valsartan) -‐ angiotensin receptor – neprilysininhibitor (ARNI)

Ø Device-‐based approachesØ Cardiac resynchronization therapy (CRT)Ø Implantable cardioverter defibrillator therapy (AICD)

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Reduction in Mortality & Standard of Care


Reduction in Mortality in Patients with Reduced EF

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Based on results of SOLVD, CHARM-‐Alternative, COPERNICUS, CIBIS-‐II, MERIT-‐HF, RALES and EMPHASIS

-‐35

-‐30

-‐25

-‐20

-‐15

-‐10

-‐5

0

Angiotensin receptor blocker

ACE inhibitor Beta blocker Mineralocorticoid antagonist

% DECRE

ASE IN M

ORTAL

ITY

Major drugs prescribed for HF

Entresto 20% ↓ on top of enalapril


Other “ hard” endpointsØ Adjusted all-‐cause mortalityØ Cause-‐specific mortalityØ LOS of Index HF hospitalization Ø Rate of re-‐hospitalization

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Hard Endpoints in HF Studies


“Hard” vs “Soft” Endpoints

Ø “Hard” EndpointsØ Well-‐defined in study protocol

Ø Definitive with respect to the disease process

Ø Require no subjectivity

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Ø “Soft” EndpointsØ Do not relate strongly to the disease process

Ø Require subjective assessments by investigators and/or patients

Some endpoints fall between these two classifications


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

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Soft Endpoints in HF Studies

Ø “Soft” EP in HFØ Functional statusØ Quality of lifeØ Worsening of HFØ Objective evaluation of functional capacity


“True/Direct” vs “Surrogate” Endpoints

Ø “True” or “Direct” EndpointsØ 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.

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Ø “Surrogate” EndpointsØ 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


Endpoints in Heart Failure Trials

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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. 2013 Oct;15(10):1082-‐94. doi: 10.1093/eurjhf/hft095. Epub 2013 Jun 19.


A composite endpoint should:Ø Provide reliable and precise estimates of efficacy and safetyØ 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 patientsØ 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

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Composite Endpoints

Source: Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiencyStefan D. Anker, Stefan Schroeder, Dan Atar, et al. European Journal of Heart Failure (2016) 18, 482–489


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 measuresØ Weight changeØ EdemaØ Hemodynamic measures

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Arena of Endpoints in HF Trials


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

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Dyspnea as an Endpoint

(ADHERE Registry. 3rd Qtr 2003 National Benchmark Report)


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

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Dyspnea and HF


Methods, timing and results of dyspnea measurement

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Acute Heart Failure Clinical Trials

Trial Year Patients Endpoint Who measured When When Measured Instrument

VERITAS 2005 1448 (1760)a Yes (primary) PatientAfter

admission

0, 3, 6, and 24 h

(AUC)VAS 3timepoints

RITZ-‐1 2001 669 Yes (primary) PatientAfter

admission0, 3, 6, and 24 h 7 point Likert scale

RITZ-‐2 2003 292Yes (co-‐primary w

CIrdiac index)Patient

After

admission0, 6, and 24 h 7 point Likert scale

OPTIME-‐CHF 2002 951 Yesb (secondary) PatientAfter

admission0, 3 days, discharge composite score

VMAC 2002 489Yes (co-‐primary

with PCWP)Patient

After

admission0, 3, 6, and 24 h 7 point Likert scale

EVEREST 2007A=2048,

B=2085Yes (secondary) Patient

After

admissionInpatient day 1 7 point scale

SURVIVE 2007 1327 Yes (secondary) PatientAfter

admission24 h 7 point Scale

REVIVE 2005 600 Yes (secondary) PatientAfter

admission6 h 7 point Scale

© 2016 Clinipace Worldwide 20

Dyspnea Assessment Instruments

Type of Scale Scale Intervals Definition of Clinical Significance

Five-‐point Likert scale

1=not short of breath2=mildly short of breath3=moderately short of breath4=severely short of breath5=very severely short of breath

≥1 point change

10 cm-‐visual analog scale

1 cm increments, anchored by “I am not breathless at all” to “I am the most breathless I have ever been”

≥3 cm change

Seven-‐point Likert scale

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”.

Only patients who responded moderately or markedly improved


Pang & Cleland Proposal

Ø European Heart Journal (2008) 29, 816–824Ø 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


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 studyØ One from the LikertØ 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)

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Dyspnea Severity ScorePDA 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• Severely short of breath 12• Moderately short of breath 13• Mildly short of breath 14• Not at all short of breath 15

Walking 50 m as fast as possible (post walk assessment) 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

Six minute walk test (post-‐6 min walk assessment) 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


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

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Evaluation of Provocative Dyspnea Severity Score in AHF


Ø Correlation of DVAS and pDS with HF severityØ At enrollment, neither DVAS nor pDS were correlated with the NT-‐proBNPlevel (p > 0.6 for both)

Ø Change in dyspnea scores over timeØ pDS and DVAS each increased over time, indicating dyspnea improvement

Ø Feasibility of provocative measures in AHFØ Provocation was feasible in only 62% of eligible patients at enrollmentØ 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

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Effect of Provocative Maneuvers on Dyspnea Severity


Determinants of Dyspnea in CHF

Ø Journal of Cardiac Failure Vol.22 No.1 2016

Ø Dyspnea is a hallmark symptom of heart failureØ Associated with impaired functional capacity and quality of lifeØ The experience of dyspnea is multifactorialØ 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


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


Why it is Problematic to Use Dyspnea as an EP?

Ø For each scale, there are unique clinical factors associated with dyspnea improvementØ Suggests that individual scales may capture different aspects of the patient’s reported

symptomsØ 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 patientsØ Lack of validated instrumentsØ Relatively rapid improvement irrespective of therapy for AHF, even using

standard of care therapy aloneØ Poor correlation with HF severity (Natriuretic peptides)Ø 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


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) questionnairesØ Minnesota Living with Heart Failure questionnaire (MLwHF)Ø Kansas City Questionnaire (KCCQ)Ø EuroQol (EQ-‐5D)Ø Chronic Heart Failure Assessment ToolØ Cardiac Health Profile congestive heart failureØ Chronic Heart Failure Questionnaire (CHFQ)Ø Left Ventricular Disease Questionnaire (LVDQ)Ø Quality of Life in Severe Heart Failure Questionnaire

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Symptoms and Quality-of-Life Questionnaires


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 solicitationØ Limited validity and reproducibility

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NYHA & INTERMACS Scores


NYHA Classes

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New York Heart Association ( NYHA) Classes


INTERMACS Interagency Registry

Level Description

Level 1 Critical cardiogenic shock (“crashing and burning”)

Level 2 Progressive decline on inotropic support

Level 3 Stable but inotrope dependent

Level 4 Resting symptoms on home oral therapy

Level 5 Exertion intolerant

Level 6 Exertion limited

Level 7 Advanced NYHA class III

7 6 5 4 3 2 1


Although there is no consensus definition of WHF, typically it is defined as:Ø Failure to improve (persistent or worsening of HF signs and

symptoms)Ø Intensification of HF therapy

Ø Mechanical cardiac (IABP, LVAD) or respiratory (mechanical ventilation) support

Ø Need for re-‐initiation or intensification of IV diuretic therapy, Vasoactive drugs

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Worsening of HF as an EP


Objective Evaluation of Functional Capacity: 6 MWT

American Thoracic Society Am J Respir Crit Care Med Vol 166. pp 111–117, 2002ATS 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


Ø Easy to performØ Safe

Ø Submaximal Ø Safe paced

Ø Reliable, valid and reproducibleØ Learning and ceiling effectØ Can be limited by patient’s general health conditionsØ How much improvement or decline in the distance is clinically

important? Ø The mean improvement of 70-‐170m was reported significant to indicate a change in functional status

Ø Minimal clinically significant deference was found to be 54m

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6MWT


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 neurohormonesØ Growth factorsØ 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

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Surrogate Endpoints in HF Trials


Ø Biomarkers of Congestion (BNP and proBNP)Ø Biomarkers of Myocardial Injury (Troponins)Ø Renal functionØ Novel markers

Ø ST-‐2Ø Galectin-‐3Ø Growth hormone differentiation factor (GDF-‐15)

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Surrogate Endpoints in HF Trials: Neurohormones and Biomarkers


Ø Rt & LV function and dimensionsØ Measures of DyssynchronyØ Measures of Diastolic dysfunctionØ LV mass and Left atrial sizeØ Myocardial tissue Doppler imaging and myocardial motion

Ø Measures of myocardial viability and fibrosis

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Imaging Studies as Surrogate EPs in HF


Ø Selecting primary endpoints for clinical trials is criticalØ Has imperative implications for:

Ø EffectivenessØ Economic valueØ 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

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Conclusion

Challenges and Potential Resolutions€¦ · ©"2016"Clinipace"Worldwide" Endpoints in Heart...

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