Initiative on Methods, Measurement, and Pain
Assessment in Clinical Trials
IMMPACT XVII
April 17-18, 2014
Westin Georgetown
Washington, DC
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Interpreting the Clinical Importance of
Improvements in Patient-reported and
“Objective” Assessments of Physical
Function
Daniel J. Clauw M.D.
dclauw@umich.edu
Professor of Anesthesiology, Medicine
(Rheumatology), and Psychiatry
Director, Chronic Pain and Fatigue
Research Center
The University of Michigan
Disclosures
■ Consulting
■ Pfizer,
Forest, Eli Lilly, Pierre Fabre,
Cypress Biosciences, Wyeth, UCB, Astra
Zeneca, Merck, J & J, Nuvo, Jazz, Abbott,
Cerephex, Iroko, Tonix, Theravance
■ Research
support
■ Pfizer, Cypress Biosciences, Forest, Merck,
Nuvo, Cerephex
■ One-time
licensing fee paid to University of
Michigan by Eli Lilly
Relationship Between Self-report and
Objective Physical Function
■ How
strong is the relationship between self-report
and objective measures of physical function in
healthy individuals or in individuals with disease?
■ In
studies that directly compare self-report and
objective measures of physical function or functional
status, what are the self-report measures really
measuring?
■ Should
we expect a strong relationship between
self-report and objective measures? Lessons from
other domains
■ Given
the differences between self-report and
objective measures, which is the “right” measure?
Relationship Between Self-report and
Objective Physical Function
■ How
strong is the relationship between self-report
and objective measures of physical function in
healthy individuals or in individuals with disease?
■ In
studies that directly compare self-report and
objective measures of physical function or functional
status, what are the self-report measures really
measuring?
■ Should
we expect a strong relationship between
self-report and objective measures? Lessons from
other domains
■ Given
the differences between self-report and
objective measures, which is the “right” measure?
Not very
■ If
we use actigraphy as the current gold standard for
measuring activity or function in real life settings . . .
■
There is a consistently poor relationship (r = 0 - .40)
between average activity levels and measures of functional
status or activity.1-4
■ There is a strong trend towards these relationships being
stronger (albeit still rather weak) when the objective
measure is compared to activity measures vs. functional
status measures.
1) Kashikar-Zuck, et. al. Arthritis Care and Research 2013, 2) Chandonnet et. al.
PLoS One 2012, 3) Ferriolli et. al. J Pain and Symptom Management 2012. 4)
Evenson et. al. J Phys Act Health 2012.
Relationship Between Self-report and
Objective Physical Function
■ How
strong is the relationship between self-report
and objective measures of physical function in
healthy individuals or in individuals with disease?
■ In
studies that directly compare self-report and
objective measures of physical function or functional
status, what are the self-report measures really
measuring?
■ Should
we expect a strong relationship between
self-report and objective measures? Lessons from
other domains
■ Given
the differences between self-report and
objective measures, which is the “right” measure?
Relationship between symptoms, selfreported, and objective measures of
activity, in fibromyalgia
■
Patients with FM have amongst the lowest selfreported functional status of any chronic illness
■
This parameter has been very difficult to
improve in interventional studies
■
How is self-reported activity related to:
■ Objective measures of activity
■ Specific symptoms
Kop et. al. Arthritis Rheum 2005
Measuring Symptoms and
Activity Simultaneously
■
Ecological Momentary
Assessment (EMA)
(Stone & Shiffman, 1994)
symptoms in ‘real-time’
■ Audible prompts
■ Obtains time-stamped
recordings
■
■
Actigraphy
■
Actiwatch-S (Mini Mitter, Bend,
OR)
■ Omni-directional
accelerometer
■ Records intensity of
movement as activity counts
Actogram I
Running
Preparing
dinner
Walking
Getting ready
In bed; reading
Office work-desk
Sleeping
Swimming
Got up
Office work-desk
Couch sitting;
reading
Walking
Methods / Subjects
■
Thirty patients with FM (mean age=41.5)
were compared with 29 sedentary control
participants (mean age=38.9).
■
Actigraphs were worn for 5 consecutive days
and four consecutive nights. Activity levels
were sampled over 5 min epochs.
Participants rated symptoms ("pain", "tired",
"stressed") on 10-point scales 5 times/day
based on actigraph-driven alerts.
Results – Objective Activity
■
Average daytime and nighttime activity
levels were nearly identical in the patient
and the control groups (p=ns).
Patients
Controls
Daytime
Nighttime
PCS
1456429
1445556
147156
152107
36
56
Peak Activity
■
Peak activity was significantly lower in the
FM patient group relative to the control
group (p=0.008).
■ 7870  3223 vs. 12178  7862 activity
units
■
Variability of peak activity was also
significantly different between groups
■ Levene’s test on SDs, p=0.001
Average and Diurnal Peak Activity
Levels of Fibromyalgia Compared to
Controls
14000
*
*
Control
Fibromyalgia
Units (Activity)
12000
*
*
10000
8000
6000
4000
Morning
*p<0.05; Error Bars=SEM
Mid-Morning
Afternoon
Evening
Actograms
FM patient
Days of higher activity
followed by days of less
activity
Control
Higher peak
activity, less
sporadic
Assessment of Pain and Activity in a
Placebo-Controlled Crossover Trial of
Celecoxib in Osteoarthritis of the Knee
■ RCT
in OA (n=47) to examine how to better
differentiate active treatment from placebo
■ The
WOMAC pain subscale was the most
responsive of all five pain measures.
■
Pain–activity composites resulted in a statistically
significant difference between celecoxib and
placebo but were not more responsive than pain
measures alone. However, a composite responder
defined as having 20% improvement in pain or 10%
improvement in activity yielded much larger
differences
Trudeau et. al. Pain Practice 2014
Assessment of Pain and Activity in a
Placebo-Controlled Crossover Trial of
Celecoxib in Osteoarthritis of the Knee
■
The most responsive actigraphy measure was peak
activity, with a between-group difference of 91.9
counts/min (P = 0.090); mean activity and total
activity did not approach statistical significance.
■ Actigraphy
was more responsive than the WOMAC
function scale, possibly due to lower placebo
responsiveness.
Trudeau et. al. Pain Practice 2014
Relationship Between Self-report and
Objective Physical Function
■ How
strong is the relationship between self-report
and objective measures of physical function in
healthy individuals or in individuals with disease?
■ In
studies that directly compare self-report and
objective measures of physical function or functional
status, what are the self-report measures really
measuring?
■ Should
we expect a strong relationship between
self-report and objective measures? Lessons from
other domains
■ Given
the differences between self-report and
objective measures, which is the “right” measure?
Self-report vs. Objective Measures of
Other Domains
■ Sleep
■
Correlation between multiple PSG measures and multiple
self-report measures in sleep apnea patients ranges from r
= .01-.24, mean r = .09.1
■ Correlations between self-report and PSG measures in
insomnia r = .05 - .36.2
■ Memory/cognition
■
Very poor relationship between subjective measures and
objective performance based measures in both healthy
individuals, and individuals with mild TBI, but there is a
modest relationship between subjective measures and
mood measures.3,4
1) Weaver, Arch Otolaryngol Head Neck, 2004. 2) Bastien et. al. Sleep
Medicine 2001. 3) Schliesher J Clin Exp Neuropsych, 2011. 4) Spencer et. al.
JRRD, 2010.
Relationship Between Self-report and
Objective Physical Function
■ How
strong is the relationship between self-report
and objective measures of physical function in
healthy individuals or in individuals with disease?
■ In
studies that directly compare self-report and
objective measures of physical function or functional
status, that are the self-report measures really
measuring?
■ Should
we expect a strong relationship between
self-report and objective measures? Lessons from
other domains
■ Given
the differences between self-report and
objective measures, which is the “right” measure?
I’ll put my money on the
objective measures as an
“anchor”
■ As
Kushang Patel presented yesterday, these measures
have become very accurate and reliable measures of
what a person is actually doing
■ Susan
Murphy’s studies in OA1-3 have been very
informative (i.e. surprising) in examining the relationship
between actigraphy and pain and other symptoms that
can help us identify differing endo-phenotypes
■
Within an OA cohort, there are markedly different patterns of
contingencies between pain and activity (in some people
activity makes pain worse, others better) and in many
individuals fatigue is much more related to inactivity than
pain
1) Murphy SL, Arthritis Care Res (Hoboken), 2011. 2) Murphy SL et. al. Arthritis Res Ther.
2011. 3) Murphy SL, et. al. Current Rheumatology Reports, 2012.
Summary
■ Even
though there is good evidence that actigraphy is an
accurate measure of physical activity and has high
reliability, there is a consistently poor (r = 0 - .40)
relationship between these measures and subjective
measures
■ There
is generally a better (but still very modest)
relationship between actigraphy and subjective measures
of activity vs. function
■ Peak
activity levels on actigraphy relate more closely to
subjective functional status measures than average activity
■ These
disparate results between subjective and objective
activity measures are not confined to pain patients (also
seen in healthy individuals) and not confined to objective vs
subjective measures of physical function
Initiative on Methods, Measurement, and Pain
Assessment in Clinical Trials
IMMPACT XVII
April 17-18, 2014
Westin Georgetown
Washington, DC