Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials

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Initiative on Methods, Measurement, and Pain
Assessment in Clinical Trials
IMMPACT XVII
April 17-18, 2014 Westin Georgetown Washington, DC
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  room.

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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_at_umich.edu
• Professor of Anesthesiology, Medicine
  (Rheumatology), and Psychiatry
• Director, Chronic Pain and Fatigue
• Research Center
• The University of Michigan

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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

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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?

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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?

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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.
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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?

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Relationship between symptoms, self-reported, and
objective measures of activity, in fibromyalgia

• Patients with FM have amongst the lowest
  self-reported 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
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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

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Actogram I
Getting ready
Preparing dinner
Running
In bed reading
Office work-desk
Walking
Sleeping
Swimming
Got up
Office work-desk
Couch sitting reading
Walking
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Methods / Subjects

• Thirty patients with FM (mean age41.5) were
  compared with 29 sedentary control participants
  (mean age38.9).
• 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.

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Results Objective Activity

• Average daytime and nighttime activity levels
  were nearly identical in the patient and the
  control groups (pns).

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Peak Activity

• Peak activity was significantly lower in the FM
  patient group relative to the control group
  (p0.008).
• 7870 ? 3223 vs. 12178 ? 7862 activity units
• Variability of peak activity was also
  significantly different between groups
• Levenes test on SDs, p0.001

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Average and Diurnal Peak Activity Levels of
Fibromyalgia Compared to Controls




plt0.05 Error BarsSEM
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Actograms
FM patient Days of higher activity followed by
days of less activity
Control Higher peak activity, less sporadic
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Assessment of Pain and Activity in a
Placebo-Controlled Crossover Trial of Celecoxib
in Osteoarthritis of the Knee

• RCT in OA (n47) to examine how to better
  differentiate active treatment from placebo
• The WOMAC pain subscale was the most responsive
  of all five pain measures.
• Painactivity 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
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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
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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?

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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.
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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?

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Ill 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 Murphys 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.
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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

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Initiative on Methods, Measurement, and Pain
Assessment in Clinical Trials
IMMPACT XVII
April 17-18, 2014 Westin Georgetown Washington, DC