Transcript Presentation

Clinical Trial Measures in ALS
Douglas A. Kerr MD/PhD
Senior Director, Biogen IDEC
February 20th, 2014
Background on Amyotrophic Lateral Sclerosis
ALS is a fatal neurodegenerative disease characterized by progressive loss of
nerves innervating muscles, loss of motor function, progressive respiratory
impairment and death
 Heterogeneity in onset and progression makes
measuring change in the rate and severity of
functional decline challenging
 Therapies that influence ALS should affect
motor and pulmonary function and survival
 Riluzole prolongs life by 2-3 months but has
not been shown to modulate motor or
respiratory function
 Despite ~30 ALS Phase II/III clinical studies in
the last 20 years, no agent has been approved
for ALS since riluzole
Measuring ALS Disease Progression
With high mortality, survival or vent-free
survival is a relevant endpoint
Patients who do not reach the endpoint do not
contribute
Ignores the functional status of survivors
ALSFRS-R1 has been the most widely
used composite measure of function in
ALS over the last 15 years
1
The ALS CNTF treatment study (ACTS) phase I-II Study Group. Arch Neurol
3
1996;53:141-7.
Cedarbaum JM, Stambler N, Malta E, et al. J Neurol Sci 1999;169:13-
The ALSFRS-R includes12 items measuring multiple
aspects of daily functioning
Cedarbaum JM, Stambler N, Malta E, Fuller
C, Hilt D, Thurmond B, Nakanishi A. The
ALSFRS-R: a revised ALS functional rating
scale that incorporates assessments of
respiratory function. BDNF ALS Study
Group (Phase III). J Neurol Sci
1999;169:13-21.
4
Challenges of Measuring Function in ALS (1)
• How do you measure function of patients who died during the trial?
– You cannot.
– Imputation?
• “0” for functional score? Too punitive since ALS patients
invariably die at scores above 0
• LOCF? Not in a progressive disease.
• Mixed imputation? Challenging to interpret and defend
• Measuring function of survivors risks a biased conclusion
– What if a drug caused enhanced mortality of late stage ALS,
leaving the healthier patients to measure?
– What if a drug prolonged survival, leaving patients with low
function to be measured?
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A Meaningful Endpoint in ALS Must…
• Measure function while statistically
accounting for mortality
• Measure meaningful measures of ALS
disease progression, i.e. motor function
and mortality
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The Combined Assessment of Function and Survival
(CAFS) in ALS
Context
• In ALS trials, death and functional status are meaningful
measures of a drug’s effectiveness
• Prior studies use either death or function as a primary
outcome; no study has used an outcome that measures
both in a single endpoint
CAFS description
• Ranks patients’ clinical outcome based on survival and
function from 1 to the number of patients in the trial
Advantages
• Reflects seriousness of death outcome in the context of
an analysis of functional data
• Statistically accounts for death in measuring function
Limitations
• To determine clinical relevance of a significant difference
in CAFS scores, an analysis of component data
(ALSFRS-R and mortality) is required
ALFRS-R = revised ALS functional rating scale; CAFS = combined assessment of function and survival
Archibald
7 D et al. Poster presented at: 10th Annual Northeast ALS (NEALS) Consortium Meeting; October 27-28, 2011;
Clearwater Beach, FL
CAFS Scoring: Step by Step
For Illustrative Purposes Only
1
Determine
functional change
or time to death
for each patient
Functional Decline
Survival Time
(Patients who survive)
(Patients who die)
-20%
-30%
-40%
Day 0
8
Cudkowicz M. Nature: 2011; 17(12):1652-1656.
Trial End
10 months
Survival time→
ALSFRS-R
-10%
1 month
CAFS Scoring: Step by Step
For Illustrative Purposes Only
Rank
2
6
Group 2
-20%
5
-30%
4
All patients are
counted on the
same scale,
including those
who did not
survive
10
months
1
month
9
4.3
3
2
1
Survival Time
Group 1
-40%
Unblind assignments,
and compare means of
rank scores by group
2.6
Group 1
Group 2
CAFS score
-10%
3
Functional Decline
Rank all patients
by function,
then by survival
Dexpramipexole Demonstrated No Effect on
CAFS Through 12 Months
p = 0. 8568
Least Square
Mean Rank Score
500
438.84
441.76
400
300
200
Placebo
(n = 468)
Dexpramipexole*
(n = 473)
*Dexpramipexole dihydrochloride 150 mg; Abbreviation: CAFS, Combined Assessment of Function and Survival
Analysis used efficacy population: all subjects who received ≥1 dose of drug (or placebo) with ≥1 post-dosing evaluation
Challenges of Measuring Function in ALS (2)
 Despite showing good internal consistency and a strong
correlation with survival in early validation studies, the
ALSFRS-R measures suffer from poor metric qualities1
 Multidimensionality argues against a single summed
score
 Poor rating category functioning suggests problems
with question wording and numbers of responses
1
Franchignoni, Mora, Giordano et al. Evidence of multidimensionality in the ALSFRS-R
Scale:
11 a critical appraisal on its measurement properties using Rasch analysis. J Neurol
Neurosurg Psychiatry Published Online June 19, 2013 doi:10.1136/jnnp-2012-304701
Other Concerns of the ALSFRS-R
A problematic feature of the ALSFRS-R is a reduced
sensitivity of raw scores to changes occurring in the extremes
of the severity continuum.
 Typical of raw scores summed from ordinal responses
 Partially derived from the types of items available for
patients to endorse
 Patients with higher functioning may not be able to endorse
enough items – i.e., there may be other domains of
functioning that are important and are not measured
 Causes problems in clinical trials
 Measurement of functioning should be consistent across time
and across the severity spectrum
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ALSFRS-R Person-Item Location Distribution
Time 1
N=1727
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Time 2
N=648
Category Response Curves
4
1
2 3
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Performance of Bulbar Items:
4
2
1
Conclusions
• Item mapping suggests that some dimensions of function
are not captured, especially at the low end of the severity
spectrum
• ALSFRS-R can be inconsistent when measuring patient
severity over time
– This is particularly problematic for conditions where progression is
an important outcome
• Category response curves indicate poor performance on
item responses
– Items could be revisited at the conceptual level to provide greater
detail on ALS-specific functional domains
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Implications
• This analysis underscores the previously demonstrated
importance of using a modified version of the instrument1
– Using fewer response categories on some questions
– Evidence of multidimensionality suggests multiple instruments that can
be used for composite scoring
• Consider developing new unidimensional measures
– Bottom-up approach to capture meaningful concepts in ALS functioning
and progression
– Address ceiling effects by capturing health domains important to low
severity patients
– Create meaningful category responses for each question
– Measure ADLs per the standard (outside of this measure)
1
17
Franchignoni, Mora, Giordano et al. Evidence of multidimensionality in the ALSFRS-R Scale: a
critical appraisal on its measurement properties using Rasch analysis. J Neurol Neurosurg
Psychiatry Published Online June 19, 2013 doi:10.1136/jnnp-2012-304701