PSS30
Sensitivity of the Functional Reading Independence
Index to Change in Size of Geographic Atrophy
Audrey Kapre1, Miriam Kimel2, Neil M. Bressler3, Rohit Varma4, Eric Souied5,
Chantal Dolan6, Elizabeth Tschosik1, and Nancy Kline Leidy2
1Genentech,
Inc., South San Francisco, CA; 2Evidera, Bethesda, MD; 3Johns Hopkins University
School of Medicine, Baltimore, MD; 4USC Eye Institute, Keck School of Medicine, University of
Southern California, Los Angeles, CA; 5Centre Hospitalier Intercommunal, University Paris Est,
CRC, Créteil, France; 6CMD Consulting, Inc., Sandy, UT
INTRODUCTION
IMPORTANCE OF THIS REPORT
• The advanced stage of age-related macular degeneration (AMD) is defined by the AgeRelated Eye Disease Study (AREDS) Group as features that can be associated with severe
vision loss, including choroidal neovascularization (CNV) and geographic atrophy (GA) of
the retinal pigment epithelium (RPE). GA is typically a progressive disease estimated to
affect more than 5 million people worldwide,1 which can impact a patient’s central visual
function used for reading, driving, or recognizing faces.
• The Mahalo study was a Phase 2 clinical trial evaluating lampalizumab, a monoclonal
antibody antigen-binding fragment (Fab) designed as an intravitreous injection to treat
patients with GA and prevent or stabilize progression of the disease.
− Patients with GA were randomized to receive sham or lampalizumab injections in 1 eye
monthly or every other month for 18 months (Figure 1).
• In patients with GA secondary to AMD, vision loss is progressive, and changes in patientreported outcomes of visual function may be identified before or concomitant with worsening
of best-corrected visual acuity (BCVA). BCVA is a standard outcome in ophthalmology trials
but may not fully capture the impact of GA on patients’ visual function, daily activities, and
thus quality of life.
• The Functional Reading Independence (FRI) Index can measure the effect of visual function
deficit on daily life, and therefore, may be a valuable endpoint for trials evaluating the
benefits of GA treatments on patients’ quality of life.
OBJECTIVE OF THIS REPORT
• To examine the sensitivity of the FRI Index to change in GA lesion size in patients with AMD.
Figure 1. Design of the Phase 2 study Mahalo.
Safety, Tolerability, and
Evidence of Activity
N = 129
Randomized 1:2:1:2
Sham
Monthly
10 mg
Lampalizumab
Monthly
Sham
Every Other Month
10 mg
Lampalizumab
Every Other Month
N = 21
N = 43
N = 21
N = 44
Month 18 Primary Endpoint: Mean Change in GA Lesion Size
Safety Follow-Up Period
or
Figure 2. Conceptual framework of the FRI Index.
Process of Performing Individual
Functional Reading Activities
Open-Label Extension Study
Level 4: Performs functional
reading activity:
• Completely independent of
vision aids, changing
behavior, or receiving help
from another person
GA = geographic atrophy.
METHODS
• Post-hoc analyses were conducted with data from the randomized, Phase 2 Mahalo study.
• The FRI Index, a 7-item patient-reported measure of independence in performing daily
activities that require reading (Figure 2), was administered in Mahalo at baseline and every
6 months.
• The FRI Index yields continuous mean scores (range 1 to 4), and ordinal-level scores from
Level 1 = “Unable to do” to Level 4 = “Totally independent.”
• For each FRI Index reading activity performed in the past 7 days, patients were asked the extent
to which they required vision aids, adjustments in the activity, or help from another person.
• A growth rate in GA lesion area of 0.94 mm2/year represents a reduction of ~50% in the
expected annual growth rate of GA lesions.2,3 Sensitivity of the FRI Index to change in disease
severity was evaluated by comparing differences in mean scores from baseline to Month 18 in
the following groups:
− Lower growth GA lesions: Change in lesion area <0.94 mm2/year
− Higher growth GA lesions: Change in lesion area ≥0.94 mm2/year
• Analysis of covariance (ANCOVA) was used to examine differences in mean changes in FRI
Index scores (continuous) from baseline to follow-up visit between lower and higher growth
rate GA lesions, controlling for age, gender, and FRI Index baseline score.
Level of Independence
Performing Individual Activities
Reading written print such as
books, magazines, or
newspapers
Reading to pay bills or write a
check
Levels 2 and 3: Performs
functional reading activity:
• Using a vision aid, and/or:
• By changing behavior to
accommodate vision, and/or:
• Receiving help from another
person
- Some of the time, or
- Most of the time
Level of
Independence
Performing
Functional
Reading
Activities
Reading to take medicine
Reading labels such as price
tags, food labels, or
clothing labels
Making or receiving
telephone calls that require
reading numbers on the
telephone, answering
machine, or caller ID device
Level 1: Performs functional
reading activity:
• Receiving help from another
person all of the time
• Does not perform reading
activity due to vision
Reading words or numbers
on screen while watching
television
Not Applicable: Does not
perform reading activity for
reasons other than vision
Reading when using a
computer
FRI = Functional Reading Independence.
RESULTS
• At 18 months, the mean change in FRI Index score (SD) from baseline for patients with
more lesion size growth was -0.3 (0.7; n = 62) vs. -0.1 (0.5; n = 13) for patients with less
growth (P = 0.02) (Figure 4).
• Findings might be consistent with expectations based on changes in GA lesion size,
although no differences with confidence were identified.
− For patients with more growth, 36% declined ≥1 FRI Level vs. 15% for patients with less
growth, difference = 21% (Chi Square = 2.612; P = 0.27) (Figure 5).
− Excluding patients at FRI Level 1 (“Unable to do”) at baseline (Table 1), 41% of patients
with more growth (n = 54) declined > 1 FRI Level vs. 18% for patients with less growth
(n = 11), difference = 23% (Chi Square = 2.606; P = 0.27).
Figure 3. The 7 Functional Reading Independence
Figure 4. Mean FRI Index score sensitivity to change in GA lesion size.
Month 18 Change in
Mean FRI Index Score
• Figure 3 depicts the FRI Levels of patients at baseline and 18 months for 7 tasks.
0.8
Lower growth
GA lesions
Higher growth
GA lesions
0.4
0.0
-0.4
-0.1
-0.3
-0.8
0.2 difference
(P = 0.02)
-1.2
<0.94 mm2/year
≥0.94 mm2/year
Change in GA Lesion Size
tasks.*,†
Level 1: Unable to do
Level 3: Moderately independent
N/A
Level 2: Help some or most of the time
Level 4: Totally independent
Missing
100%
Patients with higher growth GA lesions had 0.2 greater decline
in mean FRI Index score at Month 18 compared with those with
lower growth GA lesions.
GA = geographic atrophy.
Patients (%)
80%
Table 1. FRI level changes at Month 18 by GA lesion response:
lower and higher GA growth rate (Level 1, “Unable to do” removed)*
60%
40%
20%
0%
BL M18
BL M18
BL M18
BL M18
Read
written
print
Read to
pay bills,
write check
Read to
take
medicine
Read
labels
BL M18
BL M18
BL M18
Read numbers Read words
on phone,
or numbers
answering
on television
machine, or
caller-ID
Read when
using a
computer
Improve
27.3% (3)
13.0% (7)
Remain in same level
54.5% (6)
46.3% (25)
Decline by ≥1 level
18.2% (2)
40.7% (22)
Lower growth GA lesions
(<0.94 mm2/year)
100
80
62
60
23
40
Higher growth GA lesions
(≥0.94 mm2/year)
53
36
11
15
20
n=
3
7
FRI Level
Improved
8
33
FRI Level
Unchanged
2
22
FRI Level
Worsened
Patients with lower growth GA lesions may be more likely to have
improved or unchanged levels of functional reading independence at
Month 18 compared with those with higher growth GA lesions.
*Chi Square = 2.612; P = 0.27.
*Chi Square = 2.606; P = 0.27.
LIMITATION
Figure 5. FRI Index levels sensitivity to change in GA lesion size.*
Patients (%)
Higher GA Growth Rate
at Month 18
(n = 54)
Patients, % (n)
* Range of FRI Index Level: 1 to 4 (see Figure 2).
† Missing data from n = 6 and n = 19 patients at baseline (BL) and Month 18 (M18), respectively.
0
Lower GA Growth Rate
at Month 18
(n = 11)
• Findings from this study may be limited by the small sample sizes, particularly for the group
of patients with lower growth GA lesions.
CONCLUSIONS
• These results provide evidence that patient-reported functional
reading independence as measured by the FRI Index is linked to
GA lesion growth, an objective clinical anatomical measure of
disease progression.
• Data from Mahalo suggest that a change in mean FRI Index score
of 0.2 can differentiate patients with higher vs. lower growth rates
of GA lesion size.
• The goal of GA treatment is to slow or stop disease progression.
When stratifying by GA lesion growth, the FRI Index was able to
detect differences in progression of functional impact.
REFERENCES
DISCLOSURES
1.
2.
3.
Financial Disclosures: A. Kapre, E. Tschosik are employees of Genentech, Inc. M. Kimel and N. Leidy are employees of
Evidera. N. Bressler is Principal Investigator of grants at Johns Hopkins University sponsored by the following entities
(not including the National Institutes of Health): Bayer; Genentech, Inc.; Lumenis Inc.; Novartis Pharma AG; Regeneron
Pharmaceuticals, Inc. R. Varma is a consultant for Allergan. C. Dolan is a paid consultant for Genentech, Inc.
Wong WL, et al. Lancet Glob Health. 2014;2:e106-116.
Holz FG, et al. Ophthalmology. 2014;121:1079-1091.
Holz FG, et al, on behalf of the FAM-Study Group. Am J Ophthalmol. 2007;143:463-472.
Support for third-party writing assistance was furnished by Michael P. Bennett, PhD, and Grace H. Lee, PharmD, of Envision
Scientific Solutions, and provided by Genentech, Inc.
Presented at the International Society for Pharmacoeconomics and Outcomes Research 20th Annual International Meeting,
Philadelphia, PA, May 16-20, 2015