Brain volume change by quartile and disability progression in multiple sclerosis:
a 4-year analysis of the phase 3 FREEDOMS trial and its extension
DX41
Douglas Jeffery1, Elisabetta Verdun Di Cantogno2, Daniela Piani Meier2, Shannon Ritter3, Ernst-Willhelm Radue4, William Camu5
Piedmont Health Care, Mooresville, NC, USA; 2Novartis Pharma AG, Basel, Switzerland; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 4Medical Image Analysis Centre, University Hospital Basel, Basel, Switzerland;
5
MS Clinic, Department of Neurology, Hôpital Gui de Chauliac, Montpellier, France
1
CONCLUSIONS
• In FREEDOMS and its extension, the quartile of patients with the most brain volume loss at month 24 had the highest on-study risk of reaching milestone EDSS scores and the highest on-study rates of confirmed disability progression
• MS disease activity and severity at baseline in FREEDOMS were predictive of brain volume stability up to month 24
• These findings support the clinical relevance of brain volume changes in the long-term evolution of MS and the need to reduce brain volume loss as early as possible in the disease course
Table 1. Baseline characteristics by PBVC quartile and association with brain volume stability
• In the 2-year, phase 3 FREEDOMS trial, fingolimod reduced BVL in patients with RRMS
by approximately one-third compared with placebo6
• Patients who were randomized to placebo during FREEDOMS and switched to
fingolimod in the FREEDOMS extension also benefited in terms of reduced BVL during
the extension study7
OBJECTIVES
–– P
­ roportion of patients with Expanded Disability Status Scale (EDSS) score
≥4.0 or ≥6.0 at any time post-baseline
METHODS
• Odds ratios (ORs) and p values were derived from a logistic regression
of EDSS score ≥4.0 or ≥6.0 on PBVC quartile and baseline
EDSS score
Analyses
–– 3-month and 6-month confirmed disability progression (CDP), defined as an
increase in EDSS score of ≥1.0 if baseline EDSS score was ≤5.0 or an increase
of ≥0.5 if baseline EDSS score was ≥5.5
Figure 2. Time to reach (a) EDSS score ≥4 and (b) EDSS score ≥6
in FREEDOMS and its extension, by PBVC quartile
(a)
• Patients were categorized by quartile at month 24, based on PBVC from baseline,
and quartile 4 (Q4) was used as the reference category in subsequent analyses
• The annualized rate of BVL was determined by transforming PBVC using the formula
[(PBVC/100 + 1)(365.25/days) – 1] × 100, where ‘days’ is the number of days between
magnetic resonance imaging assessments made at baseline and at month 24
(Figure 1)
0.4
0.3
Most BVL
–13.5%
Q2
–1.7%
256
–1.46%
–1.27%
Q3
–0.8%
254
–0.60%
–0.59%
–0.2%
257
–0.25%
–0.24%
35.8% (OR=2.8, p=0.001)
27.6% (OR=2.55, p=0.003)
0.1
0.0
262
0.23%
0.14%
Least BVL
0
6
12
18 24 30 36 42 48
Time to first event (months)
56
60
The annualized rate of BVL was determined by transforming PBVC from baseline to month 24 using the
formula [(PBVC/100 + 1)(365.25/days) – 1] × 100, where days is the number of days between magnetic
resonance imaging assessments at baseline and at month 24
BVL, brain volume loss; PBVC, percentage brain volume change; Q, quartile
19.2% (OR=5.73, p<0.001)
0.2
10.6% (OR=3.92, p=0.009)
7.3% (OR=3.05, p=0.043)
0.1
0.0
Study population
• In total, 1029 patients were included in the analysis; baseline characteristics by PBVC
quartile are shown in Table 1
• At baseline, compared with patients in Q4 (least BVL), those in Q1 (most BVL) had:
–– ­More relapses in the previous 2 years
–– ­More brain tissue damage (greater T1-hypointense and T2 lesion volumes)
BVL and disability progression
• Patients with the most BVL at 24 months had the greatest risk of reaching EDSS
score ≥4.0 and ≥6.0 during the study (Figure 2)
3.1%
0
6
12
18 24 30 36 42 48
Time to first event (months)
56
60
p values are for comparison with Q4
EDSS, Expanded Disability Status Scale; OR, odds ratio; PBVC, percentage brain volume change; Q, quartile
(a)
OR=1.98
p=0.006
35
30
25
OR=2.13
p=0.002
15
28.8%
22.7%
20
17.9%
13.4%
10
5
0
Month 24
n= 256 262
p<0.001
0.20
0.18
0.10
Q3
0.20
p=0.006
p=0.442 p=0.291
0.10
0.09
p=0.182
0.08
0.03
0.5
Q4
Worsening
0.15
Q2
0.00
–0.05
–0.10
n= 256
Month 24
254
257
–0.04
–0.08
262
198
Month 48
198
193
195
(b)
p=0.537
0.06
0.03
0.00
–0.03
–0.06
0.02
0.04
p=0.420 p=0.654
p=0.030 p=0.044
–0.03
p=0.887
–0.04
0.03
0
–0.05
–0.09
–0.12
–0.15
n= 236
Month 24
234
241
–0.14
249
101
Month 48
95
88
95
Month 48
198 195
(b)
Q1
35
30
25
20
15
10
Q4
24.2%
• Higher rates of BVL at 24 months were generally associated with greater increases in
EDSS score and decreases in MSFC z-score during the study than were lower rates of
BVL (Figure 4)
1.
2.
3.
4.
5.
6.
7.
De Stefano N et al. CNS Drugs 2014;28:147–156.
Filippi M et al. Lancet Neurol. 2012;11:349–360.
Rudick RA, Fisher E. Mult Scler. 2013;19:1003–1004.
Jacobsen C et al. J Neurol Neurosurg Psychiatry 2014; 85:1109–1115.
Popescu V et al. J Neurol Neurosurg Psychiatry 2013;84:1082–1091.
Kappos L et al. N Engl J Med. 2010;362:387–401.
Kappos L et al. Neurology 2015;84:1582–1591.
Disclosures
19.1%
15.4%
10.7%
5
0
• At month 24, 14.8% of patients in Q1 and 1.1% of patients in Q4 reached EDSS
score ≥6.0 (OR, 11.85; p<0.001), and at month 48, 19.2% and 3.1% of patients,
respectively, reached EDSS score ≥6.0 (OR, 5.73; p<0.001)
References
OR=1.87
p=0.018
OR=2.17
p=0.003
• At month 24, 30.3% of patients in Q1 and 11.4% of patients in Q4 reached EDSS
score ≥4.0 (OR, 3.29; p<0.001), and at month 48, 35.8% and 13.8% of patients,
respectively, reached EDSS score ≥4.0 (OR, 2.80; p=0.001)
• Patients with the most BVL at 24 months also had the greatest risk of 3-month or
6-month CDP during the study (Figure 3)
Figure 3. In FREEDOMS and its extension, (a) 3-month CDP and
(b) 6-month CDP, for PBVC Q1 and Q4
0.3
3.0%
RESULTS
0.25
p=0.035
Q1
p values are for comparison with Q4
EDSS, Expanded Disability Status Scale; MSFC, Multiple Sclerosis Functional Composite; PBVC, percentage
brain volume change; Q, quartile
–– ­More active inflammatory disease (more gadolinium-enhancing lesions)
(b)
Q4
Cumulative probability
of EDSS score ≥6
n
Annualized rate
of BVL
Mean
Median
• p values were obtained from a rank analysis of covariance model using PBVC
quartile and baseline EDSS score as covariates
–– ­Greater levels of disability (higher mean EDSS score and lower mean MSFC z-score)
22.5% (OR=1.56, p=0.170)
13.8%
0.2
Figure 1. Annualized rate of BVL in FREEDOMS, by PBVC quartile
Q1
PBVC quartiles
Q1
Q2
Q3
Q4
0.5
Cumulative probability
of EDSS score ≥4
• Percentage brain volume change (PBVC) from baseline to month 24 was estimated
using ‘structural image evaluation, using normalization, of atrophy’ (SIENA)
PBVC from
month 0 to
month 24
–– M
­ ean changes from baseline in EDSS score and MS Functional Composite (MSFC)
z-score
Proportion of patients with
3-month CDP (%)
Study design and participants
• This analysis included all patients who were randomized and received at least one
dose of study medication during both FREEDOMS and its extension
0.171
0.137
0.727
0.011
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
• ORs and p values were derived from a logistic regression of CDP on PBVC
quartile and baseline EDSS score
–– ­Time to EDSS score ≥4.0 and ≥6.0, determined using Kaplan–Meier analysis
• In FREEDOMS, patients with RRMS were randomized to receive fingolimod 0.5 mg,
fingolimod 1.25 mg or placebo for 24 months.6 Patients completing FREEDOMS
were eligible to enter the extension on the same dose of fingolimod, and those taking
placebo were re-randomized to fingolimod 0.5 mg or 1.25 mg. All patients receiving
fingolimod 1.25 mg were subsequently switched to fingolimod 0.5 mg7
0.99
1.34
0.99
0.82
0.69
2.45
0.71
0.68
0.83
1.01
(a)
Data are mean (standard deviation) unless otherwise stated
a
Brain volume stability is defined as a PBVC within Q4
For each variable, ORs compare Q1 and Q4 and are derived from individual regression models, with the respective variable as predictor; patients categorized in Q2 or Q3 were excluded from this analysis
For continuous variables, the OR corresponds to a unit increase in the variable. For the one categorical variable, women were the reference category; therefore an OR>1 implies a higher chance of brain volume stability among
men than women
EDSS, Expanded Disability Status Scale; Gd+, gadolinium-enhancing; MSFC, Multiple Sclerosis Functional Composite; OR, odds ratio; PBVC, percentage brain volume change; Q, quartile
• Baseline patient characteristics, and the following parameters at months 24 and 48,
were also determined and analyzed by PBVC quartile at month 24
• To investigate whether BVL at month 24 is associated with and is predictive of
disability progression in FREEDOMS and its extension
Q4
(n=262)
36.6 (8.6)
180 (68.7)
7.7 (6.4)
2.0 (1.1)
2.1 (1.2)
0.16 (0.57)
0.6 (1.3)
996 (1873)
3316 (4371)
1535 (80.1)
Improvement
• In MS, BVL correlates with and predicts future disability, in terms of both physical and
cognitive decline4,5
Q3
(n=257)
36.9 (8.6)
178 (69.3)
8.5 (6.8)
2.1 (1.1)
2.3 (1.2)
0.13 (0.53)
0.6 (1.1)
1529 (2331)
4424 (5363)
1527 (78.5)
Improvement
• Both focal and diffuse damage in grey and white matter contribute to MS
progression,2 and BVL is increasingly recognized as a measure that captures
these pathologies1–3
Age, years
Women, n (%)
Time from first symptom, years
Number of relapses in the previous 2 years
EDSS score
MSFC z-score
Gd+ lesion count
T1 hypointense lesion volume, mm3
T2 lesion volume, mm3
Normalized brain volume, cm3
Q2
(n=254)
37.1 (8.6)
186 (73.2)
8.2 (6.6)
2.2 (1.3)
2.3 (1.3)
0.09 (0.55)
1.3 (3.1)
1899 (3002)
5988 (6697)
1522 (80.0)
p value
Worsening
• The estimated mean rate of BVL in patients with relapsing–remitting MS (RRMS) is in
the range of 0.5–1.35% per year, which is considerably higher than the age-related
rate of BVL in the general population (0.1–0.3% per year)1
Q1
(n=256)
37.7 (8.9)
191 (74.6)
7.9 (6.4)
2.3 (1.3)
2.7 (1.3)
−0.21 (0.75)
3.1 (5.6)
3584 (4208)
11 266 (10 215)
1484 (87.1)
OR for prediction
of brain volume
stabilitya
Proportion of patients with
6-month CDP (%)
• Accelerated brain volume loss (BVL) occurs throughout the course of multiple
sclerosis (MS) and is evident from the earliest stages1
PBVC quartile
Mean change in
EDSS score from baseline
Characteristic
Figure 4. Mean change from baseline in (a) EDSS score and (b) MSFC
z-score in FREEDOMS and its extension, by PBVC quartile
Mean change in
MSFC z-score from baseline
INTRODUCTION
Month 24
n= 256 262
Month 48
198 195
p values are for comparison of Q1 and Q4
CDP, confirmed disability progression; OR, odds ratio; PBVC, percentage brain volume change; Q, quartile
This study was funded by Novartis Pharmaceuticals Corporation | Poster presented at the 2015 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) | May 27–30, 2015 | Indianapolis, Indiana, USA
Douglas Jeffery has received honoraria for speaking, consulting and research support from Acorda Therapeutics,
Alkermes, Bayer, Biogen Idec, Genzyme, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Pfizer, Questcor,
Serono, Teva Pharmaceuticals and XenoPort. Elisabetta Verdun Di Cantogno and Daniela Piani Meier are
employees of Novartis Pharma AG. Shannon Ritter is an employee of Novartis Pharmaceuticals Corporation.
Ernst-Willhelm Radue has received honoraria for speaking and consulting for Biogen Idec,
Bayer Schering, Merck Serono and Novartis; and has received research support from Actelion,
Basilea Pharmaceutica, Biogen Idec, Merck Serono and Novartis. William Camu has received
honoraria or research support from Actelion Pharmaceuticals, Biogen Idec, Merck Serono,
Novartis Pharmaceuticals, Sanofi-Aventis and Teva Pharmaceuticals.
Acknowledgments
The authors acknowledge Oxford PharmaGenesis, Oxford, UK, for editorial support, which
was funded by Novartis Pharmaceuticals Corporation. The final responsibility for the content
lies with the authors.
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