Evidence Identified in the Systematic Literature Review
The SLR identified 40 RCTs, across 158 individual reports (Online Resource 3.1 and 3.2). More than 30% of these reports were congress proceedings, trial registry records, and HTA or regulatory agency documents. In total, 31 trials reported data on BVL. Quality assessments broadly indicated low risks of bias for these trials (Online Resource 3.3). A summary of the main characteristics of these trials is provided in Table 1, including details regarding the reporting of BVL.
Table 1 Characteristics of RCTs reporting BVL identified in the SLR
Trial name (ClinicalTrials.gov ID)
|
Study characteristics
|
Regimens
|
BVL outcome
|
Phase
|
Blinding
|
Enrolment period
|
Geographic location
|
Intervention
|
Comparator
|
Timepoints assessed (from baseline)
|
Measurement technique
|
ADVANCE
(NCT00906399)
|
3
|
Double-blind
|
2009-2011
|
NA, EUR, other
|
· peginterferon 125 ug Q2W
· peginterferon 125 ug Q4W
|
placebo
|
48 weeks,
96 weeks
|
Unclear
|
AFFIRM
(NCT00027300)
|
3
|
Double-blind
|
2001-NR
|
NA, EUR, AU/NZ
|
natalizumab 300 mg IV Q4W
|
placebo
|
52 weeks,
104 weeks
|
BPF
|
ASCLEPIOS I
(NCT02792218)
|
3
|
Double-blind
|
2016-2018
|
NA, SA, EUR, AU, RUS
|
ofatumumab 20 mg Q4W
|
teriflunomide 14 mg qd
|
52 weeks,
104 weeks
|
Unclear
|
ASCLEPIOS II
(NCT02792231)
|
3
|
Double-blind
|
2016-2018
|
NA, SA, EUR, AU, RUS
|
ofatumumab 20 mg Q4W
|
teriflunomide 14 mg qd
|
52 weeks,
104 weeks
|
Unclear
|
ASSESS
(NCT00340834)
|
3b
|
Double-blind
|
2012-NR
|
NA, SA
|
· fingolimod 0.25 mg qd
· fingolimod 0.5 mg qd
|
glatiramer acetate 20 mg qd
|
52 weeks
|
Unclear
|
BEYOND
(NCT00099502)
|
3
|
Double-blind
|
2003-2005
|
NA, SA, EUR, AU, RUS
|
· interferon beta-1b 250 ug qod
· interferon beta-1b 500 ug qod
|
glatiramer acetate 20 mg qd
|
110 weeks
|
SIENA
|
BRAVO
(NCT00605215)
|
3
|
Double-blind
|
2008-NR
|
NA, EUR, RUS, AF
|
No eligible regimensb
|
· placebo
· interferon beta-1a 30 ug intramuscular qw
|
104 weeks
|
SIENA
|
CAMMS223
(NCT00050778)
|
2
|
Single-blind
|
2002-2004
|
NA, EUR
|
· alemtuzumab 12 mg qd x5 in month 1, qd x3 in month 12, qd x3 in month 24 at discretion
· alemtuzumab 24 mg qd x5 in month 1, qd x3 in month 12, qd x3 in month 24 at discretion
|
interferon beta-1a 44 μg subcutaneous tiw
|
156 weeks
|
SBV
|
CARE-MS I
(NCT00530348)
|
3
|
Single-blind
|
2007-2009
|
NA, SA, EUR, AU, RUS
|
alemtuzumab 12 mg qd x5 in month 1, qd x3 in month 12
|
interferon beta-1a 44 μg subcutaneous tiw
|
104 weeks
|
BPF
|
CARE-MS II
(NCT00548405)
|
3
|
Single-blind
|
2007-2009
|
NA, SA, EUR, AU, RUS
|
· alemtuzumab 12 mg qd x5 in month 1, qd x3 in month 12
· alemtuzumab 24 mg qd x5 in month 1, qd x3 in month 12
|
interferon beta-1a 44 μg subcutaneous tiw
|
104 weeks
|
BPF
|
CLARITY
(NCT00213135)a
|
3
|
Double-blind
|
2005-2007
|
NA, SA, EUR, AU, RUS, AF
|
· cladribine 3.5 mg/kg
· cladribine 5.25 mg/kg
|
placebo
|
24 weeks,
96 weeksc
|
SIENA
|
CONFIRM
(NCT00451451)
|
3
|
Double-blind
|
2007-NR
|
NA, EUR, NZ
|
· dimethyl fumarate 240 mg bid
· dimethyl fumarate 240 mg tid
|
· placebo
· glatiramer acetate 20 mg qd
|
48 weeks,
96 weeks
|
SIENA
|
COPOLYMER I
(NCT00004814)
|
3
|
Single-blind
|
1991-NR
|
NA
(USA only)
|
glatiramer acetate 20 mg qd
|
placebo
|
52 weeks
|
BPF
|
DEFINE
(NCT00420212)
|
3
|
Double-blind
|
2007-NR
|
NA, EUR, AU/NZ, AF
|
· dimethyl fumarate 240 mg bid
· dimethyl fumarate 240 mg tid
|
placebo
|
48 weeks,
96 weeks
|
SIENA
|
European/Canadian GA
(n/a)
|
3
|
Double-blind
|
1997-1997
|
NA (Canada only), EUR
|
glatiramer acetate 20 mg qd
|
Placebo
|
36 weeks
|
CBV
|
FREEDOMS
(NCT00289978)
|
3
|
Double-blind
|
2006-2007
|
NA, EUR, AUS, RUS, AF
|
· fingolimod 0.5 mg qd
· fingolimod 1.25 mg qd
|
Placebo
|
52 weeks,
104 weeks
|
SIENA
|
FREEDOMS II
(NCT00355134)
|
3
|
Double-blind
|
2006-2009
|
NA, EUR, AUS
|
· fingolimod 0.5 mg qd
· fingolimod 1.25 mg qd
|
Placebo
|
52 weeks,
104 weeks
|
SIENA
|
GALA
(NCT01067521)
|
3
|
Double-blind
|
2010-NR
|
NA, EUR, RUS, AF
|
glatiramer acetate 40 mg tiw
|
Placebo
|
52 weeks
|
SIENA
|
GATE
(NCT01489254)
|
3
|
Double-blind
|
2011-2013
|
NA, EUR, RUS, AF
|
· glatiramer acetate 20 mg qd (brand name)
· glatiramer acetate 20 mg qd (generic)
|
Placebo
|
39 weeks
|
Unclear
|
GOLDEN
(NCT01333501)
|
4
|
Open-label
|
2011-NR
|
EUR
|
fingolimod 0.5 mg qd
|
interferon beta-1b 250 μg qod
|
78 weeks
|
SIENA
|
MSCRG
(n/a)
|
3
|
Double-blind
|
1990-NR
|
NA
(USA only)
|
interferon beta-1a 30 ug intramuscular qw
|
Placebo
|
52 weeks,
104 weeks
|
BPF
|
OPERA I
(NCT01247324)
|
3
|
Double-blind
|
2011-2013
|
NA, SA, EUR, AU, RUS, AF
|
ocrelizumab 600 mg Q24W
|
interferon beta-1a 44 μg subcutaneous tiw
|
96 weeks
|
SIENA
|
OPERA II
(NCT01412333)
|
3
|
Double-blind
|
2011-2013
|
NA, SA, EUR, RUS
|
ocrelizumab 600 mg Q24W
|
interferon beta-1a 44 μg subcutaneous tiw
|
96 weeks
|
SIENA
|
OPTIMUM
(NCT02425644)
|
3
|
Double-blind
|
2015-2019
|
NA, EUR, RUS
|
ponesimod 20 mg qd
|
teriflunomide 14 mg qd
|
60 weeks,
108 weeks
|
SIENA
|
Phase 2 ocrelizumab trial
(NCT00676715) a
|
2
|
Double-blind
|
2008-NR
|
NA, EUR, RUS
|
· ocrelizumab 600 mg Q24W
· ocrelizumab 2000 mg Q24W
|
· interferon beta-1a 30 μg intramuscular qw
· placebo
|
24 weeks
|
BPF
|
Phase 2 ponesimod trial
(NCT01006265) a
|
2
|
Double-blind
|
2009-2010
|
NA, EUR, AUS, RUS
|
· ponesimod 10 mg qd
· ponesimod 20 mg qd
· ponesimod 40 mg qd
|
Placebo
|
24 weeks
|
SIENA
|
RADIANCE B
(NCT02047734)
|
3
|
Double-blind
|
2013-2015
|
NA, EUR, RUS, AF
|
· ozanimod 0.5 mg qd
· ozanimod 1 mg qd
|
interferon beta-1a 30 μg intramuscular qw
|
52 weeks,
104 weeks
|
SIENA
|
REGARD
(NCT00078338)
|
4
|
Open-label
|
2004-2004
|
NA, SA, EUR, RUS
|
glatiramer acetate 20 mg qd
|
interferon beta-1a 44 μg subcutaneous tiw
|
48 weeks,
96 weeks
|
SIENA
|
SUNBEAM
(NCT02294058)
|
3
|
Double-blind
|
2014-2015
|
NA, EUR, NZ, RUS
|
· ozanimod 0.5 mg qd
· ozanimod 1 mg qd
|
interferon beta-1a 30 μg intramuscular qw
|
52 weeks
|
SIENA
|
TEMSO
(NCT00134563)
|
3
|
Double-blind
|
2004-2008
|
NA, SA, EUR, RUS
|
· teriflunomide 7 mg qd
· teriflunomide 14 mg qd
|
Placebo
|
52 weeks,
104 weeks
|
SIENA
|
TRANSFORMS
(NCT00340834)
|
3
|
Double-blind
|
2006-2007
|
NA, SA, EUR, AUS, AS
|
· fingolimod 0.5 mg qd
· fingolimod 1.25 mg qd
|
interferon beta-1a 30 μg intramuscular qw
|
52 weeks
|
SIENA
|
a RCTs were included in the SLR, but deemed ineligible for inclusion in ITCs.
bThe main intervention assessed in the BRAVO trial was laquinimod (0.6 mg orally, once daily). This intervention is excluded herein, given that the prespecified eligibility criteria for the SLR did not include laquinimod as a regimen of interest.
c The latest timepoint of BVL measurement in the CLARITY trial was 96 weeks, however the data did not reflect change from baseline. The other reported timepoint of BVL measurement was 24 weeks, which was ineligible for inclusion in the ITCs (see Methods). Therefore, none of the BVL data from this trial was included in ITCs.
dThe latest timepoint of BVL measurement in the Phase 2 trials of ocrelizumab and ponesimod was 24 weeks, which was ineligible for inclusion in the ITCs (see Methods), therefore the data from these trials were not included in ITCs.
Abbreviations: AF = Africa, AS = Asia, AU = Australia, bid = twice daily, BPF = brain parenchymal fraction, BVL = brain volume loss, CBV = central brain volume, EUR = Europe, NA = North America, NZ = New Zealand, Q#W = every # weeks, qd = once daily, qod = every other day, qw = once weekly, RUS = Russia, SA = South America, SBV = supratentorial brain volume, SIENA = Structural Image Evaluation using Normalisation of Atrophy, tid = three times daily, tiw = three times per week.
Table 1 considers all RCTs reporting BVL in any form, for the DMTs in the scope of this review. The Phase 2 trials of ponesimod and ocrelizumab were limited to 24 weeks in duration.(34, 35) Similarly, the only BVL results reported from baseline in the CLARITY trial were collected at 24 weeks.(36) Following the exclusion of these three trials, 28 trials reporting BVL between 36 weeks and 156 weeks were considered eligible for ITCs. Missing standard deviation values were imputed as described above (Equation 1), with estimated parameters: .
Feasibility of conducting indirect treatment comparisons
The ITC eligible trials were found to be comparable with regards to study design, patient characteristics, and measurement/reporting of total BVL (see Online Resource 4.1 through 4.4 for supporting tables and plots). The majority of studies were multi-national, phase III, double-blinded, and included follow-up of approximately two years.
Moreover, the measurement technique used to collect BVL varied across trials; most trials indicated the use of either SIENA or BPF calculation, with SIENA being more frequently utilized in recent trials.
Indirect treatment comparison findings
The full network of evidence included in the ITCs is provided in Figure 1. All trial data leveraged for the ITCs is provided in Online Resource 5.0. For the MBMA, the investigation of dose-response considered all drugs for which multiple doses were included: alemtuzumab, dimethyl fumarate, fingolimod, interferon β-1b, ozanimod, peginterferon β-1a, and teriflunomide. No significant difference was found between dimethyl fumarate 240 mg (twice daily) and dimethyl fumarate 240 mg (three times daily), thus these doses were pooled, and a single treatment effect was estimated for dimethyl fumarate. Peginterferon β-1a and interferon β-1b had a negligible dose-response relationship (p>0.75), and a pooled effect estimate was incorporated for each respective drug. Although not statistically significant (p>0.05), a dose-response relationship was incorporated for the remaining four drugs with data at multiple doses (alemtuzumab, fingolimod, ozanimod, teriflunomide) to ensure that any potential dose-related variability was accounted for.
Upon incorporation of time as a covariate on relative effects, results demonstrated that a relative treatment effect at 52 weeks would be approximately 38% smaller than the same treatment effect at 104 weeks [95% CI: 17% - 53%] based on the time exponent (k) estimation of 0.70 with 95% CI [0.27 – 1.1]. Compared to a model excluding any influence of time on relative effect, the final MBMA described the data significantly better (p<0.01 from ANOVA test).
A model adjusting for the number of T1 gadolinium enhancing lesions (T1 Gd+) at baseline was also considered. However, this model was not significantly better fitting than the final model, which excluded the influence of baseline T1 Gd+ lesions (p>0.45).
A random effects model was also explored. Using an ANOVA test, there was a negligible difference in how well this model described the data versus the fixed effects model.
Considering the final MBMA incorporating adjustment for dosage and timepoint, the DMTs predicted to significantly outperform placebo on BVL in order of decreasing relative efficacy included: ponesimod, alemtuzumab, teriflunomide, ozanimod, and fingolimod (Figure 2a). That is, statistically significant benefits versus placebo were noted in each case. Interferons and natalizumab appeared to perform the most poorly in this analysis.
Figure 1 Evidence network for ITCs of BVLa
a Treatment nodes are sized proportionally to sample sizes, and connections between treatment nodes are indicated with line thickness proportional to the number of trials informing the connection. All connections were incorporated in the MBMA analysis, whereas only the nodes and trials shown in boldface were included in the NMA (since DMT dosages that were not of interest were excluded from the NMA).
Abbreviations: 24W = every 24 weeks, 2W = every two weeks, 4W = every four weeks, ALE = alemtuzumab, BID = twice daily, BVL = brain volume loss, CI = confidence interval, DMF = dimethyl fumarate, FIN = fingolimod, GA = glatiramer acetate, IFNβ = interferon β, NAT = natalizumab, OFA = ofatumumab, OZA = ozanimod, PBO = placebo, PEG = peginterferon β-1a, PON = ponesimod, Q2W = every two weeks, QD = once daily, QOD = every other day, QW = once weekly, TER = teriflunomide, TID = three times daily.
Figure 2 MBMA (A) and NMA (B) results for differences in brain volume loss at two years, versus placeboa
a MBMA and NMA used fixed effect models. Measurement timepoint and dosage were covariates in the MBMA. Round parentheses indicate the probability of being better than placebo. Peginterferon could not be incorporated in the NMA due to a lack of eligible BVL data reported at two years.
Abbreviations: 24W = every 24 weeks, 2W = every two weeks, 4W = every four weeks, ALE = alemtuzumab, BID = twice daily, BVL = brain volume loss, CI = confidence interval, DMF = dimethyl fumarate, FIN = fingolimod, GA = glatiramer acetate, IFNβ = interferon β, NAT = natalizumab, OFA = ofatumumab, OZA = ozanimod, PEG = peginterferon β-1a, PON = ponesimod, Q2W = every two weeks, QD = once daily, QOD = every other day, QW = once weekly, TER = teriflunomide.
Although the confirmatory NMA utilized data from the same clinical trials as the MBMA, only data collected at approximately two years, for treatment dosages that are currently authorized for use in the US, were included (Figure 1).
The effect estimates from the confirmatory NMA were generally associated with greater uncertainty (i.e., wider 95% credible intervals) as compared to the MBMA (Figure 2b). However, the main findings were consistent. In order of decreasing relative efficacy, the DMTs predicted to significantly outperform placebo included: ponesimod, fingolimod, teriflunomide, and ofatumumab. That is, statistically significant benefits versus placebo were noted in each case. The NMA results broadly aligned with the MBMA results in that most DMT regimens, namely the first-generation injectable therapies, were not predicted to significantly reduce BVL compared with placebo. The effect estimate for ofatumumab was significant in the NMA but not the MBMA, whereas the effect estimates for ozanimod and alemtuzumab were significant in the MBMA but not the NMA.