Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives

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Progressive multiple sclerosis 3 Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives Daniel Ontaneda, Robert J Fox, Jeremy Chataway Lancet Neurol 2015; 14: 208–23 See Comment pages 132 and 133 This is the third in a Series of three papers about progressive multiple sclerosis Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (D Ontaneda MD, R J Fox MD); Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, University College London, London, UK (J Chataway PhD); and National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK (J Chataway) Correspondence to: Dr Daniel Ontaneda, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA [email protected]

208

Progressive multiple sclerosis is characterised clinically by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or can be preceded by a relapsing disease course (secondary progressive). An effective disease-modifying treatment for progressive multiple sclerosis has not yet been identified, and so far the results of clinical trials have generally been disappointing. Ongoing advances in the knowledge of pathogenesis, in the identification of novel targets for neuroprotection, and in improved outcome measures could lead to effective treatments for progressive multiple sclerosis. In this Series paper, we summarise the lessons learned from completed clinical trials and perspectives from trials in progress in progressive multiple sclerosis. We review promising clinical, imaging, and biological markers, along with novel designs, for clinical trials. The use of more refined outcomes and truly neuroprotective drugs, coupled with more efficient trial design, has the capacity to deliver a new era of therapeutic discovery in this challenging area.

Introduction Progressive forms of multiple sclerosis are characterised clinically by the accumulation of neurological disability, independent of relapses, and can present as the initial disease course (primary progressive multiple sclerosis, or PPMS) or more commonly after an initial relapsing phase of the disease (secondary progressive multiple sclerosis, or SPMS).1 The pathological process that drives the accrual of disability in progressive multiple sclerosis is unknown, but could include continued compartmentalised inflammation, mitochondrial dysfunction, and accelerated neurodegeneration, or other pathological processes.2,3 Much progress has been made in the treatment of multiple sclerosis during the past two decades with the introduction of effective drugs for relapsing-remitting multiple sclerosis (RRMS).4 Unfortunately, similar success has not been achieved for PPMS and SPMS.5 Although inflammation is well defined and treated in RRMS as focal inflammatory lesions, the underlying pathology in the progressive form of the disease is not clear, making development of treatments a great challenge. This problem is evident in the negative results of trials of anti-inflammatory drugs that have been completed so far. Additional barriers are the relative paucity of sensitive outcome measures and fully validated biomarkers in progressive multiple sclerosis. In this Series paper, we discuss the factors that need to be considered in the planning and undertaking of trials of potential treatments for progressive multiple sclerosis. We summarise the lessons learned from previous clinical trials and provide an overview of ongoing and recently completed trials, focus on methodological aspects of trials in progressive multiple sclerosis, and provide an overview of challenges that need to be addressed. The outcomes of clinical trials in progressive multiple sclerosis will depend on the selection of compounds that have a reasonable chance of success based on mechanistic, preclinical, and phase 1 studies.3 We discuss several factors separately,

from the selection of study participants to trial design, but the combination of these factors will determine the success of future efforts to identify safe and effective treatments for progressive multiple sclerosis.

Completed and ongoing clinical trials Phase 3 trials To consider how clinical trials into progressive multiple sclerosis could be improved, completed trials need to be reviewed. Table 1 lists the previous disability-driven trials in progressive multiple sclerosis from the past 25 years. These trials collectively included more than 8500 participants, about 70% of whom had SPMS.6–23 Different categories of drugs were studied, including classic immunosuppressants, beta interferons, immunomodulators, and putative neuroprotectants. Despite large efforts, the trial outcomes are mostly negative (although there are some exceptions). However, important lessons can be drawn from this experience to inform future efforts. Table 2 lists trials in progress. Although the Expanded Disability Status Scale (EDSS) has dominated this area of research, with the usual measures being time to progression of disability or proportion of patients with progression-free disability, the absolute mean EDSS difference, Multiple Sclerosis Functional Composite (MSFC), and other summary measures have also been reported. A useful way to start the analysis of results is to use elements from the CONSORT schema,25 because this is typically reported in contemporary trials. Most trials have tested immunomodulating or immunosuppressant drugs and the negative data, so far, would suggest that the focus of trials in progressive multiple sclerosis should shift to a primary neuroprotective approach.

Phase 2 trials The model of phase 2 (proof of concept) to phase 3 (clinically definitive) trials is embedded in the practice of www.thelancet.com/neurology Vol 14 February 2015

www.thelancet.com/neurology Vol 14 February 2015 ≥12

≥6

≥18

≥12

≥6 ≥6

2·5 (mean)

1

3

2

3

3

Sulfasalazine

Interferon beta-1b 3 (8M IU alternate days)

3

Cyclophosphamide (1g/alternate day IV until white cell count ≤4·5 × 10⁹, oral prednisone; or plasma exchange (weekly for 20 weeks), oral cyclophosphamide (1·5–2·0 mg/kg per day, oral prednisone)

Roquinimex (1·0, 2·5, and 7·5 mg)

Cladribine (0·07 mg/kg per day for 5 days for two or six cycles)

Interferon beta-1a (22 or 44 μg 3 per week)

Interferon beta-1a (60 μg per week)

Mitoxantrone (5 or 12 mg/m² every 3 months)

Interferon beta–1a (22 μg/week)

Interferon beta-1b (250 μg or 160 μg/m2 alternate days)

Canadian Cooperative MS Study Group;8 1991; n=168

Mayo ClinicCanadian Cooperative Trial;9 1998; n=199

European Study Group on interferon beta-1b in SPMS;10 1998; n=718§

North American Linomide Investigators;11 2000; n=715

Rice et al;12 2000; n=159

SPECTRIMS;13 2001; n=618

Cohen et al (IMPACT);14 2002; n=436

Mitoxantrone in progressive MS;15 2002; n=194

Andersen et al;16 2004; n=371

Panitch et al;17 2004; n=939

2

≥18

≥12

≥6

≥12

≥12

2

Ciclosporin (dose adjusted for trough 300–500 ng/ml)

Cyclosporine MS Study Group;7 1990; n=547

3

≥6

3

15

14

10

16

13

11

15

13

6

10

10

9

4

5

··

··

4

··

··

4

··

··

··

··

47

46

40

48

43

44

46

41

28

31

40

38

100

100

50†

100

100

70

87†

100

11†

‡

‡

19†

0

0

0†

0

0

30

0†

0

13†

‡

‡

14†

5·1

4·8

4·6

5·2

5·4

5·6

5·2

5·1

2·5

5·7

5·4

3·7

0·42

0·43

1·33

0·55

0·45

··

0·65

0·85

1·5

··

··

··

Pretrial

MS SPMS Mean SPMS PPMS Pre-trial (%) (%) progression (years) (years) age (years) (months)

Baseline EDSS (mean)

ARR

Participants

Azathioprine (2·5 mg/kg per day)

Trial duration (years)

British and Dutch MS Azathioprine Group;6 1988; n=354

Intervention

0·28

0·27

1·02

0·3

0·71

··

¶

0·64

0·99

··

··

0·84

0·16

0·25

0·60 and 0·35 (two doses)

0·2

0·50

··

¶

0·44

0·81

··

··

0·73

In-trial In-trial active placebo

6

50

Median TTP 3·1 years

Mean ΔEDSS 0·5 (worse)

3 and 6

6

MSFC used

60

Mean ΔEDSS 1·0 (worse)

60

50

75

··

Mean ΔEDSS 0·5 (worse)

··

3

3

2

3

3

3

6

3

··

EDSS con- Estimated firmation placebo (%) (months)

Progression

··

··

34**

38

··

0·60

··

0·60

(Table 1 continues on next page)

36**

41

··

··

–0·13††

0·26

0·27 Median ΔMSFC 0·096 (worse) Median ΔMSFC 0·161 (worse)

0·23

··

Δ0/0||

¶

0·47

··

Δ0·3/0||

¶

0·60

1·01

0·81 cyclophosphamide, 0·69 plasma exchange

0·69

0·66

0·33

0·62

Active*

0·55

0·80

Placebo*

60**

65**

¶

39

52

¶

50

50

35 cyclophosphamide, 32 plasma exchange

··

··

29

··

··

Actual Actual placebo active (%) (%)

EDSS change

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Table 1: Summary of baseline characteristics and results from phase 3 trials in progressive multiple sclerosis

MS=multiple sclerosis. SPMS=secondary progressive multiple sclerosis. PPMS=primary progressive multiple sclerosis. ARR=annualised relapse rate. EDSS=Expanded Disability Status Scale. TTP=time to progression. IV=intravenous. SC=subcutaneous. N/A=not applicable. MSFC=Multiple Sclerosis Functional Composite. *Positive score represents worsening; negative score represents improvements. †Remainder had relapsing-remitting multiple sclerosis. ‡Not separated. §Data taken from original publication. ¶Trial terminated early; exploratory outcomes taken from patients attending final follow-up. ||SPMS/PPMS. **Taken from Cochrane collaboration. ††12 mg/m² dose. ‡‡Active/placebo ratio of 2:1; all other studies are 1:1, 1:1:1, or 1:1:1:1.

·· ·· 55 60 70 6 ·· ·· ·· 5·9 39 61 52 ·· ·· 3 Dronabinol (max 28 mg per day) Zajicek et al (CUPID);23 2013; n=498‡‡

≥12

0·24 0·22 31 28 30 6 0·12 0·15 0·09 5·5 0 100 50 ·· 9 2 Myelin basic protein 8298 (500 mg IV 6 monthly) Freedman et al (MAESTRO);22 2011; n=612

Recent

0·33 0·45 30 39 32 3 N/A N/A N/A 4·8 100 0 50 ·· ≥12 2 Rituximab (1000 mg infusions twice in four courses) Hawker et al (OLYMPUS);21 2009; n=439‡‡

9

0·58 0·61 40 3 N/A N/A N/A 4·9 100 0 50 ·· 11 ≥6 3 Glatiramer acetate Wolinsky et al (PROMiSE);20 2007; (20 mg SC per day) n=943¶‡‡

2 Immunoglobulin (0·4 g/kg per month) Pohlau et al;19 2007; n=231

50 per year (3·0–5·0); 20 per year (5·5–6·5)

45

0·5 0 (median) (median) 48 63 ·· 3 0·30 0·26 ·· 5·6 15 85 48 ·· ··

0·5 48 44 45 3 0·46 0·46 ·· 5·2 0 100 44 5 14 ≥12 2·25 European Study on Immunoglobulin Immunoglobulin (1 g/kg per month) in MS trialists;18 2004; n=318

(Continued from previous page)

Trial duration (years) Intervention 210

≥12

0·5

Active* Placebo* EDSS con- Estimated firmation placebo (%) (months) Pretrial MS SPMS Mean SPMS PPMS Pre-trial (%) (%) progression (years) (years) age (years) (months)

Baseline EDSS (mean)

ARR Participants

In-trial In-trial active placebo

Progression

Actual Actual placebo active (%) (%)

EDSS change

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clinical trials. Phase 2 trials are done to establish toxic effects, identify drug doses that seem effective and well tolerated, and provide proof of concept before proceeding to the longer and more expensive phase 3 trials. Phase 2a and 2b trials in progressive multiple sclerosis have previously been variable in terms of trial design with a range of structures and subsequent decisions taken (table 3 lists many of these trials).26–59 For example, the decision not to pursue a phase 3 trial for alemtuzumab in progressive multiple sclerosis seems appropriate on the basis of the phase 2 results, which showed no effect on brain atrophy measures;41,42 however, the decision to proceed to a large phase 3 trial (n=612) for MBP8298 (a synthetic peptide similar to myelin basic protein) seems questionable based on a post-hoc, HLA-stratified subgroup of 20 patients.46 Likewise, with the beta interferons, no phase 2 trial was done with a pure cohort of only patients with SPMS, and the decision to move to phase 3 was based largely on extrapolation from the successful RRMS experience. The optimum primary outcomes in phase 2 trials are open to debate, with no measure fully validated. To some extent, the outcome depends on the question asked. With respect to stem-cell treatment, the phase 2a mesenchymal stem cells in multiple sclerosis study53 (MSCIMS) focused on questions about the anterior visual pathway with an appropriate battery of measures being used. By contrast, a systematic review60 (n=161, eight case-series, randomised controlled trial not done) of haemopoietic transplantation used the traditional metric of EDSS progression-free survival. As shown in the MS-STAT trial57 of high-dose simvastatin in SPMS, examination of the effect of treatments on whole or partial brain volume seems promising with a 43% reduction in atrophy rate, but this measurement needs to be confirmed by a definitive phase 3 trial with a clinically relevant primary outcome. Phase 2 trials can be useful for other (unexpected) reasons, such as the occurrence of pseudoatrophy in the lamotrigine trial,49 which has informed the design of subsequent atrophy-based trials. Sometimes, a safety signal will be undiscovered until the later stages of trials—eg, for roquinimex (Linomide) in 1996, for which serious cardiovascular events were noted only in phase 3 studies.36 Previously, phase 2 trials have tended to be small and often used mixed populations of patients, with PPMS and SPMS sometimes being amalgamated as progressive, as seen in the case of cladribine12,31 and plasma exchange trials.27 In an RRMS trial cohort, the so-called progressive group might sometimes be only a small number of participants (eg, the ibudilast51 [7%] and anti-CD4 antibody37 [<50%] trials). Drugs have also been repurposed—ie, used for another purpose than their original (eg, amiloride55 and recombinant human erythropoietin50), in many small phase 2a studies. A more systematic approach to harnessing such information might improve opportunities for drug repurposing in the future. www.thelancet.com/neurology Vol 14 February 2015

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In summary, appropriately targeted phase 2 trials have the potential to identify the treatments most likely to succeed in phase 3 and those with little chance of success. Appropriate selection of interventions with good risk– benefit profiles along with efforts to improve clinical trial design in phase 2 and 3 studies will maximise the likelihood of identification of treatment options for progressive multiple sclerosis.

Study participants At the core of any trial is the population being investigated. Investigators should consider whether the population is well defined, with a clear treatment target, and whether the number of participants is sufficient to give meaningful results. The diagnostic definition of PPMS or SPMS is not straightforward. Results from one study of SPMS showed that whether physician-based assessments or EDSS criteria were applied could change the time of onset of disease by about 5 years.61 In table 1, cohorts of young patients or those with short duration of SPMS might be a transitional group (at an early stage with more inflammation). The minimum duration of clinical progression needed before trial entry has ranged from 6 months to 18 months. In some trials, a confirmed EDSS step at entry was an inclusion criterion; generally, the allowed range for entry has been an EDSS score of between 3·0 and 7·0 (mean actual range of 2·5–6·0). Intercurrent relapses have possible confounding effects. In the European SPMS trial,10 the reported effects of interferon beta-1b have been attributed to an effect on relapse rather than on pure disability. This hypothesis could be invoked to explain the absence of benefit reported in the North American SPMS trial17 of recombinant interferon beta-1b, which had a low pre-trial and in-trial annualised relapse rate (ARR). In the Mitoxantrone in Multiple Sclerosis (MIMS) trial,15 the entry ARR was higher (1·33) than noted in previous trials, with the in-trial rates being 0·35 (active high dose) and 1·02 (placebo). These numbers are in contrast with those of the MAESTRO trial of MBP8298,22 which had a minimum entry ARR of 0·09. A low entry ARR or little change in-trial again would support the notion that disability is driven by progression rather than relapse reduction. In the OLYMPUS trial21 of rituximab in adults with PPMS, although no overall effect was noted for the confirmed progression, the inflammatory subgroup with gadolinium enhancing lesions at baseline benefited. After the rate of pre-trial progression, the expected and actual in-trial proportion of patients with progression are essential parameters from which the power of the trial is derived. Most trials postulate an effect size of 30–50% with powers of 80–90%. The behaviour of the placebo group is crucial in terms of anticipated and actual progression; if this group does not progress as anticipated, the power of the trial is reduced. In SPMS, common projections are that 30–45% of participants will have progressive disease at 2 years and 50–70% will have www.thelancet.com/neurology Vol 14 February 2015

progressive disease at 3 years. In the CUPID trial23 of the cannabinoid dronabinol in progressive multiple sclerosis, a pre-trial progression rate of 70% of patients was anticipated, but the actual progression rate was 60% (figure 1); similarly, the North American Study Group on interferon beta-1b in SPMS trial17 estimated a 50% progression rate, but had an actual rate of 35%. The PROMiSE trial20 of glatiramer acetate in PPMS was stopped early because of the lack of progression in patients. Although the mean change in EDSS is generally not used as the primary outcome because of the ordinal nature of the scale, estimates of power based on mean EDSS have been used—eg, in the ciclosporin trial7 in which the detection of a mean EDSS difference of 0·5 was used against placebo. Alternatively, MSFC changes were used in the IMPACT trial of interferon beta-1a in patients with SPMS,14 which might have a stronger statistical basis because it does not rely on a reference population. Additionally, some studies have progressive multiple sclerosis mixed with other so-called progressive relapsing or chronic progressive forms of multiple sclerosis (eg, in the Canadian Cooperative Multiple Sclerosis Study Group trial8 the proportion of patients with progressive disease other than purely progressive from onset was 50%, and in the British and Dutch Multiple Sclerosis Azathioprine Trial Group study6 it was 20%). Although this terminology is no longer used, and is being actively changed,1 there are proponents on both sides for the use of pure or mixed groups of patients with PPMS or SPMS. The allowance for cohorts of patients with SPMS to use concurrent anti-inflammatory disease-modifying therapy depends in part on location (anti-inflammatory treatments are not usually reimbursed for patients with progressive multiple sclerosis outside the USA) and in part on regulatory preference. Trial participants with SPMS tend not to have been taking immunosuppressants for 6 months or more and not to have been taking corticosteroids for 1 month or more before the trial starts.

Diagnosis Diagnosis of progressive multiple sclerosis is a clinical judgment, with no gold standard diagnostic test. In an individual patient, differentiation of progressive multiple sclerosis from other gradually progressive neurological disorders (eg, hereditary spastic paraparesis or primary lateral sclerosis) is not always straightforward,62 and there is growing consensus that RRMS and progressive forms of multiple sclerosis are not distinct entities.1 The progressive phase of multiple sclerosis probably starts during the acute inflammatory stage and, accordingly, the distinction between RRMS and SPMS for the purpose of enrolment into clinical trials is artificially binary. Moreover, differentiation of PPMS from SPMS relies on patient memory (which might be unreliable) of typical demyelinating episodes, which makes for a weak diagnostic classification. There has been a shift away from these strict subtype classifications towards two main 211

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classifications: the presence or absence of acute inflammation (ie, relapses or active lesions on MRI) and the presence or absence of gradual progression.1 Efforts to obtain clear, reliable categories for research purposes will help to ensure the success of future phase 2 and 3 trials of treatments for progressive multiple sclerosis.

Comorbidities Previous studies of treatments for multiple sclerosis had an underlying assumption that all disease activity (ie, relapses, lesions on MRI, and disability progression) is a product of multiple sclerosis alone. Studies have now identified other factors that can affect disease

Duration of Ratio of active Primary outcome progression to placebo (months)

PPMS or SPMS

Estimated completion date

Intervention

Number of people to be randomised

Entry Trial duration EDSS range (years)

PROMESS (NCT00241254)*

2013

Methylprednisolone (1 g per month) vs cyclophosphamide (750 mg/m²) every 4 weeks for year 1; every 8 weeks for year 2

360

2

4·0–6·5

≥6

1:1

EDSS progression

SPMS

INFORMS (NCT00731692)†

2014

Fingolimod (0·5 mg per day)

969

3

3·5–6·0

≥24

1:1

Time to confirmed disability progression

PPMS

ASCEND in SPMS (NCT01416181)

2017

Natalizumab (300 mg IV per month)

890

2

3·0–6·5

≥24

1:1

Proportion of participants SPMS with worsening of ≥1 on EDSS, T25FW, and 9HPT

NCT01433497

2015

Masitinib (6 mg/kg per day)

450

2

2·0–6·0

≥6

1:1

MSFC

SPMS or PPMS

NCT01194570

2017

Ocrelizumab (300 mg twice during 14 days per treatment cycle)

740

2

3·0–6·5

··

2:1

Time to confirmed EDSS progression (in ≥3 months)

PPMS

EXPAND (NCT01665144)

2016

Siponimod (BAF312; 0·25–2·0 mg per day)

1530

2–3·5

3·0–6·5

≥6

1:1

Time to confirmed EDSS progression

SPMS

EPO-ProgMS (NCT01144117)‡

2013

Erythropoietin (48 000 IU IV in 17 courses)

0·5

4·0–6·5

≥24

1:1

Composite of maximum gait distance, 9HPT, trail making

SPMS or PPMS

Abili-T (NCT01684761)

2015

Tcelna (Imilecleucel-T; 30–45 × 10⁶ total cells, five SC doses per year)

180

2

3·0–6·0

··

1:1

Brain atrophy

SPMS

1·0–7·0

··

1:1

Brain atrophy

PPMS

··

1:1

Brain atrophy

SPMS

Phase 3

Phase 2 56

IPPoMS (NCT00950248) 2018

Idebenone (2250 mg/day)

85

2

NCT01188811

2016

Lipoic acid (1200 mg/day)

56

2

SUPREMES (NCT00799890)

2016

Sunphenon EGCg (Epigallocatechin-Gallat, EGCG; 200–800 mg/day)

60

3

3·0–8·0

··

1:1

Brain atrophy

SPMS or PPMS

NCT01259388

2015

Lithium (150 or 300 mg/day)

20

2

3·0–6·5

··

1:1 cross-over

Brain atrophy

SPMS or PPMS

RIVITaLISE (NCT01212094)

2017

Rituximab (intrathecal and IV)

80

2

3·0–7·0

≥3

1:1

Brain atrophy

SPMS

MS-SMART (NCT01910259)

2017

Amiloride (10 mg) or fluoxetine (40 mg) or riluzole (100 mg) per day

440

2

4·0–6·5

≥24

1:1:1:1

Brain atrophy

SPMS

SPRINT-MS (NCT01982942)

2017

Ibudilast 100 mg/day

250

2

3·0–6·5

≥24

1:1

Brain atrophy

SPMS or PPMS

NCT01950234

2017

ACTH (3 days per month SC)

100

3

2·0–6·0

··

1:1

Proportion with ≥20% worsening of T25FW

SPMS or PPMS

NCT02057159

2017

NeuroVax (TCR peptide vaccine)

200

1

··

1:1

Cumulative number of gadolinium-enhanced lesions

SPMS

ACTiMUS (NCT01815632)

2018

Early or late autologous bone marrow infusion

80

2

4·0–6·0 ≥12

1:1

Global evoked potential

SPMS or PPMS

··

≥3·5

EDSS=Expanded Disability Status Scale. PPMS=primary progressive multiple sclerosis. SPMS=secondary progressive multiple sclerosis. MSFC=Multiple Sclerosis Functional Composite. IU=international units. IV=intravenous. SC=subcutaneous. 9HPT=9 hole peg test. ACTH=adrenocorticotropic hormone. T25FW=timed 25 foot walk. TCR=T-cell receptor. *Abstract only24 (cyclophosphamide was not better than methylprednisolone and had a higher drop-out rate, only 138 participants were randomly assigned). †Primary endpoint not met. ‡Abstract presented in 2014 (negative study).

Table 2: Planned or enrolling phase 2 and phase 3 trials in progressive multiple sclerosis

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Series

Intervention

Khatri et al;26 1985; n=54

Trial duration (years)

2 Plasma exchange (weekly for 20 weeks) in addition to low-dose prednisolone and cyclophosphamide

Pre-trial duration of progression (months)

Mean age of MS/ participants SPMS* duration (years) (years)

SPMS/ PPMS (%)

··

≥12

39

11/2

··

≥24

36

≥12

Entry EDSS range

Mean EDSS

Primary outcome(s)

Comments

Chronic 6·4 progressive

EDSS or activities of daily living

EDSS improvement or stabilisation

13

Chronic 6·3 progressive

EDSS

Negative

43

13

Chronic 6·4 progressive

Functional scale

Less functional decrease with TLI than with sham treatment

≥6

45

14

Chronic 6·0 progressive

EDSS or MRI lesion load

Negative

≥18

42

··

Chronic 5·6 progressive

Disability progression (EDSS)

Negative

Chronic 4·6 progressive

Disability progression (EDSS or SNRS); MRI lesion volume; oligoclonal band status

Cross-over design; improvement in mean paired EDSS (1·3) and SNRS (–12·5)

Negative; recruited only 24 of 56 participants needed

Gordon et al;27 Plasma exchange 1985; n=20 (eight exchanges) in addition to prednisolone and azathioprine

About 0·5

Cook et al;28 1986; n=40

TLI (1980 cGy)

2

Kastrukoff et al;29 1990; n=100

Lymphoblastoid interferon (5 × 10⁶ per day SC)

2

Bornstein et al;30 1991; n=106

Cop 1

2

Sipe et al;31 1994; n=48

Cladribine 0·7 mg/kg IV four courses

1

··

≥24

43

12

Wiles et al;32 1994; n=24

TLI (1980 cGy)

2

≤6·5

≥12

39

8

75/25

5·8

Disability progression (EDSS)

Milligan et al;33 1994; n=52

Isoprinosine (3 g/day) in addition to pulsed methylprednisolone day 6–10 (0·5 g/day)

2

<5·5

··

41

8

42/8†

2·9

Disability progression Negative (EDSS, ambulation index, MRI lesion load)

Goodkin et al;34 1995; n=60

Methotrexate 7·5 mg per week

2

≥6

44

70/30

5·4

Disability progression (EDSS, 9HPT, Box and Block Test, ambulation index)

52% active and 83% given placebo had sustained treatment failure (p=0·01), especially for upper limb function

··

44

8

··

EDSS functional systems

Cross-over design; significant improvement in EDSS

4·8

Safety; MRI GdE activity; EDSS mean change

Reduced MRI activity

5·0–6·0 (median)

MRI GdE activity

Negative

4·0–8·0 ≤7·0

2·0–6·5

3·0–6·5

8–11 (median range)

Cazzato et al;35 Methylprednisolone 1995; n=35 (1 g/day for 5 days followed by oral prednisolone, four cycles)

0·25

Karussis et al;36 Roquinimex (2·5 mg/day) 1996; n=30

0·5

3·0–7·0

≥24

42

7

Van Oosten et al;37 1997; n=71

Anti-CD4 antibody cM-T412

0·75

3·0–7·0

≥18

37

7

Cook et al;38 1997; n=46

Modified TLI (1980 cGy) in addition to low-dose prednisolone

3

3·5–6·5

≥24

41

11

Chronic 5·7 progressive

Disability progression (EDSS)

Stopped prematurely owing to low number of participants recruited

Bosco and Cazzato;39 1997; n=23

Idebenone (90 mg/day) in addition to IV methylprednisolone

0·7

3·0–6·0

··

46

12

Chronic 4·3 progressive

EDSS and ambulation index

Negative

Goodkin et al;40 1998; n=108

2 High-dose or low-dose IV methylprednisolone alternate months; followed by oral methylprednisolone

4·0–6·5

≥5

··

··

100/0

··

Disability progression (EDSS, 9HPT, ambulation, Box and Block Test, relapse)

No difference

··

0/100

100/0

46/0†

Paolillo et al;41 Alemtuzumab anti-CD52 (20 mg/day for 5 days) 1999 and Coles et al;42 2006; n=25

1·5

4·0–6·0

≥12

39

12

100/0

5·4

Disability progression Cross-over design; reduction (EDSS); immunological in inflammatory activity, but no difference in atrophy rate and MRI GdE activity or EDSS worsening

Skurkovich et al;43 2001; n=45

1

3·0–7·0

≥12

39

11/3

100/0

4·2

Disability progression (EDSS)

Antibodies to interferon γ or TNFα

Reduced disease progression in patients with antibodies to interferon γ, but not TNFα (Table 3 continues on next page)

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Intervention

Trial duration (years)

Entry EDSS range

Pre-trial duration of progression (months)

Mean age of MS/ participants SPMS* duration (years) (years)

SPMS/ PPMS (%)

Mean EDSS

Primary outcome(s)

Comments

(Continued from previous page) Leary and Thompson;44 2003; n=50

Interferon beta-1a (30 or 60 μg/week)

2

2·0–7·0

≥24

45

8

0/100

5·2 (median)

Disability progression (EDSS)

Negative

Walker et al;45 2005; n=43

Pirfenidone (max dose 2400 mg/day)

1

5·0–8·0

≥24

49

13

100/0

6·2

SNRS

Significant improvement in SNRS

Warren et al;46 MBP8298 (500 mg every 2006; n=32 6 months)

2

3·0–7·5

··

45

14

69/31

6·5 (median)

Disability progression (EDSS); reduction in CSF anti-MBP levels

Negative overall outcome, but an effect was noted in HLA DR2/4 sub-group

Montanari et al (ASPIRE);47 2009; n=85‡

Azathioprine added to interferon beta-1b

2

··

··

··

100/0

··

MSFC

Negative, although low completion rate (45/85)

Montalban et al;48 2009; n=73

Interferon beta-1b (8 MU alternate days)

2

Kapoor et al;49 Lamotrigine (mean 2010; n=120 78 mg/day)

2

Karpha et al;50 2010; n=21

0·4

Recombinant human erythropoietin (30 000 IU per week for 12 weeks)

Barkhof et al;51 Ibudilast (30 or 60 mg/day) 1 2010; n=297

··

3·0–7·0

4–6·5

≥12

49

11

0/67§

5·2

Disability progression (EDSS)

Negative

≥24

51

20/8

100/0

6·0

Atrophy rate: partial (central) brain volume

Restricted tolerability; pseudoatrophy was reported; reduced deterioration of T25FW walking speed

··

Maximum walking distance; EDSS

Non-significant improvement in maximum walking distance; EDSS unchanged

··

··

··

··

0/100

<5·5

··

36

6

7/0†

3·2

MRI, GdE lesion load

Negative, but reduction of brain atrophy

≤6·5

··

44–46 (median)

8

21/0†

3·3

MRI, GdE lesion load

Negative

100/0

6·1

Visual pathway: structural and functional measures

Improvement in some visual parameters and EDSS

Vollmer et al;52 Anti-Il 12/23 antibody 2011; n=215 (200 mg weekly or alternate weeks)

0·5

Connick et al (MSCIMS);53 2012; n=10

Autologous mesenchymal stem cells

2

5·5–6·5

··

49

14

Vermersch et al;54 2012; n=35

Masitinib (3–6 mg/kg per day)

1

2·0–6·5

≥12

48

9

··

4·9

Safety; MSFC

Trend towards MSFC improvement

Arun et al;55 2013; n=14

Amiloride (10 mg/day)

1

54 (median)

6

0/100

4·8

Atrophy rate: whole brain and tissue integrity

Significant reduction in atrophy rate

··

··

Mostert et al;56 Fluoxetine (40 mg/day) 2013; n=42

2

3·5–6·5

≥24

49

14

69/31

5·8–6·0 (median)

Disability progression (EDSS, 9HPT, ambulation index)

Overall negative; however, positive trends for EDSS and 9HPT progression

Chataway et al (MS-STAT);57 2014; n=140

2

4·0–6·5

≥24

50

21/7

100/0

5·8

Atrophy rate: whole brain

Atrophy rate reduced from 0·6% to 0·3% (adjusted 43% reduction); reduced deterioration in EDSS and MSIS29, but not MSFC

Simvastatin (80 mg/day)

Trials not listed are those in Cochrane reviews.58,59 EDSS=Expanded Disability Status Scale. MS=multiple sclerosis. SPMS=secondary progressive multiple sclerosis. PPMS=primary progressive multiple sclerosis. TLI=total lymphoid irradiation. IV=intravenous. SC=subcutaneous. 9HPT=9 hole peg test. GdE=gadolinium enhancement. TNF=tumour necrosis factor. SNRS=Scripps Neurological Rating Scale. MBP=myelin basic protein. MSFC=Multiple Sclerosis Functional Composite. T25FW=timed 25 foot walk. IU=international units. MSIS29=Multiple Sclerosis Impact Scale-29. *SPMS duration not given in most cases.†Remainder had relapsing-remitting multiple sclerosis. ‡Abstract only. §Remainder had transitional multiple sclerosis.

Table 3: Phase 2 trials in progressive multiple sclerosis

measures in multiple sclerosis. For example, several other factors can affect the progression of multiple sclerosis, including smoking, obesity, and mental and physical disorders.63 Although smoking has long been known as a risk factor for the development of multiple sclerosis, only recently has it been identified as a modifier of disease course.64 Vitamin D is a possible modifier of disease course and might even modify 214

response to anti-inflammatory treatment.65 Progressive multiple sclerosis usually develops in patients of an older age, when comorbidities typical of ageing can confound clinical measures. Brain atrophy is used in phase 2 trials of progressive multiple sclerosis, yet brain atrophy is expected in healthy adults as they age.66 Comorbidities add complexity to the study of progressive multiple sclerosis by confounding the measures of www.thelancet.com/neurology Vol 14 February 2015

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Trial design Trial design needs to be refined for the development of successful treatments for progressive multiple sclerosis. In this section we consider potential barriers, appropriate intervention selection, and novel clinical trial methods. Almost all the trials listed in table 1 are classic head-to-head, placebo-controlled trials, mostly using a 1:1 ratio to randomly assign patients (with some exceptions15,20,23). Alternatives to 1:1 randomisation might be considered in view of the difficult balance between statistical complexity and the unmet demand for recruitment of patients with a deteriorating disease. Perhaps in the future, scope for multi-arm or adaptive trial designs should be emphasised. Trial duration is also of interest. A substantial difference in confirmed (3 month or 6 month) EDSS progression, compared with placebo, is more likely to be reported in phase 3 trials with long durations (eg, 36 months) than phase 3 trials of short durations. Some drugs already tested could have small significant effects, but a follow-up of up to 5 years might be needed to show efficacy during the trial.

Dronabinol Placebo HR 0·92 (95% CI 0·68–1·23)

0·7 Probability of EDSS score progression

disease, directly affecting the disease course, and potentially modifying the response to a treatment intervention. Such data should be collected and included as potential covariates in analysis plans.

0·6 0·5 0·4 0·3 0·2 0·1 0 0

Number at risk Dronabinol Placebo

180

360

329 (0) 164 (0)

314 (15) 162 (2)

540 720 900 Time to EDSS score progression (days) 248 (27) 129 (9)

216 (36) 119 (10)

193 (42) 108 (12)

1080

1260

1440

172 (46) 95 (13)

147 (52) 87 (14)

8 (176) 3 (88)

Figure 1: Probability of disability progression from the CUPID trial of dronabinol in progressive multiple sclerosis23 Kaplan-Meier estimates of the probability of EDSS score progression. EDSS=Expanded Disability Status Scale. HR=hazard ratio. Figure reproduced from Zajicek and colleagues,23 by permission of Elsevier.

drop-out rate meant that the ciclosporin study7 had to be re-designed when in progress, underlining the importance of feasibility testing before trial design.

Novel trial design Interventions Of the trials in progressive multiple sclerosis completed so far (table 1), a third have been beta-interferon trials, which were undertaken with the aim of replicating the success of these drugs in RRMS. Although some shortterm effects were reported at 3 months on confirmed disability and relapse rate, the overall effect on sustained progression after 6 months was neutral (figure 2).16,17,67,68 All the major immunosuppressive drugs (eg, mitoxantrone, methotrexate, cyclophosphamide) have been tested in progressive multiple sclerosis and these trials have collectively included more than 1000 patients. Although on occasion some therapeutic effect (subgroup or strong trend) has been reported, this was complicated by other factors—eg, by a mixed (relapsing) cohort, such as with mitoxantrone.15 In the largest trial with azathioprine (n=354),6 only about a third of the cohort had progressive multiple sclerosis (table 1). Although three smaller studies with azathioprine have included patients with progressive multiple sclerosis (n=186), the final conclusion with respect to an effect on progression is unclear.58 Likewise, small trials of cyclophosphamide have reported a similar absence of effect on progression.59 Novel approaches with the use of immunoglobulin, myelin basic protein, and synthetic cannabinoids have not been successful.18,22,23 In the various trials in SPMS, the retention of participants for primary outcome has mostly been good, typically at about 80–90%. Perhaps not unexpectedly, trials of drugs such as ciclosporin (in view of the sideeffects), have had quite high drop-out rates, with many patients not completing the final trial follow-up. A high www.thelancet.com/neurology Vol 14 February 2015

Efficient completion of trials in progressive multiple sclerosis is a top priority. Adaptive clinical trial design allows changes during the study with the goal of added efficiency by testing more treatments in a shorter time and with fewer participants than a standard design. However, adaptive designs might raise particular ethical challenges, such as the increased complexity of informed consent and patient burden,69 while scientific issues, such as maintenance of investigator masking and selection of outcomes, can be more arduous.70 In a design of adaptive randomisation, the probability of treatment assignment can vary on the basis of the continuous analysis of data. A biomarker-adaptive design could be useful to select populations who are most likely to benefit from treatments and to select the biomarkers that will probably show an effect during a clinical trial.71 Multi-arm trials can be done with a so-called “drop the loser” design, in which treatment can be ended early on the basis of interim efficacy analysis, thus minimising patient exposure to a potentially inferior treatment and focusing resources on potentially viable treatments.72 Adaptive group sequential design is a refinement of traditional group sequential design, with the flexibility not only to halt the trial, but also to change outcomes, sample size, and even the study hypothesis.73 Seamless phase 2 or phase 3 studies are adaptive designs that are used to answer questions about clinical development (phase 2 and 3) in a single trial and have possible application in progressive multiple sclerosis.74,75 A first stage would include testing of several potential treatments by use of biomarker outcomes, and a second stage would 215

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67

Interferon

Placebo

n

N

n

N

RR (95% Cl)

European SG (1998)

147

360

174

358

0·84 (0·71–0·99)

Nordic SG (2004)16

77

186

68

183

1·11 (0·86–1·44)

North American SG (2004)17

227

631

106

308

1·05 (0·87–1·26)

Total

451 1177

348

849

0·98 (0·82–1·16)

Heterogeneity: τ2=0·01; χ2=4·68; df=2 (p=0·10); I2=57%

0·5

Test for overall effect: Z=0·26 (p=0·79)

0·7 Interferon better

1

1·5 2 Interferon worse

Figure 2: Beta-interferon studies in secondary progressive multiple sclerosis Patients with a sustained (6 months) Expanded Disability Status Scale increase during the first 3 years of treatment. The figure shows the overall neutral effect of beta interferon on disability progression in secondary progressive multiple sclerosis trials. RR=risk ratio. n=number of patients with an outcome. N=number of patients randomly assigned. SG=study group. Figure reproduced from Mantia and colleagues,68 by permission of the BMJ Publishing Group Ltd.

Several international efforts are underway to accelerate development of treatments for multiple sclerosis. The Progressive MS Alliance is an international alliance of multiple sclerosis advocacy organisations using research strategies to connect partners in several scientific disciplines and fund innovative and collaborative research worldwide.76 The Multiple Sclerosis Outcome Assessments Consortium is a collaboration between academics, industry, and regulators that aims to develop and validate a sensitive clinical measure of disease progression through pooling of clinical trial data.77 This type of collaboration has been effective in the development of clinically sensitive measures for treatment studies in other diseases, such as rheumatoid arthritis. With the involvement of regulators in the development process, the Multiple Sclerosis Outcome Assessments Consortium can help to ensure a regulatorycompliant tool at its conclusion. The outputs of these efforts are hoped to accelerate the clinical trial process through efficient and effective phase 2 and 3 trials.

Future trials

MSFC

Table 2 lists many of the phase 2 and 3 trials that are in progress and their projected reporting timescales. A number of lessons have been learnt from modern trial design in the past 25 years and new trials compare favourably with previous efforts in many ways: greater number of participants; new and, hopefully, more relevant phase 2 outcomes, such as brain atrophy; more realistic durations of phase 3 trials; and longer pre-trial progression entries (≥24 months).

The MSFC was designed as a quantitative, multidimensional composite technique to measure disability in trials of multiple sclerosis.88 The MSFC consists of the measurement of walking speed (timed 25-foot walk), arm function (9-hole peg test), and cognition (Paced Auditory Serial Addition Test [PASAT-3]). Results from these three domains are then transformed to Z scores based on a reference population and then averaged to form a composite score.89 The MSFC has advantages including being objectively obtained, has good inter-rater reliability, and can be administered by a trained technician.83,90 The MSFC has good concurrent and predictive validity with the EDSS,91,92 patient-reported outcomes,91,93–95 and MRI

Clinical trial conduct

For more about the Multiple Sclerosis Outcome Assessments Consortium see http://c-path. org/programs/msoac/

For more about the MSFC see http://www.mstrust.org.uk/ competencies/downloads/ MSFC.pdf

Outcome measures Development of treatments for RRMS has been accelerated by the use of effective imaging outcomes in phase 2 studies 216

Clinical outcomes EDSS The EDSS was first developed by Kurtzke79 as a scale to quantify disability in multiple sclerosis and is based on findings from clinical examinations and functional status. The EDSS has many advantages over other clinical outcome measures, including that it is widely accepted and understood by the neurology and regulatory community, spans several domains of neurological function, and is grounded in symptoms relevant to patients.80 However, this is an ordinal scale, so variable differences between contiguous scores make analysis difficult. Inter-rater variability can be high, particularly in ranges relevant to trials for progressive multiple sclerosis.81–84 The EDSS relies heavily on lower extremity function, with cognition and upper extremity function having a smaller contribution.85,86 Use of the EDSS to measure progression of disability has inherent problems. Disability progression can be calculated in several ways using the EDSS and have been used in trials, with the most common being the time to worsening in EDSS (normally 0·5 or 1 point sustained for 3 months or 6 months). However, patients tend to plateau at specific EDSS scores (ie, 6·0) and can remain at this score for a substantial amount of time despite progressively worsening function. Because of the unequal distribution between EDSS steps, a change will be dependent not only on actual disease progression, but also on EDSS entry level.87 Although it is a well recognised scale for neurologists, the EDSS is severely restricted as an outcome measure for trials in progressive multiple sclerosis.

take the most promising treatment forward on the basis of clinical outcomes.

For the Progressive MS Alliance see http://www. progressivemsalliance.org

and clinical outcomes in phase 3 studies.78 Unfortunately, similar outcomes do not exist in progressive multiple sclerosis, particularly for phase 2 studies. Several factors should be considered in the selection of an outcome measure: it should be easily reproducible, sensitive to change in a short time, and be meaningful to patients or be associated with meaningful outcomes in time. Advanced methods for clinical trial design should allow efficient undertaking of clinical trials, testing of a large number of drugs in short time periods, and selection of only those drugs with the greatest likelihood of success.

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measures.96,97 Furthermore, the MSFC has been successfully used to show treatment effects in clinical trials of both RRMS and progressive multiple sclerosis.95,98–100 However, the MSFC has not been accepted as a primary outcome for multiple sclerosis trials by regulatory agencies. A major concern with this method is the use of Z scores and the unknown clinical meaning of a change in the Z score with respect to a patient’s actual function in the three domains tested. Additionally, comparisons are difficult between Z scores across studies. The differential weighting of subscores based on different reference populations might also restrict the sensitivity and reliability of this measure.101 Dichotomisation of the MSFC by use of a cutoff of 15% or 20% change for the timed 25-foot walk and 9-hole peg test, sustained for either 3 months or 6 months,102,103 has been used in trials, but the optimum meaningful change interval is likely to vary across the ranges of disability. Although the use of a change score has been advocated, this measure might be less sensitive than the EDSS, especially in high ranges of disability.87 Additional potential limitations of the MSFC include the restriction to only three spheres of function, and floor and ceiling effects—eg, the PASAT-3, which has a quick learning effect followed by a ceiling effect, has been criticised by clinical trialists because of practise effects and patient frustration with the test. The Symbol Digit Modalities Test (SDMT) has been suggested as a replacement.104,105 Recommendations have called for the inclusion of lowcontrast letter acuity to assess visual function.105,106

Cognitive outcomes Despite the high burden of cognitive impairment in progressive multiple sclerosis,107 measurement of cognitive deficits has not been adequate in clinical trials. Several quicker tests have been developed to replace the slower, gold standard of dedicated neuropsychological testing. The Brief Repeatable Battery of Neurospychological Tests (BRBN)108 incorporates measurements of several cognitive domains and includes the selective reminding test,109 the spatial recall test,110 PASAT,111 SDMT,112 and the Controlled Oral Word Association Test.113 For the BRBN, staff need to be trained and administration of the test can take as long as 90 min. The SDMT is one of the most sensitive tests in cognitive batteries and has been proposed to be included in the MSFC,114 in addition to a metric for clinical trial outcomes.115 The SDMT can be completed in less than 3 min, needs little training, is highly reproducible, and correlates with results from the BRBN.116 An international effort has proposed the use of a simplified cognitive battery for multiple sclerosis that will be validated in several languages.117

Patient-reported outcomes Patient-reported outcomes are of increasing importance in trials of progressive multiple sclerosis. Several www.thelancet.com/neurology Vol 14 February 2015

measures of health-related quality-of-life have been used, including the European Quality of Life 5D118 and the Short Form Health Survey,119 which have both been validated in relation to EDSS.120 The most frequently used global patient-reported outcome in multiple sclerosis is the Multiple Sclerosis Impact Scale 29,121 which has been correlated with clinical and imaging metrics specifically in progressive forms of the disease.122 More specific patient-reported outcomes, such as the Multiple Sclerosis Performance Scale, designed to capture fatigue, vision, cognition, gait, sphincter function, and pain have been developed for multiple sclerosis. Patient-reported outcomes can be used as a basis to validate MRI or clinical metrics. Increased use of patient-reported outcomes in trials of progressive multiple sclerosis will provide a rich dataset for the validation of new metrics and will help to satisfy regulators’ requirements that treatments show relevant benefit for patients.

Imaging outcomes Clinical measures are usually slow to change and often need a large number of patients and a long follow-up to show effects. Biomarkers that enable quick screening of compounds are needed in phase 2 trials of progressive multiple sclerosis. Sensitive imaging techniques will decrease study duration and the number of participants needed.

Whole brain atrophy Quantification of brain atrophy has been extensively used in trials of RRMS. Atrophy is a logical outcome measure for phase 2 trials of progressive multiple sclerosis and might be a sensitive biomarker for clinical progression of this disease because the accumulation of disability in multiple sclerosis is thought to be related to continuing neuroaxonal loss.123,124 Several methods exist to quantify brain atrophy by use of highly automated approaches. Registration-based techniques include structural image evaluation using normalisation of atrophy (SIENA) and boundary shift integral (BSI), and statistical parametric mapping (SPM). Segmentation-based techniques include brain parenchymal fraction (BPF) and structural image evaluation using normalisation of atrophy cross sectional (x-sectional; SIENAX). Measures of whole brain atrophy have been validated with the EDSS and the temporal changes of brain atrophy have been well established.125,126 A comparison between sample size estimates for trials of SPMS127 showed that SIENA was more robust than SIENAX and central cerebral volume (CCV), with 80% power to report a 50% treatment effect with as few as 27 patients per group over 3 years with semi-annual MRI acquisitions. A 50% effect size might be an overly optimistic goal for some treatments, and sample sizes for a slight slowing of progression of brain atrophy would need to be substantially larger. Many anti-inflammatory treatments for multiple sclerosis cause a loss of brain volume in the first year of treatment, which is called 217

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pseudoatrophy.49,128 Although its implication in progressive multiple sclerosis is not fully understood, investigators should consider the possibility of pseudoatrophy when planning a study for this disease and should select the timing of outcomes accordingly.

Grey matter atrophy

For more about the FreeSurfer software see http://freesurfer. net/

Extensive demyelination of grey matter has been reported in patients with progressive multiple sclerosis and the cortex is thought to be a primary site of neurodegeneration.129–132 Cortical atrophy is associated with both disability and cognitive function in cross-sectional and longitudinal studies.132–134 Grey matter atrophy is more useful than white matter atrophy in the prediction of clinical disability and is, therefore, regarded as a good potential outcome for trials of progressive multiple sclerosis.135 Cerebral cortex thickness is an appealing measure of cortical atrophy, having correlations with disability independent of focal white matter lesions.136 FreeSurfer is the most widely available automated technique for assessment of cortical thickness.137,138 An important limitation of FreeSurfer is the misclassification of lesional tissue as cortex. Although the use of lesion masks can help, this process needs manual input and thus is time consuming. Several possible semiautomated longitudinal methods have been developed to measure cortical atrophy.139,140 Sample size estimates of cortical thickness showed as few as 26 participants per group could be used to show a 50% effect size over 3 years.140

Advanced brain MRI techniques Several new outcomes have been considered for clinical trials of progressive multiple sclerosis. Techniques that measure the integrity of brain tissue might be more sensitive than measures of volume change. Diffusion tensor imaging (DTI) estimates the three-dimensional diffusion of water in brain tissue and has been explored as an outcome in multiple sclerosis.141,142 DTI has the advantage of characterising pathological associations and specific anatomical and functional tracts.143 Magnetisation transfer ratio (MTR)-MRI has been proposed as a marker of brain myelin content, including in the cerebral cortex.144,145 Cerebral cortex and grey matter that seems healthy on MTR strongly correlates with measures of disability, such as the MSFC, and can show treatment effects.146,147 Identification of cortical lesions by use of high-field magnets and special imaging sequences, such as double inversion recovery, provide the possibility for cortical lesions to be used as potential outcome metrics for progressive multiple sclerosis.148 However, only 10–20% of cortical lesions are detected even with the most sensitive techniques.149 Multicentre implementation is an important challenge for DTI, MTR, and cortical lesions, although some progress has been made.150 218

Spinal cord imaging The accrual of disability in progressive multiple sclerosis is in part related to the accumulation of injury and neurodegeneration in the spinal cord.151 Although previously ignored, the spinal cord might have a growing role in progressive multiple sclerosis trials. Advanced spinal cord imaging modalities, including DTI and MTR, might also be useful, although standardised implementation in a multicentre trial is still challenging because of differences in MRI acquisition protocols, MRI software versions, and magnet platforms.152,153

Optical coherence tomography Optical coherence tomography is a non-invasive, quantitative, and low-cost imaging technique that provides high-resolution images of the retina.154 In multiple sclerosis, this technique has been used to quantify the retinal nerve fibre layer and ganglion cell layer. The retinal nerve fibre layer is correlated with visual function, pathology, brain atrophy, and overall disability in multiple sclerosis.155,156 Ganglion cell layer thickness correlates with EDSS.157 Macular volume has also been proposed as a measure of neuronal loss.158 Progressive thinning of the retinal nerve fibre layer has been noted despite few or no inflammatory episodes, making this measure a compelling model for neurodegeneration.159

CSF biomarkers The search for biomarkers in all forms of multiple sclerosis has been a challenging and, at times, a disappointing endeavour. The case is no different for progressive multiple sclerosis, in which the challenge is to find CSF biomarkers that coincide with the continuing neurodegenerative process and then to validate these biomarkers together with clinical and MRI data.160 Clinical trials are an ideal setting to validate a CSF biomarker, including axonal and glial biomarkers. Incorporation of CSF testing and banking in all studies of progressive multiple sclerosis is an ongoing priority. Neurofilament (Nf) chains have received much attention as potential measures of axonal injury. Heavy (NfH) and light chain (NfL) neurofilaments are indicative of continuous tissue destruction associated with gadolinium enhancing lesions in RRMS.161 NfL measurements are raised in progressive multiple sclerosis162 and correlate with EDSS scores.163 An ELISA-based technique for measurement of NfL has been developed and validated.164 NfL concentrations have shown sensitivity to treatment effects in RRMS.164,165 NfL is being used in several trials of progressive multiple sclerosis in Europe (NCT01910259) and the USA (NCT01982942), and correlations with detailed clinical and MRI data will be available in the next few years. Tubulin and actin are also axonal markers that correlate with the EDSS and might be viable biomarkers for progressive multiple sclerosis in the future.166 Glial fibrillary acidic protein (GFAP) concentration is raised in SPMS and associated with EDSS scores.167 www.thelancet.com/neurology Vol 14 February 2015

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GFAP concentration increases with time in SPMS and is predictive of future disability,168 making it an appealing biomarker outcome for trials in progressive forms of multiple sclerosis. S100B is a marker of astrocytic activation and, in addition to GFAP, is present at increased concentrations at post mortem in the grey matter of patients with multiple sclerosis.167

Conclusions and future directions Identification of effective treatments for progressive forms of multiple sclerosis continues to be the major unmet need for this disease. The studies presented in table 1 show the failure of classic immunosuppressants and antirelapse disease-modifying treatments; new molecules and targets are clearly needed that have high predicted chances of success. In parallel, to maximise the return, a more refined and efficient approach to testing of these possible treatments is essential. From the trials completed until now and from observational studies, several lessons can be learned and applied to future trials of progressive multiple sclerosis (panel). In our view, interventions selected for phase 2 trials should have shown evidence of therapeutic effect in experimental models of the disease and should act on known pathways relevant in terms of disease mechanisms, although this is constrained by the absence of optimum animal models for progressive multiple sclerosis.169 Treatments should be further selected on the basis of an adequate risk–benefit profile in phase 1 studies. The so-called repurposing of drugs for progressive multiple sclerosis should be considered. Phase 3 studies in progressive multiple sclerosis should be done after phase 2 trials have provided a clear proof of concept. Novel imaging methods should be used not only to understand whether an intervention is working, but also to establish how it has an effect on the brain or spinal cord. This approach should be supplemented by other modalities, such as CSF analysis. Participants in trials of progressive multiple sclerosis should be selected to ensure that they are actively progressing and have minimum or no inflammatory activity. Allowing patients with SPMS to continue to receive standard disease-modifying treatments, according to local practice if these are already in use before the study begins, seems appropriate, but concurrent immunosuppressants should be avoided. Phase 3 trials should last for at least 36 months, with a realistic calculation of the placebo progression rates. Investigations should be designed to detect differences in 6-month confirmed progression of the primary outcome as a minimum. Clinical measures apart from the EDSS are urgently needed, including cognitive testing and patient-reported outcomes. Innovative (eg, adaptive and multi-arm) trial designs that minimise the number and time of patient exposures to futile therapies should be encouraged.170 As many compounds enter into clinical trials (table 2 lists almost 20 studies with 5000 patients expected to report in the next 5 years alone) and knowledge about the www.thelancet.com/neurology Vol 14 February 2015

Panel: Suggested lessons for the future* Intervention selection • Treatment with evidence in animal models or efficacy in known pathways • For phase 3 studies, mandatory completion of phase 2 studies in the appropriate target group • Adequate risk to benefit profile in phase 1 or 2 studies Study participants • Secondary progressive multiple sclerosis pre-trial progression of 24 months or more† • Secondary progressive multiple sclerosis duration of 5 years or more† • Pre-trial, less than 1 relapse in the past 24 months† • Entry Expanded Disability Status Scale score of 3·0 or 4·0–6·5 • On or off disease-modifying treatment • Not taken immunosuppressants for 12 months or more Trial design • Phase 3 trial duration of 36 months or more • Anticipated 3-year placebo progression proportion of 40–50% • Phase 2b trial size of more than 140 participants; phase 3 trial size of more than 750 participants (two arms) • Confirmation of progression at 6 months minimum • Consideration of a pure primary progressive or secondary progressive multiple sclerosis cohort, or a mixed cohort Outcome measures • Conventional and advanced MRI outcomes • Optical coherence tomography • Clinical measures in addition to the Expanded Disability Status Scale (eg, Multiple Sclerosis Functional Composite+) • Patient reported outcomes • Cognitive outcomes CSF biomarkers • Mandatory or optional inclusion • Serial CSF acquisition (every 12 months) • CSF levels of neurofilament light chain *Recommendations based on clinical trial experience to date; although studies have been mostly negative these recommendations are formulated to maximise the ability to detect changes in a progressive multiple sclerosis population. †Recommendations apply to secondary progressive multiple sclerosis and are intended to recruit patients with more purely progressive courses and fewer relapses or inflammation.

Search strategy and selection criteria We searched for articles on the databases Ovid Medline(R) (In-Process & Other Non-Indexed Citations) and Ovid Medline(R) (published between Jan 1, 1946, and April 5, 2014), Ovid Embase (published between Jan 1, 1974, and April 5, 2014), and Cochrane Central Register of Controlled Trials (CENTRAL; published between its start date [1948] and April 5, 2014), and for clinical trials on PubMed (published between March 5, 2014 and April 5, 2014). We searched for the terms “randomized controlled trial“, ”controlled clinical trial” (single, double, triple randomization, blinded or masked) in combination with “multiple sclerosis”, “chronic progressive” (SPMS or SP-MS or PPMS or PP-MS), including only human and non-retracted publications. We searched for reports of randomised controlled trials and controlled clinical trials using study design search filters combined with subject terms for Medline and Embase. For CENTRAL, subject terms were adapted from the Medline search. No language restrictions were applied.

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disease improves, the prospects of achieving true disease modification in progressive multiple sclerosis are greater than ever.

13

Contributors All authors did the literature search, drafting, and editing of this Series paper.

14

Declaration of interests DO reports personal fees from Acorda Therapeutics, Biogen Idec, Alkermes, Genzyme, Malinckrodt, and Novartis, for work unrelated to the submitted paper. RJF reports personal fees from Allozyne, Avanir, Questcor, Teva, and Xenoport. RJF receives personal fees and clinical trial contracts to his institution from Biogen-Idec, and grants, personal fees, and clinical trial contracts to his institution from Novartis, for work unrelated to the submitted paper; RJF is PI of the SPRINT-MS trial, and serves on the steering committee for the BAF312 in SPMS trial. JC reports grants from the Efficacy and Mechanism Evaluation Board (EME), Multiple Sclerosis Trials Collaboration (MSTC), Moulton Foundation (Charity), and Berkeley Foundation (Charity). JC is the CI of the MS-STAT and MS-SMART trials. JC was the local PI of the trials ASCEND (Biogen) and INFORMS (Novartis) during the completion of this Series paper. JC received a grant from NOVARTIS outside the submitted work. JC has taken part in the trials in progressive multiple sclerosis of MAESTRO, CUPID, Lamotrigine, INFORMS, and ASCEND. Acknowledgments DO received grants from National Institutes of Health (NIH; CTSC KL2TR0000440) during the completion of this Series paper. RJF reports grants from National Institute of Neurological Disorders and Stroke and NIH during the completion of this Series paper. JC receives support from the National Institute of Health Research (NIHR), University College London Hospitals (UCLH)/UCL Biomedical Research Centre (BRC) funding scheme. References 1 Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83: 278–86. 2 Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 2008; 31: 247–69. 3 Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 2015; 14: 183–93. 4 Miller AE, Rhoades RW. Treatment of relapsing-remitting multiple sclerosis: current approaches and unmet needs. Curr Opin Neurol 2012; 25 (suppl): S4–S10. 5 Wiendl H, Hohlfeld R. Multiple sclerosis therapeutics: unexpected outcomes clouding undisputed successes. Neurology 2009; 72: 1008–15. 6 British And Dutch Multiple Sclerosis Azathioprine Trial Group. Double-masked trial of azathioprine in multiple sclerosis. Lancet 1988; 332: 179–83. 7 The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 1990; 27: 591–605. 8 The Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 1991; 337: 441–46. 9 Noseworthy JH, O’Brien P, Erickson BJ, et al. The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis. Neurology 1998; 51: 1342–52. 10 Kappos L, European Study Group on Interferon beta-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352: 1491–97. 11 Noseworthy JH, Wolinsky JS, Lublin FD, et al. Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators. Neurology 2000; 54: 1726–33. 12 Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI study group. Neurology 2000; 54: 1145–55.

220

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31 32 33

34

Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 2001; 56: 1496–04. Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002; 59: 679–87. Hartung H-P, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360: 2018–25. Andersen O, Elovaara I, Farkkila M, et al. Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2004; 75: 706–10. Panitch H, Miller A, Paty D, Weinshenker B, North American Study Group on Interferon beta-1b in Secondary Progressive MS. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004; 63: 1788–95 Hommes OR, Sørensen PS, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 2004; 364: 1149–56. Pohlau D, Przuntek H, Sailer M, et al. Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study. Mult Scler 2007; 13: 1107–17. Wolinsky JS, Narayana PA, O’Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007; 61: 14–24. Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009; 66: 460–71. Freedman MS, Bar-Or A, Oger J, et al. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS. Neurology 2011; 77: 1551–60. Zajicek J, Ball S, Wright D, et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol 2013; 12: 857–65. Brochet B, Deloire M, Perez P, et al. Double-blind, randomized, controlled study of cyclophosphamide versus methylprednisolone in secondary progressive multiple sclerosis: PROMESS study. Multiple sclerosis (Houndmills, Basingstoke, England) 2013; 19 (suppl 1): 51–52. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. Trials 2010; 11: 32. Khatri BO, McQuillen MP, Harrington GJ, Schmoll D, Hoffmann RG. Chronic progressive multiple sclerosis: Double-blind controlled study of plasmapheresis in patients taking immunosuppressive drugs. Neurology 1985; 35: 312–19. Gordon PA, Carroll DJ, Etches WS, et al. A double-blind controlled pilot study of plasma exchange versus sham apheresis in chronic progressive multiple sclerosis. Can J Neurol Sci 1985; 12: 39–44. Cook SD, Devereux C, Troiano R, et al. Effect of total lymphoid irradiation in chronic progressive multiple sclerosis. Lancet 1986; 1: 1405–09. Kastrukoff LF, Oger JJ, Hashimoto SA, et al. Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. I. Clinical and MRI evaluation. Neurology 1990; 40: 479–86. Bornstein MB, Miller A, Slagle S, et al. A placebo-controlled, double-blind, randomized, two-center, pilot trial of cop 1 in chronic progressive multiple sclerosis. Neurology 1991; 41: 533–39. Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994; 344: 9–13. Wiles CM, Omar L, Swan AV, et al. Total lymphoid irradiation in multiple sclerosis. J Neurol Neurosurg Psychiatry 1994; 57: 154–63. Milligan NM, Miller DH, Compston DA. A placebo-controlled trial of isoprinosine in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 1994; 57: 164–68. Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al. Low-dose (7·5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995; 37: 30–40.

www.thelancet.com/neurology Vol 14 February 2015

Series

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51 52

53

Cazzato G, Mesiano T, Antonello R, et al. Double-blind, placebo-controlled, randomized, crossover trial of high-dose methylprednisolone in patients with chronic progressive form of multiple sclerosis. Eur Neurol 1995; 35: 193–98. Karussis DM, Meiner Z, Lehmann D, et al. Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation. Neurology 1996; 47: 341–46. van Oosten BW, Lai M, Hodgkinson S, et al. Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 1997; 49: 351–57. Cook SD, Devereux C, Troiano R, et al. Modified total lymphoid irradiation and low dose corticosteroids in progressive multiple sclerosis. J Neurol Sci 1997; 152: 172–81. Bosco A, Cazzato G. A randomized, placebo-controlled, double-blind study on the efficacy of idebenone administered to patients suffering from chronic-progressive form of multiple sclerosis and are submitted to recurrent treatment with high dose of methylprednisolone. Nuova Rivista di Neurologia 1997; 7: 90–94. Goodkin DE, Kinkel RP, Weinstock-Guttman B, et al. A phase II study of i.v. methylprednisolone in secondary-progressive multiple sclerosis. Neurology 1998; 51: 239–45. Paolillo A, Coles AJ, Molyneux PD, et al. Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody campath 1H. Neurology 1999; 53: 751–57. Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006; 253: 98–108. Skurkovich S, Boiko A, Beliaeva I, et al. Randomized study of antibodies to IFN-gamma and TNF-alpha in secondary progressive multiple sclerosis. Mult Scler 2001; 7: 277–84. Leary SM, Miller DH, Stevenson VL, Brex PA, Chard DT, Thompson AJ. Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 2003; 60: 44–51. Walker JE, Giri SN, Margolin SB. A double-blind, randomized, controlled study of oral pirfenidone for treatment of secondary progressive multiple sclerosis. Mult Scler 2005; 11: 149–58. Warren KG, Catz I, Ferenczi LZ, Krantz MJ. Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment. Eur J Neurol 2006; 13: 887–95. Montanari E, Manneschi L, Pesci I, et al. ASPIRE (azathioprine secondary progressive interferon treated patients randomised evaluation) study: 2-year double-blind and 1-year open, randomised, multicentre, pilot study. Multiple sclerosis functional composite (MSFC) and magnetic resonance data. Mult Scler (Houndmills, Basingstoke, England) 2009; 250 (suppl): 822. Montalban X, Sastre-Garriga J, Tintore M, et al. A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis. Mult Scler 2009; 15: 1195–205. Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, doubleblind, placebo-controlled, parallel-group trial. Lancet Neurol 2010; 9: 681–88. Karpha I, Ramtahal J, Boggild M, Evans F. PAW25 a single-centre, pilot, randomised controlled trial of recombinant human erythropoietin in primary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2010; 81: e30. Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology 2010; 74: 1033–40. Vollmer TL, Wynn DR, Alam MS, Valdes J. A phase 2, 24-week, randomized, placebo-controlled, double-blind study examining the efficacy and safety of an anti-interleukin-12 and -23 monoclonal antibody in patients with relapsing-remitting or secondary progressive multiple sclerosis. Mult Scler 2011; 17: 181–91. Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 2012; 11: 150–56.

www.thelancet.com/neurology Vol 14 February 2015

54

55

56

57

58 59

60

61

62

63

64

65

66 67

68

69

70 71

72 73

74

75

76

77

Vermersch P, Benrabah R, Schmidt N, et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol 2012; 12: 36. Arun T, Tomassini V, Sbardella E, et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain 2013; 136: 106–15. Mostert J, Heersema T, Mahajan M, Van Der Grond J, Van Buchem MA, De Keyser J. The effect of fluoxetine on progression in progressive multiple sclerosis: a double-blind, randomized, placebo-controlled trial. ISRN Neurol 2013; 2013: 370943. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev 2007; 4: CD003982. La Mantia L, Milanese C, Mascoli N, D’Amico R, Weinstock-Guttman B. Cyclophosphamide for multiple sclerosis. Cochrane Database Syst Rev 2007; 1: CD002819. Reston JT, Uhl S, Treadwell JR, Nash RA, Schoelles K. Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult Scler 2011; 17: 204–13. Spelman T, Trojano M, Duquette P, et al. Defining secondary progressive multiple sclerosis: is it possible to diagnose early? Mult Scler 2013; 19: 38. Miller DH, Weinshenker BG, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler 2008; 14: 1157–74. Marrie R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity, socioeconomic status and multiple sclerosis. Mult Scler 2008; 14: 1091–98. Manouchehrinia A, Tench CR, Maxted J, Bibani RH, Britton J, Constantinescu CS. Tobacco smoking and disability progression in multiple sclerosis: United kingdom cohort study. Brain 2013; 136: 2298–04. Ascherio A, Munger KL, White R, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol 2014; 71: 306–14. Fjell AM, Walhovd KB, Fennema-Notestine C, et al. One-year brain atrophy evident in healthy aging. J Neurosci 2009; 29: 15223–31. Kappos L, Polman C, Pozzilli C, Thompson A, Beckmann K, Dahlke F, European Study Group in Interferon beta-1b in Secondary-Progressive MS. Final analysis of the European multicenter trial on IFNbeta-1b in secondary-progressive MS. Neurology 2001; 57: 1969–75. Mantia LL, Vacchi L, Rovaris M, et al. Interferon β for secondary progressive multiple sclerosis: a systematic review. J Neurol Neurosurg Psychiatry 2013; 84: 420–26. van der Graaf R, Roes KC, van Delden JJ. Adaptive trials in clinical research: scientific and ethical issues to consider. JAMA 2012; 307: 2379–80. Chow SC, Chang M. Adaptive design methods in clinical trials—a review. Orphanet J Rare Dis 2008; 3: 11. Wason J, Marshall A, Dunn J, Stein RC, Stallard N. Adaptive designs for clinical trials assessing biomarker-guided treatment strategies. Br J Cancer 2014; 110: 1950–57. Thall PF, Millikan RE, Sung HG. Evaluating multiple treatment courses in clinical trials. Stat Med 2000; 19: 1011–28. Muller HH, Schafer H. Adaptive group sequential designs for clinical trials: combining the advantages of adaptive and of classical group sequential approaches. Biometrics 2001; 57: 886–91. Friede T, Parsons N, Stallard N, et al. Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis. Stat Med 2011; 30: 1528–40. Chataway J, Nicholas R, Todd S, et al. A novel adaptive design strategy increases the efficiency of clinical trials in secondary progressive multiple sclerosis. Mult Scler 2011; 17: 81–88. MS International Federation. Progressive MS alliance, 2014. http:// www.msif.org/about-us/global-research-collaboration/progressivems/progressive-ms-alliance/ (accessed April 25, 2014). Rudick RA, Larocca N, Hudson LD, MSOAC. Multiple sclerosis outcome assessments consortium: genesis and initial project plan. Mult Scler 2014; 20: 12–17.

221

Series

78

79

80

81

82

83

84

85 86

87

88

89

90

91

92

93

94

95

96

97

98 99

222

Barkhof F, Simon JH, Fazekas F, et al. MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials. Nat Rev Neurol 2011; 8: 13–21. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33: 1444–52. Hobart J, Freeman J, Thompson A. Kurtzke scales revisited: the application of psychometric methods to clinical intuition. Brain 2000; 123: 1027–40. Noseworthy JH, Vandervoort MK, Wong CJ, Ebers GC. Interrater variability with the expanded disability status scale (EDSS) and functional systems (FS) in a multiple sclerosis clinical trial. The Canadian Cooperation MS Study Group. Neurology 1990; 40: 971–75. Whitaker JN, McFarland HF, Rudge P, Reingold SC. Outcomes assessment in multiple sclerosis clinical trials: a critical analysis. Mult Scler 1995; 1: 37–47. Hobart J, Kalkers N, Barkhof F, Uitdehaag B, Polman C, Thompson A. Outcome measures for multiple sclerosis clinical trials: relative measurement precision of the expanded disability status scale and multiple sclerosis functional composite. Mult Scler 2004; 10: 41–46. Verdier-Taillefer MH, Zuber M, Lyon-Caen O, et al. Observer disagreement in rating neurologic impairment in multiple sclerosis: facts and consequences. Eur Neurol 1991; 31: 117–19. Lamers I, Feys P. Assessing upper limb function in multiple sclerosis. Mult Scler 2014; 20: 775–84. Brissart H, Sauvee M, Latarche C, Dillier C, Debouverie M. Integration of cognitive impairment in the expanded disability status scale of 215 patients with multiple sclerosis. Eur Neurol 2010; 64: 345–50. Kragt JJ, Thompson AJ, Montalban X, et al. Responsiveness and predictive value of EDSS and MSFC in primary progressive MS. Neurology 2008; 70: 1084–91. Rudick R, Antel J, Confavreux C, et al. Recommendations from the national multiple sclerosis society clinical outcomes assessment task force. Ann Neurol 1997; 42: 379–82. Cutter GR, Baier ML, Rudick RA, et al. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999; 122: 871–82. Rudick RA, Cutter G, Reingold S. The multiple sclerosis functional composite: a new clinical outcome measure for multiple sderosis trials. Mult Scler 2002; 8: 359–65. Miller DM, Rudick RA, Cutter G, Baier M, Fischer JS. Clinical significance of the multiple sclerosis functional composite: relationship to patient-reported quality of life. Arch Neurol 2000; 57: 1319–24. Rudick RA, Polman CH, Cohen JA, et al. Assessing disability progression with the multiple sclerosis functional composite. Mult Scler 2009; 15: 984–97. Costelloe L, O’Rourke K, McGuigan C, Walsh C, Tubridy N, Hutchinson M. The longitudinal relationship between the patient-reported multiple sclerosis impact scale and the clinician-assessed multiple sclerosis functional composite. Mult Scler 2008; 14: 255–58. Ozakbas S, Cagiran I, Ormeci B, Idiman E. Correlations between multiple sclerosis functional composite, expanded disability status scale and health-related quality of life during and after treatment of relapses in patients with multiple sclerosis. J Neurol Sci 2004; 218: 3–07. Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002; 59: 679–87. Kalkers NF, Bergers L, de Groot V, et al. Concurrent validity of the MS functional composite using MRI as a biological disease marker. Neurology 2001; 56: 215–19. Fisher E, Rudick RA, Cutter G, et al. Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients. Mult Scler 2000; 6: 373–77. Cadavid D, Kim S, Peng B, et al. Clinical consequences of MRI activity in treated multiple sclerosis. Mult Scler 2011; 17: 1113–21. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362: 387–401.

100 Balcer LJ, O’Connor PW, Havrdova E. The effects of natalizumab on disability progression as measured by the multiple sclerosis functional composite (MSFC) and visual function in patients with relapsing MS. 18th World Congress of Neurology; Sydney, Australia; Nov 9, 2005. 101 Fox RJ, Lee JC, Rudick RA. Optimal reference population for the multiple sclerosis functional composite. Mult Scler 2007; 13: 909–14. 102 Kragt JJ, van der Linden FA, Nielsen JM, Uitdehaag BM, Polman CH. Clinical impact of 20% worsening on timed 25-foot walk and 9-hole peg test in multiple sclerosis. Mult Scler 2006; 12: 594–98. 103 Rudick RA, Polman CH, Cohen JA, et al. Assessing disability progression with the multiple sclerosis functional composite. Mult Scler 2009; 15: 984–97. 104 Balcer LJ, Baier ML, Cohen JA, et al. Contrast letter acuity as a visual component for the multiple sclerosis functional composite. Neurology 2003; 61: 1367–73. 105 Ontaneda D, Larocca N, Coetzee T, Rudick R, NMSS MSFC Task Force. Revisiting the multiple sclerosis functional composite: proceedings from the national multiple sclerosis society (NMSS) task force on clinical disability measures. Mult Scler 2012; 18: 1074–80. 106 Brochet B, Deloire MS, Bonnet M, et al. Should SDMT substitute for PASAT in MSFC? A 5-year longitudinal study. Mult Scler 2008; 14: 1242–49. 107 Julian LJ. Cognitive functioning in multiple sclerosis. Neurol Clin 2011; 29: 507–25. 108 Bever CT Jr, Grattan L, Panitch HS, Johnson KP. The brief repeatable battery of neuropsychological tests for multiple sclerosis: a preliminary serial study. Mult Scler 1995; 1: 165–69. 109 Buschke H, Fuld PA. Evaluating storage, retention, and retrieval in disordered memory and learning. Neurology 1974; 24: 1019–25. 110 Barbizet J, Cany E. Clinical and psychometrical study of a patient with memory disturbances. Int J Neurol 1968; 7: 44–54. 111 Gronwall DM. Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 1977; 44: 367–73. 112 Benedict RH, Duquin JA, Jurgensen S, et al. Repeated assessment of neuropsychological deficits in multiple sclerosis using the symbol digit modalities test and the MS neuropsychological screening questionnaire. Mult Scler 2008; 14: 940–46. 113 Borkowski JG, Benton AL, Spreen O. Word fluency and brain damage. Neuropsychologia 1967; 5: 135–40. 114 Strober L, Englert J, Munschauer F, Weinstock-Guttman B, Rao S, Benedict RH. Sensitivity of conventional memory tests in multiple sclerosis: comparing the rao brief repeatable neuropsychological battery and the minimal assessment of cognitive function in MS. Mult Scler 2009; 15: 1077–84. 115 Benedict RH, Smerbeck A, Parikh R, Rodgers J, Cadavid D, Erlanger D. Reliability and equivalence of alternate forms for the symbol digit modalities test: implications for multiple sclerosis clinical trials. Mult Scler 2012; 18: 1320-25. 116 Sonder JM, Burggraaff J, Knol DL, Polman CH, Uitdehaag BM. Comparing long-term results of PASAT and SDMT scores in relation to neuropsychological testing in multiple sclerosis. Mult Scler 2014; 20: 481–88. 117 Benedict RH, Amato MP, Boringa J, et al. Brief international cognitive assessment for MS (BICAMS): international standards for validation. BMC Neurol 2012; 12: 55. 118 Johnson JA, Coons SJ, Ergo A, Szava-Kovats G. Valuation of EuroQOL (EQ-5D) health states in an adult US sample. Pharmacoeconomics 1998; 13: 421–33. 119 Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30: 473–83. 120 Fisk JD, Brown MG, Sketris IS, Metz LM, Murray TJ, Stadnyk KJ. A comparison of health utility measures for the evaluation of multiple sclerosis treatments. J Neurol Neurosurg Psychiatry 2005; 76: 58–63. 121 Hobart J, Lamping D, Fitzpatrick R, Riazi A, Thompson A. The multiple sclerosis impact scale (MSIS-29): a new patient-based outcome measure. Brain 2001; 124: 962–73. 122 Hayton T, Furby J, Smith KJ, et al. Clinical and imaging correlates of the multiple sclerosis impact scale in secondary progressive multiple sclerosis. J Neurol 2012; 259: 237–45.

www.thelancet.com/neurology Vol 14 February 2015

Series

123 Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–85. 124 Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002; 125: 2202–12. 125 De Stefano N, Giorgio A, Battaglini M, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology 2010; 74: 1868–76. 126 Rudick RA, Fisher E, Lee JC, Duda JT, Simon J. Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon beta-1a. Mult Scler 2000; 6: 365–72. 127 Altmann DR, Jasperse B, Barkhof F, et al. Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis. Neurology 2009; 72: 595–601. 128 Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol 2006; 5: 158–70. 129 Tedeschi G, Lavorgna L, Russo P, et al. Brain atrophy and lesion load in a large population of patients with multiple sclerosis. Neurology 2005; 65: 280–85. 130 Bo L, Vedeler CA, Nyland HI, Trapp BD, Mork SJ. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003; 62: 723–32. 131 Peterson JW, Bö L, Mörk S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50: 389–400. 132 Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008; 64: 255–65. 133 Fisniku LK, Chard DT, Jackson JS, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 2008; 64: 247–54. 134 Amato MP, Portaccio E, Goretti B, et al. Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis. Arch Neurol 2007; 64: 1157–61. 135 Shiee N, Bazin PL, Zackowski KM, et al. Revisiting brain atrophy and its relationship to disability in multiple sclerosis. PLoS One 2012; 7: e37049. 136 Calabrese M, Atzori M, Bernardi V, et al. Cortical atrophy is relevant in multiple sclerosis at clinical onset. J Neurol 2007; 254: 1212–20. 137 Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. segmentation and surface reconstruction. Neuroimage 1999; 9: 179–94. 138 Fischl B. FreeSurfer. Neuroimage 2012; 62: 774–81. 139 Nakamura K, Fox R, Fisher E. CLADA: cortical longitudinal atrophy detection algorithm. Neuroimage 2011; 54: 278–89. 140 Nakamura K, Guizard N, Fonov VS, Narayanan S, Collins DL, Arnold DL. Jacobian integration method increases the statistical power to measure gray matter atrophy in multiple sclerosis. Neuroimage Clin 2013; 4: 10–17. 141 Harrison DM, Caffo BS, Shiee N, et al. Longitudinal changes in diffusion tensor-based quantitative MRI in multiple sclerosis. Neurology 2011; 76: 179–86. 142 Fox RJ, Cronin T, Lin J, et al. Measuring myelin repair and axonal loss with diffusion tensor imaging. AJNR Am J Neuroradiol 2011; 32: 85–91. 143 Harrison DM, Shiee N, Bazin PL, et al. Tract-specific quantitative MRI better correlates with disability than conventional MRI in multiple sclerosis. J Neurol 2013; 260: 397–406. 144 Schmierer K, Tozer DJ, Scaravilli F, et al. Quantitative magnetization transfer imaging in postmortem multiple sclerosis brain. J Magn Reson Imaging 2007; 26: 41–51. 145 Tortorella C, Viti B, Bozzali M, et al. A magnetization transfer histogram study of normal-appearing brain tissue in MS. Neurology 2000; 54: 186–93. 146 Hayton T, Furby J, Smith KJ, et al. Grey matter magnetization transfer ratio independently correlates with neurological deficit in secondary progressive multiple sclerosis. J Neurol 2009; 256: 427–35. 147 Hayton T, Furby J, Smith KJ, et al. Longitudinal changes in magnetisation transfer ratio in secondary progressive multiple sclerosis: data from a randomised placebo controlled trial of lamotrigine. J Neurol 2012; 259: 505–14.

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148 Calabrese M, Filippi M, Gallo P. Cortical lesions in multiple sclerosis. Nat Rev Neurol 2010; 6: 438–44. 149 Geurts JJ, Bo L, Pouwels PJ, Castelijns JA, Polman CH, Barkhof F. Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am J Neuroradiol 2005; 26: 572–77. 150 Fox RJ, Sakaie K, Lee JC, et al. A validation study of multicenter diffusion tensor imaging: reliability of fractional anisotropy and diffusivity values. AJNR Am J Neuroradiol 2012; 33: 695–700. 151 Evangelou N, DeLuca GC, Owens T, Esiri MM. Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions. Brain 2005; 128: 29–34. 152 Oh J, Zackowski K, Chen M, et al. Multiparametric MRI correlates of sensorimotor function in the spinal cord in multiple sclerosis. Mult Scler 2013; 19: 427–35. 153 Theaudin M, Saliou G, Ducot B, et al. Short-term evolution of spinal cord damage in multiple sclerosis: a diffusion tensor MRI study. Neuroradiology 2012; 54: 1171–78. 154 Frohman EM, Fujimoto JG, Frohman TC, Calabresi PA, Cutter G, Balcer LJ. Optical coherence tomography: a window into the mechanisms of multiple sclerosis. Nat Clin Pract Neurol 2008; 4: 664–75. 155 Petzold A, de Boer JF, Schippling S, et al. Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol 2010; 9: 921–32. 156 Abalo-Lojo JM, Limeres CC, Gomez MA, et al. Retinal nerve fiber layer thickness, brain atrophy, and disability in multiple sclerosis patients. J Neuroophthalmol 2014; 34: 23–28. 157 Saidha S, Syc SB, Durbin MK, et al. Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness. Mult Scler 2011; 17: 1449–63. 158 Burkholder BM, Osborne B, Loguidice MJ, et al. Macular volume determined by optical coherence tomography as a measure of neuronal loss in multiple sclerosis. Arch Neurol 2009; 66: 1366–72. 159 Narayanan D, Cheng H, Bonem KN, Saenz R, Tang RA, Frishman LJ. Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis. Mult Scler 2014; 20: 1331–41. 160 Ziemann U, Wahl M, Hattingen E, Tumani H. Development of biomarkers for multiple sclerosis as a neurodegenerative disorder. Prog Neurobiol 2011; 95: 670–85. 161 Burman J, Zetterberg H, Fransson M, Loskog AS, Raininko R, Fagius J. Assessing tissue damage in multiple sclerosis: A biomarker approach. Acta Neurol Scand 2014; 130: 81–89. 162 Malmestrom C, Haghighi S, Rosengren L, Andersen O, Lycke J. Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology 2003; 61: 1720–25. 163 Kuhle J, Plattner K, Bestwick JP, et al. A comparative study of CSF neurofilament light and heavy chain protein in MS. Mult Scler 2013; 19: 1597–03. 164 Gunnarsson M, Malmestrom C, Axelsson M, et al. Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol 2011; 69: 83–89. 165 Kuhle J, Malmestrom C, Axelsson M, et al. Neurofilament light and heavy subunits compared as therapeutic biomarkers in multiple sclerosis. Acta Neurol Scand 2013; 128: e33–e36. 166 Semra YK, Seidi OA, Sharief MK. Heightened intrathecal release of axonal cytoskeletal proteins in multiple sclerosis is associated with progressive disease and clinical disability. J Neuroimmunol 2002; 122: 132–39. 167 Petzold A, Eikelenboom MJ, Gveric D, et al. Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations. Brain. 2002; 125: 1462–73. 168 Axelsson M, Malmestrom C, Nilsson S, Haghighi S, Rosengren L, Lycke J. Glial fibrillary acidic protein: a potential biomarker for progression in multiple sclerosis. J Neurol 2011; 258: 882–88. 169 Denic A, Johnson AJ, Bieber AJ, Warrington AE, Rodriguez M, Pirko I. The relevance of animal models in multiple sclerosis research. Pathophysiology 2011; 18: 21–29. 170 Parmar MK, Carpenter J, Sydes MR. More multiarm randomised trials of superiority are needed. Lancet 2014; 384: 283–84.

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