Do you have progressive MS; is your MS salvageable?

Barts-MS rose-tinted-odometer: ★★★★★
Another Jazzy Blues Saturday #163780 (VW’s code)

As you are aware Professor Alan Thompson was awarded the Charcot prize from ECTRIMS this year. The award recognised his long and illustrious career in the field of MS and in particular his contribution to the study of progressive MS.  However, Professor Thompson’s final message in his Charcot Lecture  – Progressive multiple sclerosis – a personal perspective – ‘that once you have clinically manifest progressive MS with disability the therapeutic window has probably shut’ has had some blowback on social media. 

His final message may dampen the spirits of many of you living with progressive MS and challenges some of the research we are involved in.

I was personally disappointed that he did not mention Kurtzke’s length-dependent axonopathy hypothesis and the rationale for multiple therapeutic windows in MS, which we recently resurrected as a concept. It is because MS is a central length-dependent axonopathy that we have therapeutic lag and why we highlighted arm and hand function in pwMS in our #ThinkHand campaign and why we are doing the CHARIOT-MSORATORIO-HAND and UNDER&OVER trials. In short, we have hypothesised that it is never too late to modify the course of MS.

A few years ago during the #ThinkHand campaign one of my colleagues presented a patient who was had advanced MS (EDSS 7.5 = wheelchair-bound) who was still on interferon-beta. In keeping with NHS England guidelines, she had to stop treating this patient with interferon-beta. Three months later this patient presented with double-vision due to a brain-stem relapse. An MRI with contrast showed multiple Gd-enhancing lesions indicative of reactivation of MS disease activity, or rebound, post-interferon-beta. As this patient was not eligible to be restarted on a licensed DMT, we at the MDT recommended that the patient be offered off-label treatment with generic subcutaneous cladribine. Our position was that although the patient may be wheelchair-bound with advanced MS, she still had upper limb (arm & hand) and bulbar (swallowing and speech) function to preserve. Were we wrong to treat this patient and assume that the therapeutic window to modify her disease course has shut? This patient is not unique and almost every MS expert will have similar cases. 

As a result of these and other insights we are challenging the NHS England DMT stopping criteria, are proposing a randomised controlled trial to evaluate whether or not MS is modifiable in the population of patients who have to stop their licensed DMT.  Are these ‘unsalvageables’ salvageable? 

In short, we propose randomising pwMS who are forced to stop their existing DMT to treatment with possible generic cladribine or placebo with the primary outcome being NEDA or disease progression as defined using upper limb function, i.e. the 9-hole peg test. The plan is to make this an event-driven trial and if someone reaches the study end-point they can be unblinded and offered a course of cladribine if they were previously treated with placebo. If they had broken through on cladribine they could be offered a further course of treatment or another off-label salvage therapy, for example, rituximab biosimilar. 

Instead of assuming MS is not modifiable beyond a certain stage should we not at least try and salvage upper limb function in people with more advanced MS?

The real question is do we have the equipoise to do this study? Please note that in a small French study, stopping DMTs in pwSPMS, 35% of the cohort had relapses, or MRI activity, in the follow-up period (~5 years). Similarly, in the MS-BASE study below, of 485 DMT-stoppers vs. 854 DMT-stayers followed for at least 3-years, time to confirm disability progression was significantly shorter among DMT stoppers than stayers. The data from these two studies would indicate that we should ignore NHS England because their stopping criteria are not evidence-based and give the patient the option of stopping their DMT or continuing with it. What do you think? 

Length-dependent axonopathy

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Review Mult Scler Relat Disord. 2017 Feb;12:70-78.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and an S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

French Study

Bonenfant et al. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2016. doi: 10.1111/ene.13181

BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS.

METHODS: We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified.

RESULTS: Mean treatment duration was 60.4 ± 39.3 months, and mean follow-up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05-0.17 and 0.07, 95% CI, 0.05-0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09-0.16). Sixteen patients experienced a relapse and 19 had a gadolinium-positive MRI scan without relapse during follow-up. A gadolinium-positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation (P = 0.0004 and P = 0.03, respectively).

CONCLUSION: In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence-based guidelines for daily practice.


Kister et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1133-7.

BACKGROUND:  Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.

OBJECTIVES: (1) To compare time to first relapse and disability progression among ‘DMT stoppers’ and propensity-score matched ‘DMT stayers’ in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.

METHODS: Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.

RESULTS: Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.

CONCLUSIONS: Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Under&Over: we need your help

Since being hit by a motorbike travelling at high speed and nearly losing my life or independence I now have personal experience of the value of physical neurorehabilitation. When I say #UseItOrLoseIt I really mean it. So if you have more advanced MS and are using a walking stick (EDSS 6.0) we want you to enrol in a #CitizenScience type study in which we are testing a new hand and arm activity called Under&Over to see if it can improve or maintain upper limb function. The study is titled: “Under & Over: A controlled study to develop an upper limb rehabilitation tool for people with Multiple Sclerosis.”

The Under&Over project is an extension of our #ThinkHand campaign, i.e. you are never too disabled to be treated with DMT and we are doing the O’HAND (ORATORIO-HAND) and CHARIOT-MS studies to test ocrelizumab and oral cladribine in people with more advanced MS with the primary outcome being the 9-hole peg test; an outcome measure of upper limb function. Under&Over is simply a form of upper limb exercise. However, to get the MS community to accept arm and hand rehabilitation as a treatment we need evidence from a controlled study. So without volunteers, without you, we won’t be able to generate the evidence to prove that we can protect upper limb function with exercise.

This study is now recruiting – find out more information on the study website.

This is part of our ThinkHand project which addresses the need for more resources, research and services to support upper limb function.

What is the purpose of the study?

The research is designed to find out whether repeated use of the Under & Over tool (pictured above) can improve upper limb function in people with MS. It is also designed to gather information about the long term use of the tool based on participants’ experiences and the use of a digital platform and community integration to support this.

Who can take part?

Men and women over 18 years can take part if:

  • You have a diagnosis of MS (more than 6 months)
  • You have internet access
  • You have an Expanded Disability Status Scale (EDSS) score of ≥6 as measured using the online WebEDSS
  • You understand and able to communicate in English

You will not be Eligible to take part if:

  • You are unable to use your hands because of pain or any other reason that might interfere with your ability to complete the intervention using the Under & Over device.

It is a fully remote study, so there are no clinical visits or examinations. All study resources are online or will be posted to your home. You just need to live in the UK.

A number of baseline questionnaires will gather initial data that we will compare with the same data gathered at the end of the study (cardboard 9 Hole Peg test, WebEDSS, ABILHAND questionnaire, MSIF and MSIS-29).

Following baseline assessments, everyone who agrees to take part in this study will be randomly assigned to one of two groups; one group will receive immediate intervention and the other group will receive the delayed intervention; this is called the wait-list control group. This means that they will receive access to the rehabilitation programme after a 3-month period.  This way everyone who participates in the study will eventually get access to the rehabilitation programme.

Contact for further information about the study:

If you would like further information, answer to any questions or queries and would like to express interest to take part please contact the Under & Over Research Team ( and read the participant information on the study website.

#MSCOVID19: the storm

I have been asked many times about how COVID-19 is affecting our MS research programme. The short answer is massively and its true impact is yet to be realised because we are a far way off from anything that feels and looks like normal. We are still paralysed by the threat of a second wave of COVID-19; the social distancing requirements within the NHS means everything is going to be at half-mast and then the knock-on effects on research funding have yet to be felt. 

I am having sleepless nights about the covert threats of upcoming redundancies, whether or not our soft money will dry up, which we rely on to support administrative staff and prime research, how would one goes about declaring that you are academically bankrupt and then the massive increase in the teaching workload as we reconfigure all our teaching courses to go online. I have never worked harder and felt more unsettled than I do now. 

A good example of COVID-19’s knock-on effects is our #ThinkHand campaign. For those of you who have been following this blog for years should remember it well.  The central theme of the campaign ‘is not to write-off people with MS who have lost their lower limb function and are now having to use a wheelchair’. We have hypothesised and put forward a theory that MS is modifiable throughout its course and want to do clinical trials in people with advanced MS who are wheelchair users. The article by Timmermans and colleagues below shows that leg function declines earlier and quicker than arm function in MS, which supports our so-called ‘length-dependent axonopathy model of MS’.

Our #ThinkHand campaign started about 6 years ago and has resulted in the design and funding of two clinical trials targeting advanced MS. ORATORIO-HAND will be testing ocrelizumab in advanced PPMS (i.e. up to an EDSS of 8.0) and CHARIOT-MS that will be testing oral cladribine in advanced MS, including subjects with either SPMS and PPMS with an upper EDSS cut-off of 8.5. In both these trials, we will be using the 9-hole peg test as the primary outcome. The initiation and/or recruitment of subjects for both these trials have been suspended for the last 4 months and is unlikely to restart for another 2-3 months and maybe longer. We are talking about 6 months or more in COVID-19-related delays. If ‘Time is Brain’ or in the case of these trials ‘Time is Loss of Hand Function’ then these delays may mean that many pwMS will have progressed beyond the eligibility cutoffs for these trials.

We are not the only ones that have been affected and maybe it doesn’t help complaining. A very good friend of ours has cancer that is potentially terminal; as a result of COVID-19, her potentially life-saving surgery has been delayed by over 3 months. This week’s BMJ highlights the plight of cancer patients in the NHS and suggests that COVID-19 may result in 45,000 excess cancer deaths. What is the equivalent figure for people with MS? Will it be 10,000 people with MS lose their independence because of the progression of their MS and loss of upper limb function? Or 8,000 people with MS become unemployed because of worsening disability are a result of subclinical worsening cognition?

My philosophy is to simply get up each morning and try and get on with the task at hand. My motivation comes from an unusual source; a book “The Boy, the Mole, the Fox and the Horse” that my wife gave me at the beginning of lockdown. The quote that sums up the right attitude is the one about storms. 

“What is the best thing you’ve learnt about storms?”

“That they end”, said the horse.

Timmermans et al.  Ten-year disease progression in multiple sclerosis: walking declines more rapidly than arm and hand function. Mult Scler Relat Disord. 2020 Jun 26;45:102343.

Background and aims: From a clinical perspective there is a difference in the decline of arm and hand function and leg function in patients with multiple sclerosis (PwMS). Therefore, this study investigated the course of walking and arm and hand functions in PwMS over the first 10 years after diagnosis, including whether any function declined earlier or faster.

Methods: A long-term prospective follow-up study of an incidence cohort of 156 patients with a definite diagnosis of MS, either non-relapse onset (n=28) or relapse onset (n=128) type. Participants were systematically examined immediately after definite diagnosis, at 6 months, and at 1, 2, 3, 6 and 10 years. Walking was determined with the fast 10-meter timed walk test (10mTWT), arm and hand function with the Action Research Arm test (ARAT) and the nine-hole peg test (9HPT). The 10-year trajectories of walking and arm and hand functions were compared using standardized z-scores.

Results: From 3 years onwards the z-scores of the arm and leg function were visually diverging, with a trend towards significance at 6 years, and at 10 years the 10mTWT z-score is significantly higher than the 9HPT. This difference is more pronounced in non-relapse onset patients than in patients with relapse onset type MS, but present in both groups over the first 10 years. In the non-relapse onset group a difference in z-scores at 10 years post-diagnosis between the 10m TWT and 9HPT was found of -12.94 (95% confidence interval (CI) -20.2 to -5.73) for the right and -10.14 (95% CI -17.3 to -2.93) for the left hand. In the relapse onset group there was a difference at 10 years post-diagnosis of -2.17 (95% CI -3.75 to -0.59) for the right and a difference of -2.29 (95% CI -3.87 to -0.71) for the left hand.

Conclusion: This is the first longitudinal study that shows that walking declines earlier and more rapidly than arm and hand function in patients with MS. These results give important insights that can be linked to the pathophysiological disease process regarding the ascending order of deterioration in patients with MS.

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

CoI: multiple

Participating in Oratorio-Hand?

At the recent ORATORIO-HAND investigators’ meetings in Barcelona and Athens, several investigators’ made the point that it may be hard to retain people with PPMS in this trial because ocrelizumab has already been licensed to treat MS. I said YES and NO. 

For one a lot of neurologists, HCPs and payers don’t think the original ORATORIO trial was positive. They think the trial was driven by the 25% or so of the subjects with PPMS who had active disease, i.e. those with Gad-enhancing lesions at baseline. I have even heard some people claim that this trial was positive because it was contaminated by relapsing patients. This was not the case, all subjects had to have PPMS to get into this study. Any history of previous relapse excluded them from the trial. As a result of this doubt, many countries and insurance companies have not agreed to license or reimburse ocrelizumab for PPMS. To convince the naysayers, laggards and sceptics we need another PPMS trial to confirm the original results and extend the findings into pwPPSM with more advanced disease to show that ocrelizumab has a treatment effect in older and more disabled pwPPMS. This is why our age cutoff for the ORATORIO-HAND study is 65 and EDSS cut-off is 8.0 (wheelchair users). In the original ORATORIO study, these cutoffs were 55 years and EDSS of 6.5 (bilateral support, but still mobile). 

Statisticians will tell you that when you only do one trial, which is positive, there is about a 1 in 20 to 40 (2.5% to 5%) chance that result could be positive by chance. In statistical jargon, this is referred to as a false-positive result or type 1 error. This is why the regulators usually require two positive trials to license a product; the first trial to test the hypothesis and the second to confirm the results of the first trial. If one trial is positive and the second trial is negative, or vice versa, this usually results in a third trial being required. This is what happened with laquinimod in RRMS; you may recall the third trial (CONCERTO) turning out to be negative so the laquinimod MS development programme was halted. Herein lies a hidden danger. If ORATORIO-HAND is negative and does not confirm a significant treatment effect in PPMS it could be used by regulatory authorities to question the result of the ORATORIO trial and potentially withdraw the license. A negative result will justify payers refusal to reimburse the costs of ocrelizumab to treat PPMS. I am confident this is not going to happen, but we need your help to makes sure this does not happen. 

The ORATORIO-HAND is a very well-designed study and is adequately powered to give a positive result. The scientific principles underpinning this study are sound. However, if too many subjects drop-out to accept being treated with ocrelizumab when it is reimbursed in their countries or game the trial, i.e. find a way to unbind themselves, and drop-out this could potentially result in the study being underpowered, i.e. there are too few subjects to show a significant result when comparing placebo and active treatment groups. If this happens it could not only jeopardise treatment for themselves but the whole PPMS community. This is why I am appealing to all potential ORATORIO-HAND trial subjects if you are not sure about your longterm commitment to the trial you should not volunteer. 

We are very aware that half the trial subjects will be allocated to placebo. Someone investigators asked why didn’t we make the randomisation 2:1, i.e. for every one person on placebo two people would be allocated ocrelizumab. The logic is that by having a 2-out-of-3 chance of being on active treatment the more likely pwPPMS are likely to volunteer for the study and to stay the distance. There are two reasons for the one-to-one randomisation ratio; time and possibly cost. Increasing the time it takes to recruit study participants is important. We estimate to recruit another 500 subjects, to allow a 2:1 ratio, would take another 12-15 months, which means we would be exposing a third of the subjects to placebo for an additional 12-15 months and potentially denying many pwPPMS across the world earlier access to the ocrelizumab. A 12-15 month extension to the recruitment phase means 12-15 month delay for drug getting to wider PPMS population. These are the factors that convinced the steering committee to choose the 1:1 randomisation ratio. Although cost is an obvious potential consideration we didn’t even ask senior management at Roche the question. 

At the end of the day, we are asking pwPPMS to be altruistic. We are asking you to volunteer for a study and have a 50% chance of being randomised to a placebo knowing that ocrelizumab may be available to you as part of routine clinical practice or could become available to you during the trial. I know some people will ask does it have to be a randomised double-blind controlled trial? Could we generate the evidence in another way? The answer is no; the regulators will only change the label of ocrelizumab if the study is done to their standards. As you are aware it is virtually impossible to get a healthcare system-wide adoption of an MS treatment without a marketing authorisation from the appropriate regulatory body. 

There are also other advantages to being in a trial. We don’t know why but trial participants tend to do better than non-trial participants even if you are randomised to placebo. This may relate to better care offered in a trial or participating in a trial has psychological benefits that can’t be quantified. I favour the latter explanation. There is evidence that people who have a purpose, a sense of belonging and are valued have better health outcomes than people without. Being a trial participant gives you a sense of purpose and being valued in that they are contributing the greater good. I have also noticed over the years that trial participation expands social capital; trial participants get to know the trial staff and other trial participants. I even know of two study subjects from one of the early trials who ended up marrying each other. Others have become friends and see each other outside the trial unit; I have bumped into two of trials participants in a local east curry house together.  These intangibles can’t be quantified, but they definitely exist. 

In countries in which ocrelizumab is not licensed or reimbursed for treating PPMS the advantages of participating in the ORATORIO-HAND study are obvious. But even in countries where ocrelizumab is reimbursed receiving it as part of a trial may help as well. Although we can’t pay for you to participate in the trial all of your out-of-pocket expenses related to travel will be covered. 

I want to emphasise the positive of ORATORIO-HAND. For decades pwPPMS have felt neglected, ignored and left to smoulder away. Not anymore. The fact that the first ORATORIO trial was positive has shifted the goalposts and there will now be a flurry of PPMS trials. If ORATORIO-HAND fully recruits and is completed without too many dropouts the study will change the playing field for good. It will mean that PPMS is truly modifiable regardless of disease activity and potentially even people in wheelchairs will benefit. Getting a license for ocrelizumab in wheelchair users will affect the DMT stopping criteria, in other words even if you have to start using a wheelchair the treatment will have to be continued to preserve your arm and hand function. More importantly, it will get the whole MS community to say ‘Yes, we now agree that ocrelizumab works in PPMS’ and will allow pwPPMS across the world to access treatment. 

We acknowledge that there are many legitimate reasons for why study subjects dropouts in clinical trials. We have factored this into the power calculations. What I am focusing on here is excess drop-outs over and above what we expect to occur from experience of other ocrelizumab trials. 

This post is simply rehearsing some of the reasons for pwPPMS who volunteer for the ORATORIO-HAND study to stay the distance and complete the study. Please let me know if you agree, or disagree, with these points. I am also keen to find other reasons to help the many participating centres retain their patients in this trial. 

CoI: multiple; importantly, I am the principal investigator on the ORATORIO-HAND study and I want to give this trial the maximum chance of being successful. Our #ThinkHand campaign will only be judged a success if and when we get a DMT licensed to protect upper limb and hand function in pwMS. 


I am very excited and proud to be attending and speaking at the first European Oratoria-HAND, or O’Hand, study investigator meeting in Barcelona. With Chariot-MS, the O’HAND study is the culmination of more than 4 years of work and campaigning for Barts-MS. 

However, our #ThinkHand campaign will only be considered a true success if we get a positive outcome from one of our studies and a DMT gets licensed to protect, or delay loss of, hand and arm function in people with more advanced MS. These trials have the potential to change the field and make more advanced MS modifiable. Many cynics think we are wasting our time. But if you have MS and you lose your lower limb function you become dependent on your hand and arms to maintain your independence. In other words, your arms become your legs. 

The following is my presentation from the meeting, which you can download from my bespoke SlideShare site. 

O’HAND Eligibility Criteria

Ages Eligible for Study:  18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:  All
Accepts Healthy Volunteers:  No

Inclusion Criteria:

  • EDSS score at screening and baseline >= 3.0 to 8.0, inclusive
  • Disease duration from the onset of MS symptoms:

Less than 15 years in patients with an EDSS at screening > 5.0 Less than 10 years in patients with an EDSS at screening <= 5.0

  • Documented history or presence at screening of at least one of the following laboratory findings in a cerebrospinal fluid specimen: Elevated IgG index or one or more IgG oligoclonal bands detected by isoelectric focusing
  • Screening and baseline 9-HPT completed in > 25 seconds (average of the two hands)
  • Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline
  • Patients previously treated with immunosuppressants, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
  • For female patients without reproductive potential: Women may be enrolled if post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

Exclusion Criteria:

  • History of relapsing-remitting or secondary progressive MS at screening
  • Confirmed serious opportunistic infection including: active bacterial, viral, fungal, mycobacterial infection or other infection, including tuberculosis or atypical mycobacterial disease
  • Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy (PML)
  • Known active malignancy or are being actively monitored for recurrence of malignancy
  • Immunocompromised state
  • Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
  • Inability to complete an MRI or contraindication to Gd administration.
  • Patients requiring symptomatic treatment of MS and/or physiotherapy who are not on a stable regimen. Patients must not initiate symptomatic treatment of MS or physiotherapy within 4 weeks of randomization.
  • Contraindications to mandatory premedications for infusion-related reactions, including:

uncontrolled psychosis for corticosteroids and closed-angle glaucoma for antihistamines

  • Known presence of other neurologic disorders
  • Pregnant or breastfeeding, or intending to become pregnant during the study and 6 months after last infusion of the study drug
  • Lack of peripheral venous access
  • Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study
  • Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
  • History of alcohol or other drug abuse
  • History of primary or secondary immunodeficiency
  • Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS
  • Previous treatment with B-cell targeting therapies
  • Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
  • Any previous history of transplantation or anti-rejection therapy
  • Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
  • Systemic corticosteroid therapy within 4 weeks prior to screening
  • Positive serum hCG measured at screening or positive urine β-hCG at baseline
  • Positive screening tests for hepatitis B
  • Any additional exclusionary criterion as per ocrelizumab (Ocrevus®) local label, if more stringent than the above
  • Lack of MRI activity at screening/baseline if more than 650 patients without MRI activity have already been enrolled, as defined by T1 Gd+ lesion(s) and/or new and/or enlarged T2 lesion(s) in the screening, to ensure that at least 350 patients with MRI activity will be randomized

Eligibility Criteria for Open-Label Extension Phase:

  • Completed the double-blind treatment phase of the trial or have received PDP OCR in the FU1 phase, and who, in the opinion of the investigator, may benefit from treatment with Ocrelizumab. Patients who withdrew from study treatment and received another disease-modifying therapy (DMT) or commercial ocrelizumab will not be allowed to enter in the OLE phase.
  • Meet the re-treatment criteria for ocrelizumab
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
  • For female patients without reproductive potential: Women may be enrolled if post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

CoI: I am the principal investigator on the O’Hand study