Sunday, 6 August 2017

#ClinicSpeak & #ThinkHand: stopping DMTs - are you salvageable?

Could the SALVAGE trial be something the NIHR and/or MS Society would fund? #ClinicSpeak #ThinkHand

At least once a month Barts-MS have a MDT (multidisciplinary team) meeting to discuss difficult cases. One of my colleagues presented a patient who was had advanced MS (EDSS 7.5 = wheelchair bound) who was still on interferon-beta. So in keeping with NHS England guidelines she stopped the interferon-beta. Three months later this patient presented with double-vision due a brain-stem relapse. An MRI with contrast showed multiple Gd-enhancing lesions indicative of reactivation of MS disease activity, or possibly 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 try and preserve. This patient is not unique and almost every MSologist I know working in the NHS has similar cases. 

Since Thursday I have been thinking about this case and as NHS England get more militant with implementing their DMT stopping criteria we as a community need to do some proactive about this. I am therefore suggesting we do a randomised controlled trial to assess the efficacy of generic cladribine in patients with advanced MS? In essence as someone stops their existing DMT they are randomised to treatment with generic cladribine or placebo with the primary outcome being NEDA or disease progression as defined using upper limb function. We can make this an event driven trial and if someone reaches 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. 


Should we at least try and salvage upper limb function in more advanced MS?

The real question is do we have equipoise to do this study? Please note that in a small French study below, of 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 confirmed 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? 



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.

MS-BASE STUDY

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.

CoI: multiple

12 comments:

  1. I am salvageable and I am not sure I would want to stop my DMT when I need a wheelchair. I am not sure you will be able to do this trial; most people with MS would be reluctant to stop their treatments.

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    1. I agree. This trial is unethical and will be very difficult to recruit. I am not sure my colleagues, and I, would be prepared to stop a DMT in someone and randomise them to a placebo. Although NHS England may force us to. I suspect we switch these patients to off-label treatments anyway.

      We will focus on getting CHARIOT-MS funded; these people have advanced MS and will not be on a DMT. Due to institutionalised therapeutic nihilism we have a large number of pwMS in the UK who fall into this group.

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    2. Is it ethical to keep a patient on a drug that has been proved ineffective? Is it ethical to perpetuate the fuss of injections, adverse events, pain and disappointment and at the same time witness disability climb on 7.5 EDSS undisturbed?

      I think it would be useful for MSologists to injected themselves with a CRAB every now and then to keep in touch with their patients.

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  2. Thanks for the link to the NHS England document, I've never seen this before. Wiki definition of clinical equipoise was also very interesting to read.
    https://en.wikipedia.org/wiki/Clinical_equipoise

    Is SALVAGE not a mini version of CHARIOT-MS only applicable to a small group of those fortunate enough to have recently qualified for interferon but now unfortunately do not? So, I guess the same question applies i.e. if neuro accepts the evidence that cladribine effective then it should be prescribed and a trial is unethical. However, if neuro is dogmatic/lazy/never reads papers then a trial would force him/her to sit up and pay attention. As Barts cannot realistically treat the entire UK advanced MS population CHARIOT-MS is badly needed. If I were a Barts patient would I be willing to be randomised to placebo for the greater good? Probably not. But if the trial was to be out at centres around the country and the choice was trial or nothing then it's a no-brainer (no pun intended).

    When could CHARIOT-MS start? £4m is such a huge sum, could it start with a mini version if funds not forthcoming? Or do you start recruiting in advance of funds? Build it and they will come?

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  3. "35% of the cohort had relapses, or MRI activity, in the follow-up period (~5 years)."

    Half truth. They had relapses and MRI activity before discontinuation too:
    "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"

    Could you tell us the number of relapses & gd-positive MRIs prior to discontinuation? The article is not free.

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  4. Dr. G, just wondering, what is the regimen for subcutaneous Cladribine that you are offering to your patients? Are you using this as an induction therapy or a pulsed therapy? I'm guessing induction, but not sure since the Cladribine MS trials were done using the oral form of the drug. Are you offering this therapy to people with all forms of MS? Thanks in advance…

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    1. Not ProfG, but here you are: There is no principal difference between oral and other administrations of cladribine except for bioavailability, which means you have to calculate and adjust the dose accordingly. Whatever administration you chose, cladribine appears to be an induction (or pulsed immune reconstitution) therapy, though some will require re-treatment similar to alemtuzumab due to recurring/ongoing disease activity.

      You can find our current information pack here: https://www.slideshare.net/KlausSchmierer/bartsms-informationpackcladribine
      This is due for update soon following the licensing of Mavenclad in Europe, and some further work by our group.

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    2. Thanks, Klaus. Is this option only being offered to relapsing patients, or are some progressive patients also being given this option, in light of Dr. G's therapeutic lag theories?

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    3. pwMS who don't meet NHS England criteria for disease modifying treatment have been the main motivation to set up this service, which we also hope will help us getting #ChariotMS underway. Most referrals I receive are for people with progressive MS who have no other option. Some pwMS were eligible, however chose cladribine over licensed DMTs.

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  5. If I get SPMS and told to stop treatment with the NHS refusing further treatment I would simply get an antiiflamitory myself from abroad. Basically treat myself. That is what people will and should start doing. If it goes wrong the NHS would have to fix it.

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  6. '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? '

    Surely the above comment is commonsense.I am an mser in a wheelchair, although for reasons beyond MS, who, having completed both courses of Alemtuzumab, apparently would not qualify for a third course were it to be authorised because of the chair!? NHS England and blueteq being responsible. I have been offered mitoxantrone which I am not keen on so yes the trial you suggest sounds a good idea.

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