Monday, 26 June 2017

Questions for today's Symposium

ProfG is at the European Neurology Meeting in Amsterdam.

Today, there is a SANOFI GENZYME Satellite Symposium: From clinical data to real world experience – similar results, similar benefits for multiple sclerosis patients?

I guess MS CARE extension data will be presented. The message will be alemtuzumab is a very good drug.

The bad news will be that the proportion of people with secondary autoimmunities from the trials, about 20% will have dramatically increased to about 50%.

Here is the programme

Chairperson 
Rogier Q. Hintzen, Rotterdam, The Netherlands

Welcome and Introduction. Rogier Q. Hintzen, Rotterdam, The Netherlands

Mechanism of Action:New Insights into Immunomodulation
Luisa Klotz, , Germany

From Phase 3 controlled trials to extension trials: What do the data tell us? Celia Oreja-Guevara, Madrid, Spain

Daily practice: How does real world evidence reflect clinical data? Tjalf Ziemssen, Dresden, Germany (lead author of ECTRIMS abstract-2013 on binding and neutralizing antibody responses).

Q & A:Rogier Q. Hintzen, Rotterdam, The Netherlands

We can see there is a Q & A session which is great. 

If you are there scratching you head seeking a question, maybe you can ask a few questions.

I wonder what are the new insights? Weren't they publish last week:-)? http://jamanetwork.com/journals/jamaneurology/article-abstract/2630681

What is the mechanism?
Wonder if memory B cells will get a mention? Give us a tweet.

If they don't here's a few questions for the Q&A.

Q. Why do you think MS is a CD4 Th17 T cell mediated disease given that treatments targeting CD4 T cells have typically failed in MS?

Q. Why do you think there is an increase in Treg T cells when their absolute numbers are decreased by over 80%?

Q. Why are you not associating Tregs influences as a major influence on B cell autoimmunities?

Q. Do you think memory B cells are involved in the action of alemtuzumab?

I will guess. Most people don't get a third course, few got 3 or fewer get 4 courses of drug. This indeed impressive.

I guess this is not mentioned that most people develop binding and neutralizing antibodies, which they must do given the levels at cycles one and two (about 80%).

Q. How many people develop binding and neutralizing antibodies on cycle 3 and cycle 4? 
Q. At 12 months after last infusion how many people have persistent anti-drug antibodies and do they affect depletion.

Q. What is the proportion of people who stop depleting or what is the proportion of people who only partially deplete? We already known at the population level there is depletion (Kousin-Ezewu et al. 2014) but at the individual level, are there people who neutralise the alemtuzumab response.
Q. If there are, what is the titre of neutralizing antibodies associated with lack of efficacy.
Q. Are their any non-depleters.
Q. Is there any difference in anaphylaxis/anaphylactoid reactions after third or forth infusion given that most people make binding antibodies and over 70% of people have persistent anti-drug antibodies. Does this relate to pre-existing titres of alemtuzumab binding antibodies?
I suspect if you ask these questions there may be some blank looks .
COI None relevant

More fingolimod rebounds

Forci B, Mariottini A, Mechi C, Massacesi L, Repice A. Disease reactivation following fingolimod withdrawal in multiple sclerosis: Two case reports. Mult Scler Relat Disord. 2017 Jul;15:24-26.
BACKGROUND:
Severe multiple sclerosis reactivation following second line treatment withdrawal, defined "rebound syndrome", is becoming a prominent issue to consider when deciding to discontinue a treatment. In particular disease recurrence after cessation of fingolimod is actually poorly characterized as to date, only case reports and small case series have been described.
CASE PRESENTATION: We herewith describe 2 cases of severe disease reactivation associated to a high number of brain gadolinium enhancing lesions at magnetic resonance imaging (MRI) despite high dose steroid treatment, observed a few weeks after cessation of fingolimod administration, causing a substantial and persistent worsening of patient disability that required long term hospitalization. The severity of the neurological symptom worsening and of the brain lesion largely exceeded the disease activity observed during treatment.
CONCLUSIONS: Our patients developed a rebound syndrome after ceasing fingolimod treatment, defined as the development of severe neurological symptoms and multiple new or enhancing lesions exceeding previous activity. Further analysis are needed to identify patients at greatest risk of a rebound syndrome.
When you start treatment you have to consider how you stop treatment if it is not working for you and importantly you need to think about how you transition from a migration inhibitor. These would be natalizumab and fingolimod. We have had a lot of discussion about switching off fingolimod but this is about fingolimod. This is yet another example of an attack shortly after stopping  fingolimod.  So it is important you discuss how disease activation is going to be minimized before you stop fingolimod

Sunday, 25 June 2017

The Burden of Multiple Sclerosis

This study examines the cost of MS in different European Countries if you go East the amount spent on people with MS is lower. However you can see that the costs are not harmonised across Europe. 

In the UK the cost is low. Is this because of efficiency or are we near the bottom of the pile (yes you could add about 10-20%  to get a fairer view, because I used todays exchange rates).

Switzerland is out in front on the amount it spends

Multiple et al. New insights into the burden and costs of multiple sclerosis in Europe Mult Scler. 2017 Aug;23(2_suppl):4-216

BACKGROUND:To assess the value of management strategies in multiple sclerosis (MS), outcome data have to be combined with cost data. This requires that cost data be regularly updated.

OBJECTIVE AND METHODS: This study is a cross-sectional retrospective study in 16 countries collecting current data on resource consumption, work capacity and health-related quality of life (HRQoL). Descriptive analyses are presented by level of severity; costs are estimated in the societal perspective, in 2015

A total of 208 patients (mean age: 38.5 years) participated in the Russian study; 97% were below retirement age, and of these, 49% were employed. MS was reported to affect productivity at work in 63% of patients. Overall, 87% and 41% of patients felt that fatigue and cognition were a problem. The mean utility and costs were 0.769 and 578,000 RUB at Expanded Disability Status Scale (EDSS) 0-3, 0.509 and 826,000 RUB (€12,407) at EDSS 4-6.5, and 0.071 and 1,013,000 RUB (€15,214) at EDSS 7-9. The average cost of a relapse was 33,000 RUB (€496) 

A total of 747 patients (mean age 47 years) participated in the Czech Republic; 86% were below retirement age and of these, 49% were employed. Employment was related to disease severity, and MS affected productivity at work for 82% of those working. Overall, 92% and 66% of patients experienced fatigue and cognitive difficulties as a problem. Mean utility and annual costs were 0.832 and 257,000CZK (€9,776) at Expanded Disability Status Scale (EDSS) 0-3, 0.530 and 425,500CZK (€16,183) at EDSS 4-6.5 and 0.141 and 489,000CZK (€18,606) at EDSS 7-9. The average cost of a relapse was estimated at 12,600CZK (€480)
A total of 521 patients (mean age 47 years) participated in Hungary; 85% were below retirement age, and of these, 47% were employed. Employment was related to disability and MS affected productivity at work for 82% of those working. Overall, 94% and 66% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and annual costs were 0.691 and 3,432,000HUF (€11,0680) at Expanded Disability Status Scale (EDSS) 0-3, 0.491 and 5,262,000HUF (€16,970) at EDSS 4-6.5 and 0.076 and 6,235,000HUF (€20,108) at EDSS 7-9, respectively. The average cost of a relapse was estimated at 240,500HUF (€776).


A total of 779 patients (mean age = 57 years) participated; 72% were below retirement age and of these, 36% were employed. Employment was related to disease severity, and MS affected productivity at work for 84% of patients. Overall, 96% and 72% of the patients experienced fatigue and cognition as a problem. Mean utility and annual costs were 0.735 and 11,400GBP (€12,949) at Expanded Disability Status Scale (EDSS) = 0-3, 0.534 and 22,700GBP (€25,785)at EDSS = 4-6.5, and 0.135 and 36,500GBP  (€41,460) at EDSS = 7-9. The mean cost of a relapse was estimated at 790GBP (€870).

A total of 411 MS patients (mean age = 40 years) participated in Poland; 94% were below retirement age, and of these, 59% were employed. Employment was related to disability, and MS affected productivity for 85% of those working. Overall, 97% and 71% of patients experienced fatigue and cognition as important problems, respectively. Mean utility and total annual costs were 0.686 and 48,700 PLN (€11,523) at Expanded Disability Status Scale (EDSS) 0-3, 0.521 and 59,200 PLN (€14,008) at EDSS 4-6.5 and 0.208 and 81,600 PLN (€19,308) at EDSS 7-9, respectively. The average cost of a relapse was 3,900 PLN.(€924)


A total of 462 patients (mean age 43 years) participated in Spain; 96% were below retirement age and of these, 45% were employed. Employment was related to disability, and MS affected productivity at work for 72% of those working. Overall, 92% and 64% of patients experienced fatigue and cognitive difficulties as a problem, respectively. Mean utility and total annual costs were estimated at 0.772 and €20,600 at Expanded Disability Status Scale (EDSS) 0-3, 0.486 and €48,500 at EDSS 4-6.5 and 0.182 and €68,700 at EDSS 7-9, respectively. The mean cost of a relapse was €2050.
A total of 491 patients (mean age 47 years) participated in France; 82% were below retirement age, and of these 56% were employed. Employment was related to disease severity, and MS affected productivity at work for 90% of patients. Overall, 95% and 67% of patients experienced fatigue and cognition as a problem, respectively. The mean utility and annual costs were 0.735 and €22,600 at Expanded Disability Status Scale (EDSS) 0-3, 0.500 and €38,100 at EDSS 4-6.5, and 0.337 and €48,100 at EDSS 7-9, respectively. The average cost of a relapse was estimated at €2300.

A total of 5475 patients (mean age 52 years) participated in Germany. In all, 84% were below retirement age, and of these, 51% were employed. Employment was related to disease severity, and MS affected productivity at work for 80% of patients. Overall, 96% and 78% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and total annual costs were 0.786 and 28,200€ at Expanded Disability Status Scale (EDSS) 0-3, 0.586 and €44,000 at EDSS 4-6.5 and 0.273 and €62,700 at EDSS 7-9, respectively. The mean cost of a relapse was estimated at €2500.
A total of 516 patients (mean age, 53 years) participated in Austria; 72% were below retirement age, and of these, 46% were employed. Employment was related to disability, and MS affected productivity at work for 77% of those working. Overall, 94% and 67% of patients experienced fatigue and cognition as a problem. Mean utility and total annual costs were 0.778 and 25,100€ at Expanded Disability Status Scale (EDSS) 0-3, 0.579 and 44,100€ at EDSS 4-6.5, and 0.244 and 73,800€ at EDSS 7-9. The mean cost of a relapse was estimated at 2563€

A total of 1010 patients (mean age = 45 years) participated in Italy. In total, 94% were below retirement age, and of these, 56% were employed. Employment was related to disability, and MS affected productivity at work in 77% of the patients. Overall, 96% and 65% of the patients experienced fatigue and cognitive difficulties as a problem, respectively. Mean utility and total annual costs were 0.735 and €22,900 at Expanded Disability Status Scale (EDSS) of 0-3, 0.534 and €40,100 at EDSS of 4-6.5, and 0.135 and €53,300 at EDSS of 7-9. The mean cost of a relapse was estimated to be €2600.
A total of 535 patients (mean age 48.5 years) participated in Portugal ; 92% were below retirement age and of these, 43% were employed. Employment was related to disease severity, and MS was felt to affect productivity at work by 72% of patients, most often through fatigue. Overall, 98% and 74% of patients felt that fatigue and cognition were a problem. Mean utility and costs were 0.756 and €16,500 at the Expanded Disability Status Scale (EDSS) 0-3, 0.572 and €28,700 at EDSS 4-6.5 and 0.206 and €34,400 at EDSS 7-9. The average cost of a relapse was estimated at €2930.
A total of 1856 patients (mean age: 54 years) participated in Belgium; 66% were below retirement age, and of these, 44% were employed. Employment was related to disease severity, and MS affected productivity at work in 85% of the patients. Overall, 95% and 72% of the patients experienced fatigue and cognitive difficulties, respectively, as a problem. Mean utility and annual costs were 0.703 and €26,400 at Expanded Disability Status Scale (EDSS) 0-3, 0.478 and €45,300 at EDSS 4-6.5, and 0.193 and €62,000 at EDSS 7-9. The mean cost of a relapse was estimated to be €3000.
A total of 382 patients (mean age: 54 years) participated in the Netherlands; 81% were below retirement age and of these, 31% were employed. Employment was inversely related to disease severity, and MS affected productivity at work for 82% of patients. Overall, 96% and 73% of patients experienced fatigue and cognitive difficulties, respectively, as a problem. Mean utility and annual costs were 0.744 and €23,100 at Expanded Disability Status Scale (EDSS) 0-3, 0.595 and €32,300 at EDSS 4-6.5, and 0.297 and €50,500 at EDSS 7-9. The mean cost of a relapse was estimated at €3000.
A total of 1864 patients (mean age 56 years) participated in Sweden; 74% were below retirement age, and of these, 55% were employed. MS was reported to affect productivity at work in 78% of patients. Overall, 94% and 72% of patients felt that fatigue and cognition were a problem, respectively. The mean utility and costs were 0.757 and 244,000SEK (€24953) at Expanded Disability Status Scale (EDSS) 0-3, 0.563 and 384,000SEK (€39,271) at EDSS 4-6.5 and 0.202 and 888,000SEK (€90,814) at EDSS 7-9, respectively. The average cost of a relapse was 36,900SEK (€3774).
A total of 721 patients (mean age 48 years) participated in Switzerland; 90% were below retirement age, and of these, 65% were employed. Employment was related to disease severity, and MS affected productivity at work for 69% of patients. Overall, 93% and 64% of patients experienced fatigue and cognition as a problem, respectively. The mean utility and annual costs were 0.799 and 29,600CHF (€27,272) at Expanded Disability Status Scale (EDSS) 0-3, 0.614 and 66,800CHF (€61,547) at EDSS 4-6.5 and 0.348 and 110,800CHF (€102,087) at EDSS 7-9, respectively. The mean cost of a relapse was estimated at 7,600CHF. (€7,002)

Saturday, 24 June 2017

The ProfG's need a kick up the backside. Publish trials

Stefaniak JD, Lam TCH, Sim NE, Al-Shahi Salman R, Breen DP. Discontinuation and non-publication of neurodegenerative disease trials: a cross-sectional analysis. Eur J Neurol. 2017. doi: 10.1111/ene.13336. [Epub ahead of print]

BACKGROUND AND PURPOSE:Trial discontinuation and non-publication represent major sources of research waste in clinical medicine. No previous studies have investigated non-dissemination bias in clinical trials of neurodegenerative diseases.
METHODS: ClinicalTrials.gov was searched for all randomized, interventional, phase II-IV trials that were registered between 1 January 2000 and 31 December 2009 and included adults with Alzheimer's disease, motor neurone disease, multiple sclerosis or Parkinson's disease. Publications from these trials were identified by extensive online searching and contact with authors, and multiple logistic regression analysis was performed to identify characteristics associated with trial discontinuation and non-publication.
RESULTS: In all, 362 eligible trials were identified, of which 12% (42/362) were discontinued. 28% (91/320) of completed trials remained unpublished after 5 years. 


Trial discontinuation was independently associated with number of patients (P = 0.015; more likely in trials with ≤100 patients; odds ratio 2.65, 95% confidence interval 1.21-5.78) and phase of trial (P = 0.009; more likely in phase IV than phase III trials; odds ratio 3.90, 95% confidence interval 1.41-10.83). 

Trial non-publication was independently associated with blinding status (P = 0.005; more likely in single-blind than double-blind trials; odds ratio 5.63, 95% confidence interval 1.70-18.71), number of centres (P = 0.010; more likely in single-centre than multi-centre trials; odds ratio 2.49, 95% confidence interval 1.25-4.99), phase of trial (P = 0.041; more likely in phase II than phase IV trials; odds ratio 2.88, 95% confidence interval 1.04-7.93) and sponsor category (P = 0.001; more likely in industry-sponsored than university-sponsored trials; odds ratio 5.05, 95% confidence interval 1.87-13.63).
CONCLUSIONS: There is evidence of non-dissemination bias in randomized trials of interventions for neurodegenerative diseases. Associations with trial discontinuation and non-publication were similar to findings in other diseases. These biases may distort the therapeutic information available to inform clinical practice

Last week we reported a discontinued Cambridge trial, where the results have not been reported yet (Only at least 15 months from termination), we have mentioned the Ely Lilly Trial that has yet to be reported..

This paper has spotted that loads of  trials don't get finished and loads don't reported. I can see that recruiting for trials is a problem, the PROXIMUS is eighteen months late but now fully recruited, the Canbex trail is very late too but almost there

However before having a rant, you've said "kettle and black"...

You are right we have to hold our hands up and say yes we need to give ourselves a bit of a kick or should I say I need to give the Profs a good kicking 

We (you and I ) know, but the rest of the World don't... that the INSPIRE trial has expired, but a failure is no reason not to publish. 

I heard a "a negative trial can tell us as much as a positive trial"...rubbish....negative trials always leave us with two questions.

It may not always tell us about biology but it may tell us that we do some poorly designed or executed trials. If we aspire to negative trials we have lost before we start. 

I have said that many of our good ideas have been killed off because of bad trials. Not popular with the Neuros and Funders of the trials, but I will stick to my guns on this one. 

I have been saying until I am blue in the face, if you don't have a trial that can work, it doesn't matter which drug you try, it won't work. 

Until beta interferon came along we didn't know how to do relapsing trials not it is easy to work out if an agent is active of not. For progressive trials we are not sure if we are using good outcomes or maybe the trials aren't long enough. 

Our idea of cannabinoids controlling nerve loss is supported by more biology that you can shake a stick at, but the trial failed. 

Speaking to one of the investigators this week. 
They said, the placebo arm just did not progress as expected
(if you are in a trial you do better even if you are on placebo) , so if tyou don't get worse in the placebo arm how can you ever find a positive result of stopping people getting worse. 
It took 6 years to learn this lesson. 

Maybe if the trial was loaded with people who could respond and in people who may get worse if they don't get treated, then we would see something

If you have evidence that your disease is worsening in may be easier to get on to trials or to get access to drugs.

So are you monitoring? 

Do you have a 9 hole peg test, do you know your time for a 25m walk. Because to get into trials or to get access to drugs you may have to show that you have documented worsening

Anyway, we need to come clean, the ProfGs needs to put pen to paper, because until they do that we can't give anyone a roasting,

Oh I forgot ProfG the CLARITY extension is also only about 3 years late so still time:-)....Yeah I know the third reviewer;-)

We collect so many metrics, maybe the number of trials reported has to be a good one when deciding who is funded to do more trials. 

People are risking a lot to participate in the studies, they have a right to know what happened. 

Friday, 23 June 2017

July comes Early

I came across this clock many months ago ticking away in French and English after I stumbled on a Norwegian Website

I nearly made a post for April the first..... so July comes early



Maybe the name will be a grower, but cladding does not have a good reputation in the UK at the moment :-) Don't understand Click

Well done, Prof G, DrK & Merck.

The Tortoise gets there in the end. Will it beat the Hare?