Regarding the past, what is the trial you have always been dreaming of in CIDP?

revue neurologique 172 (2016) 620–626

Available online at

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International meeting of the French society of neurology 2016

Regarding the past, what is the trial you have always been dreaming of in CIDP? R.A.C. Hughes *, M.P.T. Lunn Cochrane Neuromuscular, MRC Neuromuscular Disease Centre, Institute of Neurology, Queen Square, WC1N 3BG London, UK

info article

abstract

Article history:

Chronic inflammatory demyelinating polyradiculoneuropathy is an orphan disease of poorly

Received 1st June 2016

understood cause. While first line treatments with corticosteroids, intravenous immuno-

Accepted 29 July 2016

globulin and plasma exchange have at least short-term efficacy, no trial has shown that

Available online 13 September 2016

immunosuppressants work. In our dream, we will take advantage of the recently improved EU regulations to launch a Europe wide trial which will investigate the cause of the disease. It

Keywords:

will compare three parallel groups, the anti-B cell agent rituximab, the anti-T cell agent

Chronic inflammatory

abatacept and usual care. The trial will not be blinded and the design will be very simple. The

demyelinating

primary outcome measure will be improvement from baseline of the overall neuropathy

polyradiculoneuropathy

limitations scale (ONLS) score by 1 or more grades at 12 weeks without increase in conco-

Randomised controlled trial

mitant corticosteroids or IVIg or use of plasma exchange. There will be an option to substitute

treatment

improvement in the Rasch-built overall disability scale depending on future experience with

Rituximab

that scale as the primary outcome measure. The trial will require 3 groups of 60 participants to

Abatacept

detect an increase from 20% in the usual care group to 30% with one of the other agents with a power of 90% and P-value of 5%. It will be larger than any trial of an immunosuppressant agent so far performed in CIDP. However, recruitment will be easier because inclusion criteria will be broad and allow randomisation of any patient in whom their neurologist wishes to introduce an immunosuppressant. Avoidance of blinding and use of simple monitoring with facetime will simplify running the trial and reduce expense. The trial will follow participants and measure outcomes at 12 months. Other outcomes will consist only of grip strength, time to walk 10 m and Euroqol, the last allowing us to estimate the cost per QALY of rituximab or abatacept. Even including central analysis of key biomarkers, the trial will only cost 3 million euros, a fraction of the cost of the usual phase III pharmaceutical company trial. # 2016 Elsevier Masson SAS. All rights reserved.

1.

Prevalence of CIDP

The rarity of CIDP creates a major problem for investigating its treatment. The worldwide prevalence lies between 0.8 and 8.9 * Corresponding author. E-mail address: [email protected] (R.A.C. Hughes). http://dx.doi.org/10.1016/j.neurol.2016.07.020 0035-3787/# 2016 Elsevier Masson SAS. All rights reserved.

per 100,000 and the prevalence in South East England in 2008 was 2.84 (95% confidence interval 2.31–3.45) per 100,000 [1]. The prevalence studies used broad definitions of CIDP similar to or based on the EFNS/PNS criteria [2]. They include typical forms with classical symmetrical motor and sensory

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neuropathy and atypical forms. Atypical CIDP includes asymmetrical, pure sensory, pure motor, distal acquired demyelinating symmetrical and focal forms. Cases associated with diabetes and other diseases are usually included with CIDP. The frequency of diabetes in CIDP ranged from 4% to 26% in different studies around the world and was 9.9% in a South East England population of 101 people with CIDP [1]. Paraproteinaemia is the other disease particularly commonly associated with CIDP, occurring in about 10% of cases of acquired demyelinating neuropathy [3]. If there is no associated malignant plasma cell dyscrasia and if the paraprotein is not an IgM with antibody activity against myelin-associated glycoprotein, it is usual to include paraprotein associated demyelinating neuropathy as CIDP [2]. The even rarer condition of multifocal motor neuropathy has a different clinical picture from CIDP and an acknowledged difference in response to treatment (lack of response to corticosteroids) so that it is best kept separate and not included in CIDP treatment trials [4]. CIDP may be associated, albeit less commonly, with a wide variety of other diseases including connective tissue disorders and inflammatory bowel disease [5,6]. To make the results of a treatment trial generally applicable, we should include all forms of CIDP including those with associated diseases provided that any associated disease does not contraindicate the treatment being tried. However, we should exclude IgM anti- myelin-associated glycoprotein neuropathy and multifocal motor neuropathy because of their known differing pathology, pathogenesis, clinical course and response to treatment. If we accept a conservative estimate of the prevalence of CIDP of 2 per 100,000, then we will have 1292 patients in France’s population of 64.6 million. At first glance, this seems enough to conduct a trial but only a small proportion attend academic centres, fulfil entry criteria into a trial and are willing to accept randomisation, so in practice, only a fraction of this number perhaps 10%, roughly 130, would be available for a trial. Recent trials of immunoglobulin preparations and of immunosuppressive agents have all recruited much more slowly than hoped or even failed to recruit the number desired. Consequently, we need to launch our dream trial at a multinational level. If the trial were done in Europe, we could take advantage of a potential 14,850 patients from the 742.5 million population (www.worldometers.info). Ten per cent of this would generate nearly 1500 patients and should allow us to recruit, say, 180 patients with a large margin for error. It would be possible to go for worldwide international recruitment but restricting the trial to Europe will allow us to take advantage of the trans-border agreements which facilitate trials in the EU. For instance, according to regulation (EU) No. 536/2014, the EU will foster ‘‘clinical trials for the development of medicinal products addressed to subjects affected by severe, debilitating and often life-threatening diseases affecting no more than one person in 50,000 in the Union (ultra-rare diseases)’’. The regulation will avoid ‘‘the multiple submission of largely identical information’’, allow ‘‘the submission of one application dossier to all the Member States concerned through a single submission portal’’, set ‘‘strictly defined deadlines for the assessment of clinical trial applications’’. It will simplify ‘‘reporting procedures which will spare sponsors from submitting broadly identical information separately to various bodies and different Member

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States’’. The new regulation will start ‘‘no earlier than May 2016’’. Modern European treatment trials need to take advantage of this Brave New World and are yet another argument for the United Kingdom to remain in the EU, a moot point at the time of writing.

2.

Pathogenesis of CIDP

Investigations of the pathogenesis of CIDP give abundant evidence of the presence of inflammation but fail to identify the precise underlying mechanisms [7,8]. Biopsies of active disease sites show perivascular infiltration of CD8+ and CD4+ T cells and macrophages in the endoneurium. The T cell repertoire of CD8+ cells in particular is restricted indicating their activation. There is upregulation of MHC class I and II molecules on macrophages and Schwann cells and secretion of inflammatory cytokines. Conversely, the numbers of circulating regulatory T cells are reduced and those that remain have reduced regulatory function. In animal, models immunisation with the compact myelin protein antigens P0, P2 and PMP22 has long been known to be capable of inducing experimental autoimmune neuritis whose pathology resembles CIDP. Furthermore, manipulation of immunoregulatory genes in mice has resulted in the development of three different models of spontaneous autoimmune neuropathy which resemble CIDP. The major peripheral myelin protein P0 is the target antigen in at least one of these. Against expectations, these advances have not been matched by the discovery of cellular or humoral immunity to the same antigens in significant numbers of patients with CIDP although there is some evidence of antibodies to P0 in a small proportion [9]. Most recently, interest has focussed on antibodies to nodal antigens: antibodies to contactin and neurofascin 155 have been found but only in very small percentages of patients. While the numbers are very small the finding is likely to be significant because the findings have been confirmed and the clinical features of patients with these antibodies are similar in different series. Antibodies to contactin 1 were present in 3 of 46 patients in one series [10], 4 out of 54 in another [11] and 13 out of 533 [12] in a third: all had an acute onset and poor response to IVIg with predominant motor disease in the first two series and sensory ataxia in the third. Antibodies to neurofascin 155 were present in 2 out of 113 [13] and 2 out of 53 patients [14] who had severe disease with a marked tremor and poor response to IVIg. An interesting common characteristic of these patients was that the antibodies were predominantly of the IgG4 subclass, which is not complement fixing and may exert its effects by blocking the function of its target molecule, thus disrupting the adhesion of the Schwann cell paranodal loops. In conclusion, CIDP seems to be multifactorial with evidence of CD4 and CD8 T cell involvement and complement fixing and function blocking antibodies in different patients. Treatment trials need to take account of this diversity.

3.

Past treatment trials

There have been many observational studies of steroid, IVIg, plasma exchange and immunosuppressive treatments [15].

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However, the clinical course of the disease is so variable that conclusions about efficacy can only be drawn from randomised controlled trials (RCTs). According to at least moderate evidence from RCTs synthesized in Cochrane reviews [16–18], corticosteroids, intravenous immunoglobulin and plasma exchange each have short-term efficacy. There is also evidence from RCTs of a long-term duration of efficacy of IVIg [19] and corticosteroids [20]. In clinical practice, continuous or intermittent corticosteroids or repeated IVIg are commonly used as maintenance treatment and plasma exchange sometimes. However, these treatments are inconvenient, potentially dangerous, expensive or all three. Only a small number of RCTs have tried to find an efficacious, more permanent solution [15]. One trial of azathioprine (27 participants), two of interferon beta-1a (77 participants in total) and one of methotrexate (60 participants) failed to show significant benefit but were probably all underpowered. Case reports and small series have reported benefit in 28 out of 88 patients treated with azathioprine, 34 of 50 with cyclophosphamide, 33 of 53 with cyclosporin, 8 of 23 with methotrexate, 22 of 49 with mycophenolate, 12 of 17 with rituximab, 15 of 34 with interferon beta-1a and 7 of 8 with haematopoietic stem cell transplantation. There have also been reports of the use of alemtuzumab, etanercept, interferon alpha, natalizumab [21] and tacrolimus in smaller numbers. The regularly updated Cochrane review gives references [15]. The possible greater efficacy of haematopoietic stem cell transplantation is counterbalanced by its greater toxicity. Otherwise, literature review does not provide grounds for preferring one treatment to another in future trials. There are only two relevant ongoing trials one international trial of fingolimod (clinicaltrials.gov: NCT01625182) and one French trial of mycophenolate (clinicaltrials.gov: NCT02494505), both of which are near to conclusion. Since many candidate immunosuppressive drugs have been tested, shown effective and even licensed for multiple sclerosis and rheumatoid arthritis, it is shameful that so little effort has been directed at CIDP.

4.

Agents to be tested

In choosing agents to test, the lack of agreement about the disease mechanism and the absence of a leading candidate from the literature is a problem which we can turn into an opportunity. It makes us free to select and compare agents which will help determine the underlying pathogenesis and if we make the trial large enough, we will be able to provide at least pilot data about differential effects in different disease subtypes. Therefore, we propose to investigate whether CIDP is a predominantly B cell or T cell disease by comparing an antiB cell agent with an anti-T cell agent simultaneously with placebo. Admittedly, the complex relationship between T and B cell functions means that any B cell agent may also interfere with T cell function and vice versa so that a positive result will not prove that CIDP is predominantly B or T cell driven. However, the comparative trial proposed will be much more informative than a trial testing a blunderbuss agent such as alemtuzumab which depletes all lymphocytes and monocytes. The most readily available anti-B cell agent will be rituximab which has been licensed for rheumatoid arthritis

and the subject of a successful trial in multiple sclerosis [22]. An ENMC consensus workshop recommended its trial in CIDP nearly 10 years ago but no trial has been launched [23]. Rituximab is a chimeric mouse-human monoclonal antibody given by intravenous infusion. It reacts with the CD20 antigen present on mature B cells but not plasma cells. It causes prolonged depletion of circulating B cells. Rituximab is expensive but is nearing the end of its patent so that cheaper forms may soon become available. Next generation partially and fully humanised anti-CD20 monoclonal antibodies are under development. The standard treatment regimen of rituximab for rheumatoid arthritis is two single intravenous infusions of 750 mg/m2 (usually 1000 mg) 2 weeks apart, repeated after 24 weeks if necessary. Such a regimen will be practical for our dream CIDP trial. For our anti-T-cell agent, abatacept will be an appropriate choice having much greater specificity for T-cells than other agents such as natalizumab or alemtuzumab. It is a fusion protein of the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and part of the Fc portion of IgG1. It binds to CD80 and CD86 on antigen presenting cells, inhibits their interaction with CD28 (previously called T-cellspecific surface glycoprotein) on the T-cell and so preventing full T-cell activation [24]. Abatacept has a license for use in combination with methotrexate in ‘‘moderate to severe active rheumatoid arthritis in adult patients who responded inadequately to previous therapy with one or more diseasemodifying antirheumatic drugs’’ (www.medicines.org.uk/ emc/medicine/19714/SPC/ORENCIA). It is also licensed for use with methotrexate in children with idiopathic juvenile articular polyarthritis which is an advantage since we want to include children in our trial. The dose for rheumatoid arthritis is 10 mg/kg by intravenous infusion repeated after 2 and 4 weeks and then monthly. Alternatively, 125 mg may be given weekly by subcutaneous injection. To permit a regimen similar to that for rituximab the intravenous regimen will be preferable for our trial. Because abatacept did not prevent renal allograft rejection, the analogue belatacept was developed and has been approved for that purpose, although not for any other indication [25,26]. The dose regimen for renal transplantation is slightly more arduous involving intravenous infusions on the day of transplant and then at 5, 14 and 28 days and then monthly. It requires co-administration of corticosteroids and mycophenolate. Since abatacept is approved for rheumatoid arthritis, has been used for longer and is better known, we prefer it to belatacept for our trial. There is no disguising the fact that immunosuppressive agents carry risks. Rituximab, abatacept and belatacept all carry risks of immediate hypersensitivity reactions and causing infections including at least a theoretical risk of progressive multifocal leukoencephalopathy. However, both rituximab and abatacept are in common usage and are felt to be relatively ‘‘low risk’’ and easy to use. A Cochrane systematic review of adverse events of biologics containing a complex comparative network meta-analysis demonstrated that, within the limitations of the trial evidence available, abatacept and rituximab are very safe [27]. Information and consent forms in our trial will need to specify the risks but patients with severe CIDP may be attracted by the opportunity to help

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find a treatment which may reduce their disability and current, often arduous, treatment regimen. Other agents remain either too experimental or remain unavailable for clinical use. The wish list is almost infinite! A very promising potential agent would be an interleukin 15 (IL15) inhibitor. IL15 is a small signalling molecule which controls both T-cell and NK-cell activation and proliferation and works in conjunction with IL2. In animals, IL15 prevents activated T-cell apoptosis and thus provides survival support to activated and memory T-cells. In humans the effects of IL15 are similar [28] and an IL15 inhibitor was shown to be capable of reducing T-cell activity and clinical symptoms in mice and patients with coeliac disease [29]. There is some redundancy in the T-cell stimulation and apoptosis survival pathway and adjuvant or combination therapy might be required. If we were allowed a second dream, IL15 blockade would be worth considering.

5.

Participants

Previous trials have been bedevilled with tight inclusion criteria and innumerable exclusion criteria which have made recruitment difficult and slow. We will place as few restrictions on trial entry as possible not just because it will facilitate recruitment but especially because it will make the results of the trial more generalizable. There is no reason to exclude children, except for infants who cannot walk and could not contribute to the primary outcome measure. CIDP is more common in the elderly which makes it all the more important that they be included. Therefore, the trial will include all ages, both genders and all the types of CIDP fulfilling the definite EFNS/PNS criteria [2] regardless of the presence of diabetes mellitus, a paraprotein or other systemic diseases. Exclusion criteria will be as few as possible. Alternative diagnoses such as multifocal motor neuropathy and anti-MAG antibody IgM paraprotein associated neuropathy will exclude participation. The trial will not include patients in whom the risks of rituximab or abatacept outweigh the possible advantages of using one of them. Concomitant treatment with immunosuppressants drugs such as azathioprine, mycophenolate or cyclophosphamide will not exclude patients but such participants will be encouraged to reduce such medication 12 weeks after randomisation. Active infection of any sort will be the most important exclusion criterion but this will not preclude trial entry after treatment of the infection. For ethical reasons, participants will need to be able to understand what the trial involves so that they have the legal capacity to provide informed consent. The trial will capture participants who are considering what treatment to add or use next when at least one of the standard treatments, corticosteroids and IVIg, are insufficient. This will mean that they will have been on treatment for at least 6 months. To provide a baseline for comparison, participants will be followed on their existing treatment for 4 weeks before randomisation unless the proposed outcome measures are already available in the hospital notes for the same period. As a rule, all participants will have weakness and impaired disability with a score of at least 1 on the ONLS but

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participants who have had weakness and disability recorded in the hospital records upon reduction of treatment during the past 6 months will be eligible.

6.

Outcome measures

A workshop at the ENMC wisely proposed that the primary outcome for CIDP trials should measure disability, being more directly relevant to the needs of the patient than impairment and more directly relevant to the biological effect of the drug than quality of life [30]. The only outcome successfully used to obtain registration of a drug by the FDA is a modified version of the Inflammatory neuropathy cause and treatment (INCAT) scale [31]. In our dream trial, we are free to choose the scale which we regard as the best so that we will select the Overall neuropathy limitations scale (ONLS) which was adapted from the similar Overall disability sum score scale and is more explicit than that and the INCAT scale [32]. This will be the primary outcome measure because it is simple, validated and responsive and it has a known minimum clinically significant difference of about 0.67 of a grade [33]. However, the ONLS does have the disadvantage of being an ordinal non-linear scale and we will also collect the Rasch-built overall disability scale (RODS). This has the properties of being truly linear and it can be confidently manipulated with parametric statistics [34–36]. By the time our dream trial starts, we will have had more experience of the RODS and may want to use it as the primary outcome in place of the ONLS. Right hand grip strength with the Martin Vigorimeter [37] and the time to walk 10 m will be our measures of impairment. The Euroqol will provide a simple measure of quality of life to allow economic assessments [38]. Adverse events and serious adverse events will be collected in the usual way. We still have no reliable or widely applicable biochemical or immunological biomarkers for CIDP diagnosis or treatment response. Because this trial will be very effective in treating patients with at least one of the agents, we will have the opportunity to examine the effect of treatment in homogeneous and carefully phenotyped groups of patients. The trial will collect samples of serum, CSF, urine and DNA which will be used in exploratory secondary analyses. Highly sensitive platforms (for example, the fully automated immunoassay platform with multiplexing and custom assay, SiMOA) for measuring cytokines, neurofilaments, and products of axonal degeneration and Schwann cell damage will provide pathogenic and biomarker information.

7.

Trial design

The trial will be a randomised but not blinded parallel group trial of people not responding adequately to current treatment, as described in the paragraph on participants, with equal numbers in each group. The trial will have a simple telephonic randomisation system which will assign patients to rituximab, abatacept or usual treatment alone using a minimisation schedule so that treatments will be balanced between centres or at least countries. The trial will need to be multicentre and multinational in order to achieve the

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numbers needed for an adequately powered trial. Ideally, the trial would be double-blinded but double-blinding enormously increases the complexity and expense of the trial. Only the most philanthropic drug company would sponsor and fund a trial which compares its own drug with another which is as likely to be as effective and might be more effective or safer. The simplest design will be to randomise participants to one of the three treatments and ask them to persevere with their assigned treatment for a period of 24 weeks. They will continue with their other treatment which will be likely to be corticosteroids or IVIg or possibly intermittent plasma exchange. The primary outcome will be measured at 24 weeks and will be improvement from baseline of the ONLS by 1 or more grades without increase in corticosteroids or IVIg or use of plasma exchange. Secondary outcomes will be change in grip strength, 10-m walk time and Euroqol from baseline. In the initial analysis, these changes will be calculated disregarding any supplementary treatment which might have been added. At the end of the 24 weeks, participants will have the option to continue in their assigned group if they have improved or at least not deteriorated as measured on the ONLS scale. If they have deteriorated, then the investigator will increase the amount of corticosteroids or IVIg or add plasma exchange at their discretion. Follow-up and where possible treatment according to the assigned group will continue for 12 months as recommended by the ENMC consensus workshop [39]. The primary outcome at 12 months will be improvement from baseline of the ONLS by 1 or more grades without increase in corticosteroids or IVIg or use of plasma exchange or maintenance of ONLS grade with reduction of concomitant treatment by 50% or more during the last 3 months compared with baseline or stopping of concomitant immunosuppressive drugs. Participants randomised to standard treatment who had increased their corticosteroids or IVIg or use plasma exchange during the first 24 weeks will be considered as non-responders at 12 months but will be offered the opportunity of being rerandomised between rituximab or abatacept at 24 weeks. The results from these participants will be added to those from the main trial in an exploratory analysis comparing rituximab with abatacept. After 24 weeks, investigators will be encouraged to adjust the concomitant treatment according the needs of the participant. Non-responders to rituximab or abatacept at 12 months will be offered the opportunity of receiving the alternative treatment and then followed for a further 12 months.

8.

Statistical analysis

If this dream trial becomes a reality, we will need a friendly statistician to be a key member of the trial team and help with the design, especially with the calculation of the sample size. There will be two primary comparisons one between rituximab and standard treatment and one between abatacept and standard treatment. We will be looking for a fairly large effect. Let us suppose that the number of responders (people who improve by one ONLS grade) on standard treatment is 20%, then we would like to see at least 30% of responders on rituximab or abatacept, i.e., a 50% increase compared with

standard treatment. We need to know how many participants would need to be in each group for us to detect such a difference with a power of 90%, a two-tailed probability of 5% and an allowance of 10% for dropouts. According to preliminary estimates, the first calculation would require a total sample of 180 participants, larger than any trial of an immunosuppressant agent so far performed in CIDP. For the comparison between rituximab and abatacept, the calculation will depend on the success of each.

9.

Economic analysis

Treatment of CIDP is very expensive because many patients are treated with IVIg. McCrone calculated that the cost per QALY of using IVIg rather than oral prednisolone was 350,000 euros per year [40]. Mahdi-Rogers calculated that the annual cost of treating CIDP in England 28,750 euros per patient and was much higher in those being treated with IVIg [41]. By introducing the Euroqol as an outcome measure into this trial, we will be able to calculate the difference in QALYs gained by the participants over the course of the year and make educated estimates of the costs per QALY of rituximab and abatacept. Although both drugs are expensive, they might reduce the costs of treatment if they result in reduction of the use of IVIg.

10.

Trial management

A trial steering committee will be the senior body responsible for preparing the trial protocol, obtaining funding for the trial and overseeing trial management. It will consist of an executive team and at least one peripheral neuropathy expert from each participating country. The executive team will manage the trial, consisting of one or more peripheral neuropathy experts, a neurophysiologist, an immunologist, at least one patient representative and a statistician. The team will have support from an experienced full time trial manager, an assistant trial manager and a database manager. Each participating country will have a part time trial monitor. The monitors will use facetime or similar technology to achieve monitoring of baseline demographic information and ONLS score and 24-week ONLS score in every participant without having to visit the trial centre. Participating centres will email copies of nerve conduction study data for approval by the executive neurophysiologist before randomisation. Regardless of the fact that a safety monitoring committee is not strictly necessary for an open study, it will be safer to have such a committee with an independent peripheral nerve expert, immunologist, patient representative and statistician.

Funding Ideally, this trial will be double-blinded and employ infusions of rituximab, abatacept and placebo, substituting placebo where necessary so that the frequency of infusions matched those of the more intensive abatacept regimen. Having identical blinded infusions manufactured would multiply

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the cost of the trial many fold and their use would enormously complicate the trial. Even an open trial will be expensive. The executive team will need funding for the chief investigator (0.2 full time equivalent), neurophysiologist (0.1), immunologist (0.1), statistician (0.2), trial manager (1.0), assistant trial manager (1.0) and database manager (1.0) for 5 years (1 year start up, 2 years recruitment, 1 year follow-up, 1 year analysis and writing up). There will be about 20 country monitors (0.1) each. Not all these staff are needed for the full 5 years that the trial will take to initiate, run and analyse but at an average cost of 52,000 euros per year per full time staff member, the bill comes to 1.2 million euros. In 2016 in the UK, the drug costs will be 600  £6985 for rituximab (2 infusions at baseline, 2 at 24 weeks), and 60  £11800 for abatacept (3 loading infusions of 750 mg every 2 weeks followed by monthly infusions to 12 months) totalling about 1.5 million euros. Collection, shipment and analysis of biosamples from 180 patients will cost, say, 50,000 euros. Administrative costs and contingencies will need another 250,000 euros so that the total cost with an allowance for contingencies will be in the order of 3 million euros, an order of magnitude cheaper than a standard pharmacological registration trial. It will be an expensive dream but a successful result will bring great benefits to patients and reduce the costs to healthcare providers. The trial steering committee and management team will need to identify a sponsor, probably the institution in which the chief investigator and the trial are based, and seek funding from the companies which market the selected drugs, the EU Framework programme for research and innovation, national research bodies such as the UK National institute for health research and CIDP related charities especially GBS-CIDP Foundation International.

Disclosure of interest RACH has consultancies with CSL Behring and LFB which manufacture human immune globulin and with Novartis which is conducting a randomised trial of fingolimod in CIDP. RACH is an honorary board member of GBS CIDP Foundation International and patron of ‘‘gain’’, the British charity which covers CIDP. MPTL has received teaching and consultancy honoraria from CSL Behring and Grifols, manufacturers of immunoglobulin products. He has been PI in clinical trials run by CSL Behring and Novartis for CIDP related products. He is joint coordinating editor of Cochrane Neuromuscular and on the Medical Advisory Board for ‘‘gain’’. Richard Hughes, MD FRCP FMedSci FEAN, was consultant neurologist at Guy’s Hospital and is now Emeritus professor of neurology at King’s College London and Honorary Professor at University College London. His research has focussed on the cause and treatment of inflammatory neurological diseases. He founded Cochrane Neuromuscular. He was formerly editor of the Journal of neurology neurosurgery and psychiatry and President of the European federation of neurological societies. Michael Lunn, MBBS FRCP PhD, is consultant neurologist at the National Hospital for Neurology and Neurosurgery, Queen Square. He trained in Cambridge and London in the UK and the

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Johns Hopkins hospital in the USA. His research covers many topics in the inflammatory peripheral nerve diseases from paraproteinaemic neuropathies and POEMS syndrome, to CIDP and the Guillain-Barre´ syndrome. Biomarkers and outcome measures as well as treatment trials are areas of significant interest. As well as seeing many patients with inflammatory neuropathy, he runs a diagnostic laboratory and is currently Joint coordinating editor of Cochrane Neuromuscular.

references

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