129th ENMC International Workshop: Clinical Trials for Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Multifocal Motor Neuropathy, 27th October 2004, Schiphol airport, The Netherlands
Article Outline
- 1. Need for a trial
- 2. Intervention
- 3. Participants
- 4. Outcome measures
- 5. The way forward
- 6. Participants
- Acknowledgements
- References
- Copyright
1. Need for a trial
There is uncertainty about the best immunosuppressive treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) and consequently a wide variation in practice. CIDP affects between 2 and 8 per 100,000 and MMN has a prevalence about 10 times lower. Both conditions are economically important because intravenous immunoglobulin (IVIg) is often used in their treatment and is very expensive especially because of the need for repeated courses. Multicentre trials are necessary to provide sufficient participants for adequately powered trials and need to be conducted at a multinational level. The evidence for treatment has been systematically reviewed in Cochrane reviews [1], [2] and a previous ENMC workshop had already considered MMN [3]. In CIDP steroids, IVIg or plasma exchange (PE) and in MMN IVIg provide short-term benefit but the value of immunosuppressant treatment has not been adequately evaluated.
Encouragingly there are four ongoing trials in CIDP and one in MMN. A Bayer trial compares IVIg with placebo over a longer period than has been tested before (M Maas-Enriquez, personal communication). A Biogen-Idec trial tests whether interferon-beta 1a will reduce the requirement for IVIg [4]. A Dutch trial aims to find out whether pulsed high dose dexamethasone induces remissions more often and more rapidly and is more effective than standard prednisolone treatment (I van Schaik personal communication). An Italian trial aims to compare IVIg and high dose intravenous methylprednisolone (IVMP) for 6 months (E Nobile-Orazio, personal communication). A Utrecht trial of mycophenolate mofetil in MMN with 28 participants is in progress (L van den Berg, personal communication). With the exception of the last, none of these trials address the question whether immunosuppressant agents are effective and the workshop agreed that such trials are needed.
2. Intervention
Unfortunately the detailed pathogenesis of CIDP and MMN is obscure [5], [6]. The presence of antibodies to ganglioside GM1 in about 50% of patients with MMN and the response of CIDP to plasma exchange suggest but are far from proving an antibody mediated mechanism. There is also evidence of activation of T cells especially in CIDP and the animal models of CIDP are clearly driven by T helper cell mechanisms. The lack of understanding of the pathogenesis of CIDP and MMN hinders the choice of immunosuppressive drug to be tried. Furthermore review of the non-randomised literature does not reveal a favourite drug to be tested (Table 1). There is more anecdotal evidence concerning some drugs such as cyclophosphamide (and in CIDP ciclosporin) than others such as azathioprine and methotrexate but not to an extent that should determine the choice of drug for a randomised trial. In most patients CIDP and certainly MMN are not life threatening diseases and less toxic drugs than cyclophosphamide or ciclosporin would be preferred. Azathioprine has been used as the immunosuppressant of choice because neurologists are familiar with its use in other situations, for instance in multiple sclerosis. Familiarity is not an adequate reason for selecting a drug. In the absence of convincing theoretical arguments to favour a B cell as opposed to T cell mechanism the choice of a drug, such as rituximab, which specifically targets the B cell would be unwise.
Table 1. Summary of the evidence for the use of immunosuppressant drugs derived from the Cochrane reviews [1], [2]
| Mechanism | Cost | Evidence | Safety | ||
|---|---|---|---|---|---|
| CIDP | MMN | ||||
| Cyclophosphamide | Broad | + | + | + | −−− |
| Azathioprine | Broad | + | + | ? | −− |
| Methotrexate | Broad | + | 0 | 0 | − |
| Ciclosporin | Broad | ++ | + | 0 | −− |
| Mycophenolate | Lymphocyte | +++ | + | ? | − |
| Rituximab | B cell | +++ | ? | + | − |
| Beta interferon 1a | Broad | +++ | + | + | − |
| Alpha interferon | Broad | +++ | + | 0 | − |
| Etanercept | T cell | +++ | ? | 0 | − |
Methotrexate in an oral dose of 7.5–15
mg (up to 25mg) weekly is preferred by rheumatologists as their first line disease modifying drug on account of greater efficacy observed in practice and better safety profile [7], [8]. Methotrexate has the advantage of being inexpensive but the need for careful monitoring of the blood count, liver function and lungs are drawbacks. Mycophenolate mofetil is a possible alternative because of its specific suppression of lymphocytes and not other cells and superior tolerance and safety profile [9], [10], [11], [12]. Its use is encouraged by favourable experience compared with azathioprine, ciclosporin and cyclophosphamide in the prevention of transplant rejection. There are anecdotal reports and small series of its successful use in non-neurological chronic inflammatory diseases, including Graves' ophthalmopathy, lupus nephritis, psoriasis, rheumatoid arthritis and inflammatory bowel disease [13]. There are encouraging reports and a small encouraging but inconclusive randomised trial of its use in myasthenia gravis and a large randomised trial is in progress [14]. The published reports describe no or only occasional responses to treatment in CIDP [9], [10], [11], [12] but J Pollard (personal communication) reports favourable results in 10 patients with CIDP. The drawback of mycophenolate mofetil is expense but if it were to reduce the need for IVIg and other treatments it might be cost effective. The workshop agreed that methotrexate and mycophenolate mofetil were the preferred candidate drugs.
The duration of treatment should be at least 4 months since shorter times might not be adequate, longer times of placebo treatment would be unacceptable to patients and a drug which took longer than 4 months to show an effect would be likely to be deemed unsatisfactory.
Although it would be tempting to have a three arm trial testing drug A v drug B v placebo, recruitment of adequate numbers of patients and blinding patients and investigators would be difficult.
3. Participants
A trial of starting an immunosuppressant when inducing remission with steroids or IVIg would be attractive but would include about 50% of patients who would have gone into long-term remission which would reduce its power to detect an effect. The workshop agreed that the most appropriate trial population would be those who were established on IVIg or prednisolone or plasma exchange who had failed to show an adequate response on at least one of these. This would mean that participants would have to be randomised at least 6 months after starting treatment with steroids, IVIg or plasma exchange.
An EFNS Task Force led by R Hughes is preparing consensus criteria for use in clinical practice as part of a Management Guideline. A Guillain-Barré Syndrome Foundation International working party led by C-L Koski is researching diagnostic criteria for CIDP using epidemiological consensus techniques. The criteria used in a clinical trial may need to be more restrictive but should not differ too much because if they do the trial conclusions may not be generalizable. Provisional diagnostic criteria for CIDP for use in a randomised trial were agreed as listed in Table 2 and electrophysiological criteria in Table 3. Diagnostic criteria for randomised trials in MMN proposed in the earlier workshop were endorsed with minor revisions (no upper age limit; upper limb weakness should be present but need not be predominant; CSF examination need not be mandatory).
Table 2. Diagnostic criteria for CIDP for use in randomised trials
| Inclusion criteria |
| Diagnosis of CIDP by a consultant neurologist with a special interest in peripheral neuropathy |
| Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least 2 months; cranial nerves may be affected |
| Absent or reduced tendon reflexes in all extremities |
| At least moderate disability in arms or legs (INCAT scale grade 2) and MRC grade 4 or less weakness in at least one muscle OR continued need for IVIG or steroid or PE to remain in a satisfactory neurological condition, demonstrated during the past 6 months by the development of at least moderate disability in arms or legs (INCAT scale grade 2) and MRC grade 4 or less weakness in at least one muscle group on one side |
| Electrophysiological evidence of primary demyelination (see Table 3) |
Exclusion criteria |
| Age<18 years |
| Pregnancy, planned pregnancy or unwillingness to practice contraception |
| Severe concurrent medical conditions which would prevent treatment or assessment |
| Alternative cause such as drug or toxin, hereditary neuropathy or concomitant diseases such as HIV infection, Lyme disease, chronic active hepatitis, systemic lupus erythematosus, IgM paraprotein with anti-MAG antibodies, vasculitis, hematological and non-hematological malignancies |
| Presence of a sensory level or sphincter disturbance |
| Multifocal motor neuropathy |
| Atypical CIDP (pure sensory, focal presentations, significant central nervous system involvement) |
| Treatment with immunomodulatory agents other than IVIG, PE or steroids during the previous 3 months |
Table 3. Electrodiagnostic criteria for CIDP based on Van den Bergh and Piéret [19] and Thaisetthawatkul et al. [20]
| I Definite: |
| A. At least 50% prolongation of motor distal latency above the upper limit of normal values in 2 nerves, or |
| B. At least 30% slowing of motor conduction velocity below the lower limit of normal values in 2 nerves, or |
| C. At least 20% prolongation of F-wave latency above the upper limit of normal values in 2 nerves (50% if amplitude of distal negative peak CMAP<80% of lower limit of normal values), or |
| D. Absence of F-waves in 2 nerves if amplitude of distal negative peak CMAP at least 20% of lower limit of normal values + at least one other demyelinating parameter in at least one other nerve, or |
| E. Partial motor conduction block: at least 50% amplitude reduction of the proximal negative peak CMAP if distal negative peak CMAP at least 20% of lower limit of normal values in 2 nerves or in 1 nerve + at least one other demyelinating parameter in at least one other nerve, or |
| F. Abnormal temporal dispersion (>30% duration increase between the proximal and distal negative peak CMAP) in at least 2 nerves, or |
| G. Distal CMAP duration (interval between onset of the first negative peak and return to baseline of the last negative peak) of at least 9ms in at least 1 nerve + at least one other demyelinating parameter in at least one other nerve |
| II Probable: At least 30% amplitude reduction of the proximal negative peak CMAP, excluding the posterior tibial nerve, if distal negative peak CMAP at least 20% of lower limit of normal values in 2 nerves or in 1 nerve + at least one other demyelinating parameter in at least one other nerve |
4. Outcome measures
The selection of outcome measures for use in trials of treatment is difficult for both CIDP and MMN. The disability in CIDP affects upper and lower limbs but is usually predominant in the lower limbs. The disability in MMN is usually predominant in the upper limbs. For both conditions outcome measures should cover disability, impairment and quality of life. They should be simple, valid, reliable and responsive and correlate with disease severity. They should also allow comparison with earlier trials to facilitate systematic review. For the reasons stated above the primary outcome should be measured 6 months after randomisation. The measures for consideration were reduced to those listed in Table 4. There was a consensus that the primary outcome measure should be a measure which would be meaningful to patients with a preference for a disability measure. For CIDP the choice lies between the INCAT Overall Disability Status Scale (ODSS) [15], [16] which has been validated for CIDP and which is being used in the two large pharmaceutical company trials mentioned above and the Amsterdam Linear Disability Status Scale (ALDS) currently being developed [17]. The ALDS consists of a questionnaire providing a list of tasks of graded severity which the patient has to state whether they can or cannot undertake. Ivo van Schaik provided data from an ongoing study in which he is validating the scale in CIDP: his results suggest that it correlates with the ODSS and is superior in not having a ceiling effect. The workshop agreed that this scale should be incorporated in the trial and might be considered as the primary outcome measure if the ongoing study demonstrated that it was more responsive. Work is urgently needed to validate the ODSS and the ALDS in MMN and to decide whether the upper limb component of the ODSS should be selected in preference to the overall scale. The workshop did not consider impairment measures other than those listed in Table 4. The Mayo clinic Neuropathy Impairment Score (NIS), formerly called the Neurological Disability Score, summates the neurological examination and has been used successfully in single centre trials of treatment for CIDP, and in other neuropathies, and also deserves consideration [18]. The workshop did not consider that electrophysiological outcome measures would be useful because of the difficulties in obtaining reproducible longitudinal results arising from variations in electrodes placement. Electrophysiological measures also lack easily interpretable meaning to patients. Further consideration will be given to outcome measures at a workshop in December 2004.
Table 4. Outcome measures for use in randomised trials of CIDP and MMN
| CIDP | MMN | |||
|---|---|---|---|---|
| Outcome | Evidence | Outcome | Evidence | |
| Disability level | ||||
| ALDS | Primary/secondary | – | Primary/secondary | – |
| INCAT overall 12-point disability scale | Primary/secondary | v,rl,rp | Primary/secondary | |
| INCAT arm 6-point disability scale | – | Primary/secondary | – | |
Impairment level | ||||
| MRC sum score | Secondary | v,rl,rp | Secondary | – |
| Martin vigorimeter (grip strength) | Secondary | v,rl,rp | Secondary | – |
| INCAT sensory sumscore | Secondary | v,rl,rp | – | |
| Amount IVIg used | Secondary | na | Secondary | na |
| Amount prednisolone used | Secondary | na | – | |
| Amount plasma exchange used | Secondary | na | – | |
QoL | ||||
| SF-36 | Secondary | v,rl,rp | Secondary | – |
| EuroQol | Secondary | v,rl,rp | Secondary | – |
Adverse events | ||||
| Number of all and serious adverse events | Secondary | na | Secondary | na |
Although not a critical outcome measure, the opportunity should be taken to collect serum (and in some centres if feasible white cells) at randomisation and at the end of the trial. Assays would include measuring antibodies to gangliosides by ELISA and TLC and to myelin proteins by ELISA and Western blot. Serum should also be stored for testing against appropriate candidate antigens as they are discovered.
Because of the high costs of treatment for IVIg the trials should include health economic outcomes. Treatment costs include the cost of the intervention and the costs of other services which may be affected by any change in the intervention and the costs of side effects. To measure the cost of other services the trials will need to use an instrument such as the Client Service Receipt Inventory (CSRI) which records service contacts over a retrospective period (6 months for example). The CSRI has been used in around 200 studies including a recent trial of IVIg and prednisolone for CIDP. Cost data should be combined with information on effectiveness so that the most appropriate intervention can be determined. If a particular treatment resulted in better outcomes and lower costs than an alternative then it would be preferred. However, it might well produce better outcomes and higher costs. In this case it is necessary to calculate the cost of achieving one extra unit of outcome (or a clinically important change in outcome) and then see if this is acceptable. To make valid comparisons we will need a generic measure of outcome, usually quality of life. The most widely used is the EuroQol which rates five areas of health-related quality of life with one of three scores. The SF-36 is a possible alternative.
5. The way forward
The workshop agreed to pursue the preparation of applications for funding for multicentre multinational trials of immunosuppression in CIDP and MMN. To strengthen the applications more work is needed to validate the ALDS in CIDP and MMN and compare its responsiveness with the INCAT ODSS. In MMN work is needed to compare the responsiveness of the upper limb component with the whole of the INCAT ODSS. In both diseases work is needed to collect retrospective and preferably prospective data concerning the use of the candidate drugs methotrexate and mycophenolate mofetil. Trials will need to obey the very demanding regulations of the European Clinical Trials Directive and to be planned and conducted with the agreement and support of the patient community.
6. Participants
- P Blomkwist
The Netherlands
- R Hughes
United Kingdom
- I Illa
Spain
- J-M Léger
France
- P McCrone
United Kingdom
- C Murphy
United Kingdom
- E Nobile-Orazio
Italy
- A Swan
United Kingdom
- L van den Berg
The Netherlands
- P van den Bergh
Belgium
- P van Doorn
The Netherlands
- I van Schaik
The Netherlands
Acknowledgements
The participants thank the following corresponding members of the workshop: Dr V Chaudhry, Dr D Cornblath, Dr C-L Koski and Professor J Pollard. This workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Telethon Foundation (Italy), Muscular Dystrophy Campaign (UK), Muskelsvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Osterreichische Muskelforschung (Austria), Vereniging Spierziekten Nederland (The Netherlands).
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PII: S0960-8966(05)00025-8
doi:10.1016/j.nmd.2005.01.005
© 2005 Elsevier B.V. All rights reserved.
