E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic inflammatory demyelinating polyradiculoneuropathy |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Does methotrexate decrease the requirement for corticosteroids or intravenous immunoglobulin (IVIg) in patients with (CIDP) who have improved with such treatment and are still receiving it, while improving or at least maintaining levels of impairment and disability? |
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E.2.2 | Secondary objectives of the trial |
Is change in dose of or is change in impairment or disability the most responsive outcome measure? |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men or women aged >18 years.
2. Diagnosis of CIDP by a consultant neurologist with a special interest in peripheral neuropathy.
3. Chronically progressive, stepwise, or recurrent weakness, with or without sensory dysfunction, of all extremities, developing over at least 2 months 4. Absent or reduced tendon reflexes.
5. Ongoing treatment with at least one of IVIg (equivalent to at least 0.4 g/kg every 4 weeks) or corticosteroid (equivalent to at least prednisolone 15 mg daily). The dose must have been stable (within 25%) for at least 12 weeks and not changed for the past 4 weeks. Patients who are going to withdraw from IVIg in the trial must be receiving it at least every 8 weeks.
6. Duration not less than 6 months.
7. At least moderate disability in arms or legs (overall neuropathy disability scale (ONLS) which has been very slightly modified from the INCAT overall disability status scale 17 grade 2) and MRC grade 4 or less weakness in at least one muscle at baseline OR following reduction of steroid or IVIg dose at some time during the past 12 months.
8. Fulfillment of definite or neurophysiological criteria10 proposed by INCAT or EFNS/PNS (Appendix 1) within the past 3 years. In some centres, nerve conduction data as specified in the EFNS/PNS criteria will be collected at the screening or baseline visit.
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E.4 | Principal exclusion criteria |
1. Pregnancy, planned pregnancy, breast feeding or unwillingness to practice contraception.
2. Severe concurrent medical conditions which would prevent treatment or assessment, including significant haematological, renal, liver function (including liver enzymes >twice the upper limit of normal) or chest radiograph abnormalities.
3. Alternative cause of peripheral neuropathy 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. Diabetes mellitus will not be an exclusion criterion. IgG, IgA and IgM paraproteins without anti-MAG antibodies will not be exclusion criteria.
4. Presence of neurogenic sphincter disturbance.
5. Multifocal motor neuropathy (fulfilling proposed EFNS/PNS criteria Appendix 2).
6. Atypical CIDP with pure sensory or persistent unifocal impairment or significant CNS involvement.
7. Immunomodulatory treatment other than IVIg or corticosteroids during the previous 12 weeks. Treatment with methotrexate at any time.
8. Participation in a controlled trial of an investigational medicinal product within the past 12 weeks
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E.5 End points |
E.5.1 | Primary end point(s) |
Our preferred primary outcome measure would have been change in disability but it is considered likely that participants will be receiving optimal doses of corticosteroids or IVIg which will make the detection of improvement difficult. The same argument applies to the use of change in impairment. Both of these will be captured as secondary outcome measures after 16 weeks. We have therefore selected change in percentage dose of corticosteroid between the beginning and end of the trial as the primary outcome measure but set procedures for prescription of corticosteroids or IVIg which are designed to prevent deterioration, ie Percentage change in mean weekly dose of corticosteroid or IVIg during weeks 37 – 40 compared with weeks 1 – 4. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial is defined as the last visit of the last patient |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |