Recombinant interferon beta or glatiramer acetate for delaying conversion of the first demyelinating event to multiple sclerosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary objective of this review will be to evaluate the efficacy and safety of early treatment with GA or IFN beta on proportion of CIS patients delayed to convert to MS.
Secondary objectives will be:
1. In those patients who develop CDMS to asses the time to second relapse and the annual relapse rate.
2. To assess the effect on surrogate markers of disease activity, such as MRI occurrence of new active lesions or changes of disease burden.
Background
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system that most commonly affects women with an onset typically between 20 and 40 years of age. MS is the most common cause of neurological disability in young adults. A diagnosis of MS requires the occurrence of at least two neurological events consistent with demyelination that are separated both in space, i.e. corresponding to two different location in central nervous system (CNS) and in time [Mc Donald 2001].
Treatment of relapsing‐remitting MS (RRMS) is currently based on glatiramer acetate (GA) or recombinant interferons (IFN beta‐1a and IFN beta‐1b).
GA has been demonstrated to be more effective than placebo in reducing relapse rate, slowing 1.5 point Expanded Disability Status Scale (EDSS) progression [Johnson 1995], and reducing MRI signs of disease activity [Comi 2001]. Several meta‐analyses [La Mantia 2000, Durelli 2002, Munari 2003, Martinelli 2003] of the published randomized controlled trials obtained controversial results. When intention‐to‐treat principles were carefully applied [Durelli 2002], risk ratio, absolute risk reduction, number needed to treat were not significantly better than placebo. In addition the risk of having a relapse was reduced only during the first year of treatment [Munari 2003]. Recombinant interferon beta has been demonstrated to be effective in reducing relapse rate [The IFNB 1993,Jacobs 1996,PRISMS 1998], disability progression [Jacobs 1996;PRISMS 1998], and the development of brain lesions at MRI [The IFNB 1993,Jacobs 1996, PRISMS 1998]. A previous Cochrane review [Rice 2001] concluded that interferon has a modest effect in patients with RRMS, in reducing exacerbations and disability during the first two years of treatment.
It was supposed that the partial efficacy of GA or IFN beta in RRMS can be ascribed to the fact that, in the studies which led to their approval, they have been used in patients with a disease history of several years. Recent pathological [Ferguson 1997, Trapp 1998] and MRI studies suggest that axonal damage, supported by inflammation processes, is an early event in MS evolution. Axonal damage results in irreversible neurological deficit that immunomodulatory agents cannot reverse.
Epidemiological studies have shown that clinically isolated syndromes (CIS) suggestive of demyelinating events carry a high risk to convert to clinically definite MS (CDMS), particularly if the MRI scan has typical white matter lesions. Conversion to CDMS is defined as: a) the occurrence of a second attack and clinical evidence of two separate lesions in CNS; or b) in case of a second attack with clinical evidence of one lesion and paraclinical evidence of another separate lesion [Poser 1983]. The two attacks must involve different parts of the CNS, must be separated by a period of at least one month, and must each last a minimum of 24 hours according to the follow‐up time of the included studies [Poser 1983]. Paraclinical evidence can be detected with MRI or visual evoked potentials [Mc Donald 2001].
There are two main rationales for the administration of GA or IFN beta in the early phases of MS: firstly to prevent axonal damage [Ferguson 1997; Fu 1998,Trapp 1998], and, secondly to prevent the conversion from CIS to CDMS.
The purpose of this review is, therefore, to examine the published evidence for the efficacy of early treatment to prevent the conversion from CIS to CDMS.
Objectives
The primary objective of this review will be to evaluate the efficacy and safety of early treatment with GA or IFN beta on proportion of CIS patients delayed to convert to MS.
Secondary objectives will be:
1. In those patients who develop CDMS to asses the time to second relapse and the annual relapse rate.
2. To assess the effect on surrogate markers of disease activity, such as MRI occurrence of new active lesions or changes of disease burden.
Methods
Criteria for considering studies for this review
Types of studies
We will include only randomised, double‐blind, controlled trials. Pseudo‐randomised trials will be included. Single‐blind trials will be excluded.
Types of participants
Patients who presented a first isolated, clinically defined neurological event suggestive for demyelination and a positive brain MRI scan, defined as a scan with at least three white matter lesions on T2 weighted MRI or one Gadolinium‐diethylenetriaminepenta‐acetic acid (Gd‐DTPA) enhancing lesions. [Mc Donald 2001, Frohman 2003]. Demyelination in MS is known to involve certain parts of the CNS much more frequently that others, and thus certain signs and symptoms are more frequently noted [Poser 1983; Matthews 1985]. Patients with an optic neuritis as first episode will be included.Patients with a prior neurological event suggestive for demyelization and lasted longer than 48 hours will be excluded.
We will exclude trials which included patients previously treated with immunosuppressant or immunomodulatory agents.
Types of interventions
We will consider all trials in which GA or IFN beta treatment is compared to placebo in patients with CIS, independently of dose, duration of treatment, route of administration, or length of follow up.
Types of outcome measures
The primary outcome measure will include:
1. The proportion of CIS patients who convert to CDMS. Conversion to CDMS is defined as the occurrence of a second attack and clinical evidence of two separate lesions or in case of a second attack with clinical evidence of one lesion and paraclinical evidence of another separate lesion. Another separate lesion can be detected with MRI or visual evoked potentials [Mc Donald 2001]. The two attacks must involve different parts of the CNS, must be separated by a period of at least one month, and must each last a minimum of 24 hours [Poser 1983].
2. To evaluate the prevalence and severity of side effects and adverse events.
The secondary outcome measures will include:
1.Time to conversion to CDMS according to the previous definition.
2. Distribution of number of new relapses (0, 1, 2, >2) in the treatment groups during the follow‐up.
3. The annual relapse rate, that is the total number of relapses divided by the period of observation expressed in years.
Search methods for identification of studies
We will search the following databases:
(1) Cochrane MS Group Specialised Register
(2 Cochrane Central Register of Controlled Trials (CENTRAL)
(3) MEDLINE (January 1966 to.... )
(4) EMBASE (January 1974 to..... )
(5) screening of reference lists of all available review articles and primary studies found;
(6) handsearching of the references quoted in the recent abstract books of ECTRIMS, EFNS, ENS, AAN, ANA and ACTRIMS;
(7) contact with corresponding authors of relevant trials or reviewers and other multiple sclerosis experts;
(8) contact and inquiry of drug manufactures.
No language or time restriction will be applied.
We used the following terms in MEDLINE (with slight variations for different databases):
1."Interferon beta*". tw
2. avonex.tw
3. betaseron.tw
4. rebif.tw
5. "interferon‐beta".mh
6. #1 OR #2 OR #3 OR #4 OR #5
7. Copolymer. tw
8. "Copolymer‐1OR Cop‐1 OR Cop1".tw
9. "Glatiramer Acetate". tw
10. "Copaxone OR cpx". tw
11 Glatiramer.tw
12. #7 OR #8 OR #9 OR #10 OR #11
13. #6 OR #12
14. "neuromyelitis optica".tw
15. adem.tw
16. devic.tw
17. "optic neuritis".tw
18. " transverse myelitis".tw
19"multiple sclerosis".tw
20. #14 OR #15 OR #16 OR #17 OR #18 OR #19
21. "Encephalomyelitis, Acute Disseminated".mh
22. " Demyelinating Diseases".mh
23. "Myelitis, Transverse".mh
24. "Multiple Sclerosis".mh
25. #21 OR #22 OR #23 OR #24
26. #20 OR #25
27. "clinically isolated".tw OR "early phase*".tw OR early.tw OR first*.tw
28. #26 AND #27
29. 28‐limits:((("Clinical Trial"[ptyp]+OR +"Controlled Clinical Trial"[ptyp]+OR+"Multicenter study"[ptyp]+OR+"Randomized Controlled Trial"[ptyp]
30. Placebos.mh
31. placebo.tw
32. placebo effect.mh
33. "Clinical Trials".mh
34. "Cross‐Over Studies".mh
35. "Double‐Blind Method".mh
36. "Random Allocation".mh
37. "Research Design".mh
38. "Follow‐Up Studies".mh
39. "Prospective Studies".mh
40. "Randomized Controlled Trials".mh
41. "Controlled Clinical Trials".mh
42. random*.tw OR "clinical trial*".tw
43 "doubl*".tw OR "trebl*".tw OR "tripl*".tw
44. "mask*".tw OR "blind*".tw
45. "cross over".tw OR "crossover".tw OR "follow up".tw
46. "multicenter OR multicentr*".tw
47. "comparative study".tw
48. #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47
49. #28 AND ( #29 OR #48)
50. #49 AND #13
Data collection and analysis
Study selection
Titles and abstracts identified from the searches will be independently checked by two reviewers. If it is clear that the study does not meet the eligibility criteria, it will be excluded. If it is not clear from the abstract and title, the full text of study will be obtained and evaluated independently by the reviewers. If no consensus is met about the possible inclusion/exclusion of any individual study, additional two reviewers will independently assess the full text of the studies to decide whether they fit the inclusion criteria. A final decision will be made by discussion amongst all the reviewers.
Reviewers will not be masked to the name(s) of the author(s), institution(s) or publication source at any level of the review.
Quality assessment of trials
Two reviewers will independently assess the methodological quality of each trial. In particular the following factors will be examined:
-
Adequate allocation concealment
-
Randomisation
-
Intention to treat analysis
-
Number lost to follow‐up and withdrawn
-
Blinding of patient and physician who measured outcome
-
Baseline comparison between treatment groups as regard relevant clinical factors (time interval from the first clinical event to randomisation, baseline EDSS, age, gender)
We will assign a quality rating for allocation concealment to each trial, using the criteria outlined in the Cochrane Reviewers' Handbook [Alderson 2004]: (A)adequate, (B) unclear, (C)inadequate, or (D) not used.
When that information is not reported, we will submit a formal request to the study authors or drug's company. If the investigators will not respond, the item will be considered unclear.
Data extraction
It will be performed independently by two reviewers. The methodological quality of the studies will be extracted using a pre‐agreed data extraction form. Particular attention will be paid to: study design, description of randomisation, characteristics of the participants (age, gender, clinical findings of initial attack and EDSS score), inclusion/exclusion criteria, description of the study, outcome measures, length of follow up, and number of patients withdrawn or dropping out of the trial. Results will be compared between reviewers and difference of opinion will be settled by discussion.
Data analysis
We will considered GA or INF beta in a separate analysis. We will analyse binary outcomes by calculating odds ratios for each trial with the uncertainty in each trial being expressed using 95% confidence intervals (CI). We will analyse continuous outcomes according to the difference between their means. For each outcome a weighted treatment effect across trials will be calculated using a fixed effect model. We will express aggregated results as a weighted estimate of relative risk with the relative 95% CI for binary outcomes, and weighted difference between means across trials for continuous outcomes. Methodological heterogeneity will be treated with sensitivity analysis, clinical heterogeneity (length of follow‐up, clinical findings of initial attack, mono‐ or multi‐symptomatic onset, baseline T2 lesion count) will be treated with subgroup analysis. Pooling of time‐to‐event the outcomes will be calculated by computing hazard ratios for each trial and pooling them using the inverse variance method [Deeks 2001].
In order to make our review more incisive in terms of implication for practicing neurologists we will perform , if possible, subgroup analyses based on the different type of presentation (optic neuritis, brainstem‐cerebellar, spinal syndromes).
All these results will be organised and processed by the RevMan 4.2 (RevMan) developed by the Cochrane Collaboration.
