Types of studies

All randomized controlled clinical trials (RCTs) evaluating daclizumab, alone or combined to other treatments, versus placebo, or any other treatment for patients with RRMS. Uncontrolled, non‐randomised or quasi‐randomised trials will be excluded. Both parallel group and cross‐over design will be included. Trials with a length of follow‐up shorter than one year will be excluded.

Types of participants

Male or female age 18 to 65 years, inclusive.

Diagnosis of RRMS by the criteria of Poser (Poser 1983) for clinically definite or laboratory‐supported definite multiple sclerosis or original or revised Mc Donald criteria (McDonald 2001; Polman 2005).

EDSS between 1.0 and 7.0.

Exclusion criteria,including diagnosis of other type of MS, such as secondary‐progressive, primary‐progressive, and primary‐relapsing; pregnant or breast‐feeding woman, significant abnormality on ECG, malignancy, HIV infection, positive serology for HBV or HCV, significant organ dysfunction.

Types of interventions

Experimental intervention: treatment with daclizumab intravenously or subcutaneously, alone or combined with other treatment.
Control intervention: Placebo & Other treatments for MS.

Types of outcome measures

Electronic searches

We will search the following databases:

1.Cochrane Multiple Sclerosis Group Trials Register;

2.The Cochrane Central Register of Controlled Trials (CENTRAL) "The Cochrane Library" (present issue) (Appendix 1);

3. MEDLINE (PubMed) (January 1966 to date) (Appendix 2);

4.EMBASE (1974 to date) (Appendix 3);

Searching other resources

Handsearching of the references quoted in the identified trials, congress reports (1998 to present), from the most important neurological associations and MS Societies in Europe and America; contact with researchers who were participating in trials on daclizumab; and contact with Roche or other pharmaceutical companies.

Selection of studies

Two review authors (LJ, WL) will independently screen titles and abstracts of the citations produced by the literature search to determine if the inclusion criteria are met, and obtain the full text of potentially relevant studies. Two review authors (LJ, WL) will independently evaluate the eligibility (on the basis of information accessible in the published data), and assess the methodological quality of these studies. Any disagreement will be resolved by discussion or by an independent party if necessary.

Data extraction and management

Two independent reviewers (LJ, WL) will extract eligible data from the published reports onto standardised forms, and cross‐check them for accuracy. Disagreements regarding inclusion will be resolved by consensus between reviewers and will be explained.

We will use checklists to independently record details of the below items:

• methods of generating randomisation schedule;

• method of concealment of allocation;

• blinding of assessors;

• use of an intention‐to‐treat analysis (all participants initially randomised will be included in the analyses as allocated to groups);

• adverse events and drop outs for all reasons;

• important imbalance in prognostic factors;

• participants (country, number of participants, age, gender, EDSS scores,inclusion and exclusion criteria);

• comparison (details of the intervention in treatment and control groups; details of co‐intervention(s) in both groups; duration of treatment);

• outcomes and time points of measures (number of participants in each group and outcome, regardless of compliance).

Assessment of risk of bias in included studies

Methodological quality of each included trial will be assessed independently by two reviewers (LJ, WL) using the new "risk of bias tool" under the categories adequate sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other biases. The quality of the included studies will be also evaluated according with the Cochrane Collaboration Handbook criteria (based on the allocation concealment). We will assess whether the treatment groups will be comparable with regard to demographics, clinical characteristics and the number of patients excluded or lost to follow up within each trial and whether the definition of outcomes and entry and exclusion criteria were comparable across the different trials. Sources of bias will be considered on a study‐by‐study basis and studies will be excluded if the reviewers agree that they are significantly biased. In such cases, reasons for exclusion will be specified. Adjunctive items will be added assessing specifically the methodological quality of crossover trials (washout period, identification of carry over and period effects). The crossover studies will be included, only if results from all periods and if the knowledge about number, allocation and period of loss to follow‐up will be available for analysis in order to estimate both the period and carry‐over effects, and the bias introduced by imbalance of comparison groups.

Measures of treatment effect

We expect the RCTs and crossover trials to measure both event (dichotomous) data and continuous data. Continuous data will be expressed as weighted mean differences (WMD) or standard mean differences (SMD), and dichotomised data will be expressed as relative risks (RR). We will calculate the WMD with 95% confidence intervals (CI). If studies do not use the same outcome, we will use the standardised mean difference (SMD) with 95% CI. For all binary outcomes we will calculate relative risks (RR) with 95%CI. As it is possible that some trials (or groups within a trial) will have no adverse events or no drop outs, we will calculate risk differences(RD) instead of RRs in these specific situations, again with 95%CI.

Unit of analysis issues

We will only include the first period of cross‐over trials, and we will assess trials with multiple observations for the same outcome if randomized.

Dealing with missing data

We will attempt to contact the authors of the studies for further details if any data are missing and establish the characteristics of unpublished trials through correspondence with the trial co‐ordinator or principal investigator. We will only analyze the available data. Different scenarios (best and worst‐case) will be considered for taking into account missing data.

Assessment of heterogeneity

To test for heterogeneity we will use the I² (Higgins 2003) statistic (alpha level 50%) for all comparisons. If we find statistically significant heterogeneity, we will calculate the overall effects using a random‐effects model instead of a fixed effect model.

Assessment of reporting biases

If sufficient RCTs are identified, potential publication bias will be examined using a funnel plot.

Data synthesis

Formal meta‐analysis using the RevMan software will be performed if possible, although substantial heterogeneity between the studies may prevent this. Where we cannot combine outcome data from different studies we will give a descriptive summary of the results.

Subgroup analysis and investigation of heterogeneity

We will analyse subgroups of studies categorised according to therapeutic approach, as outlined under 'Types of interventions'. This will include a comparison of daclizumab alone or combined versus placebo treatment, and direct comparisons of daclizumab versus other pharmacological treatment.

As a formal method of comparing subgroups, we will use the Chi² test (to test for significant differences between both subgroups of participants). For all statistical analyses we will use the latest version of the Cochrane Collaboration's Review Manager software (RevMan 2008).

Sensitivity analysis

We will undertake sensitivity analyses to assess the robustness of results to fixed‐effect versus random‐effects assumptions and the inclusion or exclusion of studies at high risk of bias, i.e. inadequate allocation concealment and lack of blinded outcome assessor. We will use best and worst‐case scenarios for taking into account missing data .