Table 6 Challenging areas in trial design and possible options

Patient selection and sample size

• Exclude seronegative patients

• Define the disease activity using a validated disease activityindex

• Define refractory disease as either failure to respond to one ormore immunosuppressants and an assigned dose of corticosteroids

• Ensure adequate sample size based on statistical power calculationto allow detection of even small therapeutic effects

• Allow for proportional representation of patients taking intoaccount factors such as race, age, the duration of disease and type of organinvolvement. For example, different histological types of nephritis may havevariable sensitivity to B-cell depletion therapy

B-cell depletion

• Standardise the definition of adequate degree of B-cell depletion;for example, <5 cells/μl

The treatment protocol and the rituximab regimen

• A randomised trial of adequate sample size to distinguish whetherthe two-dose or four-dose regimen ± cyclophosphamide is effective atachieving an effective B-cell depletion and a favourable clinicalresponse

• Determine an appropriate time to retreat

• Using a standard rituximab regimen would allow for a bettercomparison between trials

Standardising concomitant therapy

• Classify a change in concomitant immunosuppressant therapy >25%above baseline as partial failure and >50% as complete failure

• Define an increase in the dose of prednisolone >7.5 mg as partialfailure and >30 mg as complete failure

Choosing the right disease activity index

• Choosing an index that is validated and is able to captureorgan-specific changes: SLE Responder Index and British Isles LupusAssessment Group, respectively

Defining the endpoints

• Define practically achievable primary endpoints, based on a pilotstudy and/or taking into account the predicted failure rate for the definecohort, which would detect even small therapeutic benefit

• Define both clinical and nonclinical parameters in the secondaryendpoints

• Assess steroid-sparing effect. For example, allow only low-doseprednisolone <10 mg/day and any clinical requirement to increase the doseby >50% as partial failure and >100% as complete failure

Duration of follow-up

• The duration of follow-up should be defined to allow capture of bothearly and late effects including both safety and efficacy of the therapeuticintervention.

• Defining the adverse events

The reporting of adverse events could be standardised adhering to theOMERACT-recommended guidance [63]