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 activity index

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

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

• Allow for proportional representation of patients taking into account factors such as race, age, the duration of disease and type of organ involvement. For example, different histological types of nephritis may have variable 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 whether the two-dose or four-dose regimen ± cyclophosphamide is effective at achieving an effective B-cell depletion and a favourable clinical response

• Determine an appropriate time to retreat

• Using a standard rituximab regimen would allow for a better comparison 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 partial failure and >30 mg as complete failure

Choosing the right disease activity index

• Choosing an index that is validated and is able to capture organ-specific changes: SLE Responder Index and British Isles Lupus Assessment Group, respectively

Defining the endpoints

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

• Define both clinical and nonclinical parameters in the secondary endpoints

• Assess steroid-sparing effect. For example, allow only low-dose prednisolone <10 mg/day and any clinical requirement to increase the dose by >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 both early and late effects including both safety and efficacy of the therapeutic intervention.

• Defining the adverse events

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