Exploratory treatment trials in multiple sclerosis using MRI: sample size calculations for relapsing-remitting and...

Area of Science:

• Neuroimaging in Multiple Sclerosis
• Clinical Trial Design and Methodology
• Biostatistics in Clinical Research

Background:

• Serial brain Magnetic Resonance Imaging (MRI) is a standard tool for assessing treatment efficacy in pilot studies for multiple sclerosis (MS), particularly for relapsing-remitting (RR) and secondary progressive (SP) subtypes.
• Current sample size calculations for RR-MS subgroups are based on limited data, and specific calculations for SP-MS have not been established, posing challenges for trial planning.
• This study addresses the need for robust sample size estimations for both RR-MS and SP-MS patient groups in early-phase clinical trials.

Purpose of the Study:

• To determine appropriate sample sizes for pilot clinical trials in relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) using serial brain MRI.
• To evaluate the impact of including a run-in scan period on sample size requirements for MS treatment trials.
• To provide data-driven recommendations for planning future pilot MRI outcome trials in MS.

Main Methods:

• Sample size calculations were performed using bootstrap analysis based on six months of monthly T2-weighted and gadolinium-enhanced MRI data from untreated RR-MS and SP-MS patients.
• The study considered a placebo-controlled, parallel-group design lasting six months, aiming for an 80% likelihood of detecting a specified treatment effect.
• Calculations were conducted with and without a one-month run-in scan period prior to treatment initiation.

Main Results:

• For a single pre-treatment scan, demonstrating a 70% reduction in newly active lesions required 2x30 RR-MS patients and 2x50 SP-MS patients.
• Incorporating an additional run-in scan reduced the required sample sizes to 2x20 for RR-MS and 2x30 for SP-MS patients.
• The SP-MS group consistently required larger sample sizes than the RR-MS group, likely due to higher interpatient variability in MRI lesion activity.

Conclusions:

• The sample sizes determined for RR-MS are consistent with previous smaller studies.
• Larger sample sizes are necessary for SP-MS trials, but a pre-treatment run-in scan effectively reduces patient numbers for both MS subtypes.
• These findings offer crucial guidance for optimizing the design and sample size of pilot MRI outcome trials in multiple sclerosis research.