A Systematic Review and Meta-analysis of the Response to Placebo in Clinical Trials of Inclusion Body Myositis

Objectives: Inclusion body myositis (IBM) is characterized by slowly progressive muscle weakness making it challenging to detect weakness changes during a clinical trial. Trial participants receiving placebo may behave differently than in natural history studies. We aimed to quantify the decline in muscle strength and IBM functional rating scale (IBMFRS) of IBM patients receiving placebo during clinical trials.

Methods: Several databases were searched. Randomized double-blinded placebo-controlled trials without treatment intervention on the placebo group were included. Standardized mean differences (SMD) for change in muscle strength and mean differences for IBMFRS were used to calculate pooled effects, using DerSimonian-Laird continuous random effect models. Meta-regression determined change in muscle strength. Heterogeneity was evaluated using the I2 indicator.

Results: Eleven eligible trials were identified with 257 participants receiving placebo and a low risk of bias (RoB) per the Cochrane Collaboration RoB 2 tool. Participants receiving placebo on average had a measurable decline in muscle strength with a mean effect size of-0.398 [-0.652,-0.144] (p = 0.002). SMD changed by -0.009 [-0.016,-0.002] points per week (p = 0.015). Manual muscle testing was associated with higher heterogeneity (I2= 67.68%) compared with quantitative muscle testing (I2= 0%). Only 3 studies reported IBMFRS results. The pooled change in IBMFRS at 12 months was -2.189 points [-3.893,-0.485] on this 0-40 scale (p = 0.012), with relatively high heterogeneity.

Conclusion: Participants with IBM displayed a measurable decline in their muscle strength and IBMFRS during clinical trials, in keeping with the disease's slowly progressive nature. These estimates can inform sample size calculations in future studies.