Statistical analyses
The endpoint used for the analyses was the reduction in MMDs. We used the published data for each clinical study to extract or calculate the change from baseline in MMDs over weeks 1‒12. If the average change from baseline from weeks 1‒12 was not reported in the publication, the mean changes from baseline to weeks 4, 8, and 12 were calculated, and the SE of the change from baseline to week 12 was used, since SE values were comparable across all timepoints.
For the random-effects meta-regressions, we used the rma function from the ‘metafor’ package in R . A DerSimonian-Laird estimator was used . To estimate the impact of route of administration on placebo response, the route of administration was included as a dummy variable, in which the value was set as 1 if placebo administration was IV (namely for PROMISE-1, PROMISE-2, and DELIVER) and as 0 if placebo administration was via a different route of administration (i.e., SC), as shown inTable 1 . Coefficient estimates, SE, and 95% confidence intervals (CI) were reported. For P -values, a threshold of 0.05 was used to determine if changes in the predictor were significantly associated with changes in the response. Importantly, given that the number of trials utilising IV administration was small, P -values were interpreted with caution.