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.