This multicentre, double-blind, parallel-group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8-week therapy, either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) was given. Thereafter, in the 8-week combination/high-dose therapy period, only nonresponders received 120 mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI-MSF] 24-hour average pain change after combination/high-dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high-dose monotherapy (groups 1, 4 pooled). Secondary end points included response rates, BPI-MSF severity items, and comparison of duloxetine and pregabalin in BPI-MSF average pain. Eight hundred four patients were evaluated for initial therapy and 339 for combination/high-dose therapy. There were no significant differences between combination and high-dose monotherapy regarding BPI-MSF average pain (mean change: combination: -2.35; high-dose monotherapy: -2.16; P = 0.370) and most secondary end points, which, however, consistently favoured combination therapy. Fifty-percent response rates were 52.1% for combination and 39.3% for high-dose monotherapy (P = 0.068). In exploratory analyses of the initial 8-week therapy uncorrected for multiple comparisons, 60 mg/day duloxetine was found superior to 300 mg/day pregabalin (P < 0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated.
Summary
Standard network meta‐analysis (NMA) and indirect comparisons combine aggregate data from multiple studies on treatments of interest, assuming that any effect modifiers are balanced across populations. Population adjustment methods relax this assumption using individual patient data from one or more studies. However, current matching‐adjusted indirect comparison and simulated treatment comparison methods are limited to pairwise indirect comparisons and cannot predict into a specified target population. Existing meta‐regression approaches incur aggregation bias. We propose a new method extending the standard NMA framework. An individual level regression model is defined, and aggregate data are fitted by integrating over the covariate distribution to form the likelihood. Motivated by the complexity of the closed form integration, we propose a general numerical approach using quasi‐Monte‐Carlo integration. Covariate correlation structures are accounted for by using copulas. Crucially for decision making, comparisons may be provided in any target population with a given covariate distribution. We illustrate the method with a network of plaque psoriasis treatments. Estimated population‐average treatment effects are similar across study populations, as differences in the distributions of effect modifiers are small. A better fit is achieved than a random effects NMA, uncertainty is substantially reduced by explaining within‐ and between‐study variation, and estimates are more interpretable.
The proportion of patients who met combined remission or recovery criteria is low. Early treatment adaptations in case of early non-remission are mandatory.
questions (1) how is remission defined? (2) how many patients achieve remission? and (3) which parameters predict remission? Several prospective and retrospective studies in first-1-4 and multiple-episode patients 5-8 provided definitions for remission using a wide range of criteria and time periods during which the criteria must be maintained. 9,10 The lack of consistent definitions of remission and the heterogeneity of assessed populations thereby hampered cross-study comparisons and limited the generalizability of these results. 9 Most recently, in accordance with previous studies, 1-8 the Remission in Schizophrenia Working Group published a consensus statement on the criteria and the time frame of remission in schizophrenia. 9 Remission was defined as a state of no greater than low-to-mild intensity in core symptoms, sustained for a minimum duration of 6 months. These criteria were recently applied in a 1-year
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