Dataset Information

Run-in periods and clinical outcomes of antipsychotics in dementia: A meta-epidemiological study of placebo-controlled trials.

ABSTRACT:

Purpose

Run-in periods are used to identify placebo-responders and washout. Our aim was to assess the association of run-in periods with clinical outcomes of antipsychotics in dementia.

Methods

We searched randomized placebo-controlled trials of conventional and atypical antipsychotics for neuropsychiatric symptoms (NPS) in dementia in electronic sources and references of selected articles. We extracted (a) the presence of a run-in period, use of placebo/investigated drug during run-in (versus washout only), and run-in duration (1 week or more) and (b) the reduction in NPS, number of participants with somnolence, extrapyramidal symptoms (EPS), and deaths per treatment group. We pooled clinical outcomes comparing antipsychotic and placebo groups in trials with and without run-in.

Results

We identified 35 trials. Twenty-nine trials used run-in. The pooled standardized mean difference in the reduction of NPS was -0.170 (95% CI, -0.227 to -0.112) in trials with run-in and -0.142 (95% CI, -0.331 to 0.047) in trials without run-in. The pooled odds ratio for somnolence was 2.8 (95% CI, 2.3-3.5) in trials with run-in and 3.5 (95% CI, 1.2-10.7) in trials without run-in; for EPS, these ORs were 1.8 (95% CI, 1.4-2.2) and 2.0 (95% CI, 1.3-3.1) respectively, and for mortality 1.4 (95% CI, 1.0-2.0) and 1.6 (95% CI, 0.7-3.4). The use of placebo/investigated drug during run-in and run-in duration did not affect the estimates in a consistent way.

Conclusions

The use of run-in in trials might have led to overestimated efficacy and especially underestimated risks of side effects of antipsychotics compared with placebo for NPS in dementia.

SUBMITTER: Hulshof TA

PROVIDER: S-EPMC7027584 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Run-in periods and clinical outcomes of antipsychotics in dementia: A meta-epidemiological study of placebo-controlled trials.

Hulshof Tessa A TA Zuidema Sytse U SU Gispen-de Wied Christine C CC Luijendijk Hendrika J HJ

Pharmacoepidemiology and drug safety 20191115 2

<h4>Purpose</h4>Run-in periods are used to identify placebo-responders and washout. Our aim was to assess the association of run-in periods with clinical outcomes of antipsychotics in dementia.<h4>Methods</h4>We searched randomized placebo-controlled trials of conventional and atypical antipsychotics for neuropsychiatric symptoms (NPS) in dementia in electronic sources and references of selected articles. We extracted (a) the presence of a run-in period, use of placebo/investigated drug during r ...[more]

PMID: 31730266

Similar Datasets

Project description:BackgroundAntipsychotics improve the positive symptoms of schizophrenia. However, little is known about the extent of antidepressive effects of antipsychotics and their correlation with effects on other symptom domains in schizophrenia. The aim was to investigate whether antidepressive effects of antipsychotics have a significant correlation with the effects on specific symptom domains of schizophrenia.MethodsElectronic databases were searched to identify eligible studies that reported antidepressive effects of antipsychotics for the treatment of adult patients with schizophrenia in double-blind, randomized placebo-controlled trials (RCTs). Mean change from baseline in depressive symptoms was meta-analyzed, and the correlation with the effects on other symptom domains was examined through meta-regression analysis.ResultsThirty-five RCTs (13 890 patients) were included in this meta-analysis. Overall, antipsychotics showed greater efficacy than placebo in reducing depressive symptoms, with small to medium effect sizes (standardized mean difference = -0.27, 95% confidence interval -0.32 to -0.22, P < .001). All the antipsychotics, except for chlorpromazine, haloperidol, and ziprasidone, were associated with significantly greater decreases in depressive symptoms compared with placebo (standardized mean difference = -0.19 to -0.40). A higher antidepressive effect was significantly correlated with a higher improvement in Positive and Negative Syndrome Scale/Brief Psychiatric Rating Scale total, positive, and negative, and Positive and Negative Syndrome Scale-general psychopathology symptoms (β = .618, P < .001; β = .476, P < .001; β = .689, P < .001; β = .603, P < .001, respectively).ConclusionsSecond-generation antipsychotics (except for ziprasidone) were associated with small to medium effects sizes on improvement in depressive symptoms among adult patients with schizophrenia. The antidepressive effect of antipsychotics was significantly correlated with improvement in other symptom domains, with the highest correlation observed for improvement in negative symptoms.Prospero registration numberCRD42019133015.

Project description:BackgroundChronic painful conditions have an important influence on the ability to work. Work-related outcomes, however, are not commonly reported in publications on trials investigating the treatment of chronic painful conditions. We aim to provide an overview of the reporting of work-related outcomes in such trials and investigate the relationship between work-related outcomes and pain outcomes.MethodsWe conducted a systematic literature search in PubMed with the aim of identifying randomised placebo-controlled clinical trials investigating treatments for chronic painful conditions or rheumatic diseases that also reported on work-related outcomes. Methodological study quality was assessed with the Oxford Quality Scale (OQS). Meta-analyses were conducted for the outcomes of interference with work and number of patients with at least 30% reduction in pain intensity (30% pain responders). The correlation between work-related and pain outcomes was investigated with regression analyses.ResultsWe included 31 publications reporting on 27 datasets from randomised placebo-controlled trials (with a total of 11,434 study participants) conducted in chronic painful or rheumatic diseases and reporting on work-related outcomes. These 31 publications make up only about 0.2% of all publications on randomised placebo-controlled trials in such conditions. The methodological quality of the included studies was high; only nine studies scored less than four (out of a maximum five) points on the OQS. Sixteen different work-related outcomes were reported on in the studies. Of 25 studies testing for the statistical significance of changes in work-related outcomes over the course of the trials, 14 (56%) reported a significant improvement; the others reported non-significant changes. Eight studies reported data on both interference with work and 30% pain responders: meta-analyses demonstrated similar, statistically significant improvements in both these outcomes with active therapy compared to placebo and regression analysis showed that these outcomes were correlated.ConclusionsDespite the importance of pain as a reason for decreased ability to work, work-related outcomes are reported in substantially less than 1% of publications on placebo-controlled trials in chronic painful and rheumatic diseases. Work-related outcomes and pain responder outcomes are closely related.

Project description:BackgroundEarly identification of participants at risk of run-in failure (RIF) may present opportunities to improve trial efficiency and generalizability.MethodsWe conducted a partial factorial-design, randomized, controlled trial of calcium and vitamin D to prevent colorectal adenoma recurrence at 11 centers in the United States. At baseline, participants completed two self-administered questionnaires (SAQs) and a questionnaire administered by staff. Participants in the full factorial randomization (calcium, vitamin D, both, or neither) received a placebo during a 3-month single-blinded run-in; women electing to take calcium enrolled in a two-group randomization (calcium with vitamin D, or calcium alone) and received calcium during the run-in. Using logistic regression models, we examined baseline factors associated with RIF in three subgroups: men (N = 1606) and women (N = 301) in the full factorial randomization and women in the two-group randomization (N = 666).ResultsOverall, 314/2573 (12 %) participants failed run-in; 211 (67 %) took fewer than 80 % of their tablets (poor adherence), and 103 (33 %) withdrew or were uncooperative. In multivariable models, 8- to 13-fold variation was seen by study center in odds of RIF risk in the two largest groups. In men, RIF decreased with age (adjusted odds ratio [OR] per 5 years 0.85 [95 % confidence interval, CI; 0.76-0.96]) and was associated with being single (OR 1.65 [95 % CI; 1.10-2.47]), not graduating from high school (OR 2.77 [95 % CI; 1.58-4.85]), and missing SAQ data (OR 1.97 [1.40-2.76]). Among women, RIF was associated primarily with health-related factors; RIF risk was lower with higher physical health score (OR 0.73 [95 % CI; 0.62-0.86]) and baseline multivitamin use (OR 0.44 [95 % CI; 0.26-0.75]). Women in the 5-year colonoscopy surveillance interval were at greater risk of RIF than those with 3-year follow-up (OR 1.91 [95 % CI; 1.08-3.37]), and the number of prescription medicines taken was also positively correlated with RIF (p = 0.03). Perceived toxicities during run-in were associated with 12- to 29-fold significantly increased odds of RIF.ConclusionsThere were few common baseline predictors of run-in failure in the three randomization groups. However, heterogeneity in run-in failure associated with study center, and missing SAQ data reflect potential opportunities for intervention to improve trial efficiency and retention.Trial registrationClinicalTrials.gov: NCT00153816 . Registered September 2005.

Project description:ObjectiveTo quantify and compare the treatment effect and risk of bias of trials reporting biomarkers or intermediate outcomes (surrogate outcomes) versus trials using final patient relevant primary outcomes.DesignMeta-epidemiological study.Data sourcesAll randomised clinical trials published in 2005 and 2006 in six high impact medical journals: Annals of Internal Medicine, BMJ, Journal of the American Medical Association, Lancet, New England Journal of Medicine, and PLoS Medicine.Study selectionTwo independent reviewers selected trials.Data extractionTrial characteristics, risk of bias, and outcomes were recorded according to a predefined form. Two reviewers independently checked data extraction. The ratio of odds ratios was used to quantify the degree of difference in treatment effects between the trials using surrogate outcomes and those using patient relevant outcomes, also adjusted for trial characteristics. A ratio of odds ratios >1.0 implies that trials with surrogate outcomes report larger intervention effects than trials with patient relevant outcomes.Results84 trials using surrogate outcomes and 101 using patient relevant outcomes were considered for analyses. Study characteristics of trials using surrogate outcomes and those using patient relevant outcomes were well balanced, except for median sample size (371 v 741) and single centre status (23% v 9%). Their risk of bias did not differ. Primary analysis showed trials reporting surrogate endpoints to have larger treatment effects (odds ratio 0.51, 95% confidence interval 0.42 to 0.60) than trials reporting patient relevant outcomes (0.76, 0.70 to 0.82), with an unadjusted ratio of odds ratios of 1.47 (1.07 to 2.01) and adjusted ratio of odds ratios of 1.46 (1.05 to 2.04). This result was consistent across sensitivity and secondary analyses.ConclusionsTrials reporting surrogate primary outcomes are more likely to report larger treatment effects than trials reporting final patient relevant primary outcomes. This finding was not explained by differences in the risk of bias or characteristics of the two groups of trials.

Project description:Background:There is debate in the literature as to whether inclusion of a placebo arm may alter characteristics of antidepressant trials. However, previous research has focused on response rates of various antidepressants on average only, ignoring potential differences among drugs or other aspects of trial findings. Little is known about the impact of a placebo arm on all-cause dropout and dropout due to adverse events. Methods:We carried out a systematic review of published and unpublished double-blind randomized controlled trials (RCTs) for the acute treatment of unipolar major depression (update: January 2016). The probability of being allocated to placebo (?) was the exposure of interest, and we examined its influence on responders (efficacy), all-cause dropouts (acceptability) and dropouts due to adverse events (tolerability), while accounting for differences in drugs, trials and patient characteristics in multivariate random effects meta-regression. Results:We included 421 studies (68 305 participants) comparing 16 antidepressants or placebo; ? ranged from 20% to 50%. Response rate was lower [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.83, 0.92] and all-cause dropout rate higher (RR 1.19; 95% CI 1.08, 1.31) for the same antidepressants in placebo-controlled trials compared with head-to-head trials. The probability of responding decreased by 3% (95% CI 2-5%) for every 10% increase in ?, whereas the risk of all-cause dropout increased by 4% (95% CI 1-7%). Tolerability was unaffected by ?. Response rate was inversely correlated with dropouts due to any cause (correlation coefficient -0.48; 95% CI -0.58, -0.36) and due to adverse events (-0.34; 95% CI -0.44, -0.23). Conclusions:For the same antidepressant, response rate was on average smaller and dropouts higher when placebo was included; however, no association was found with dropouts due to adverse events. Decreased patient expectations, larger dropout rates and use of inappropriate statistical methods to impute missing data may explain this phenomenon. The findings call for caution in the integration of randomized evidence involving placebo arms.

Project description:Background:A typical antipsychotics for neuropsychiatric symptoms in dementia have been tested in much larger trials than the older conventional drugs. The advantage of larger sample sizes is that negative findings become less likely and the effect estimates more precise. However, as sample sizes increase, the trials also get more expensive and time consuming while exposing more patients to drugs with unknown safety profiles. Moreover, a large sample size might yield a statistically significant effect that is not necessarily clinically relevant. Objective:To assess (1) the variation in sample size and sample size calculations of antipsychotic trials in dementia, (2) the size of reported treatment effects and related statistical significance, and (3) general study characteristics that might be related to sample size. Study Design and Setting:We performed a meta-epidemiological study of randomized trials that tested antipsychotics for neuropsychiatric symptoms in dementia. The trials compared conventional or atypical antipsychotics with placebo or another antipsychotic. Two reviewers independently extracted sample size, sample size calculations, reported treatment effects with p-values, and general study characteristics (drug type, trial duration, type of funding). We calculated a reference sample size of 83 and 433 per study group for the placebo-controlled and head-to-head trials respectively. Results:We identified 33 placebo-controlled trials, and 18 head-to-head trials. Only 14 (42%) and 2 (11%), respectively, reported a sample size calculation. The average sample size per arm was 34 (range 6-179) in placebo-controlled trials testing conventional drugs, 107 (8-237) in such trials testing atypical drugs, and 104 (95-115) in such trials testing both drug types; it was 31 (10-88) in head-to-head trials. Thirteen out of 18 trials with sample sizes larger than required (72%) reported a statistically significant treatment effect, of which two (15%) were clinically relevant. None of the head-to-head trials reported a statistically significant treatment effect, even though some suggested non-inferiority. In placebo-controlled trials of atypical drugs, longer trial duration (>6 weeks) and commercial funding were associated with higher sample size. Conclusion:Sample size calculations were poorly reported in antipsychotic trials for dementia. Placebo-controlled trials of atypical antipsychotics showed large sample size fallacy while head-to-head trials were massively underpowered.

Dataset Information

Run-in periods and clinical outcomes of antipsychotics in dementia: A meta-epidemiological study of placebo-controlled trials.

Purpose

Methods

Results

Conclusions

Publications

Run-in periods and clinical outcomes of antipsychotics in dementia: A meta-epidemiological study of placebo-controlled trials.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure