Validation of the GetReal Trial Tool - Facilitating discussion and understanding more pragmatic design choices and their implications.

BACKGROUND: The GetReal Trial Tool is a decision support tool to assess the impact of design choices on generalizability of clinical trials to routine clinical practice, while taking into account the risk of bias, precision, acceptability and operational feasibility. This study describes the validation of the GetReal Trial Tool. METHODS: Twelve experts took part in the GetReal Trial tool validation using the protocols of 6 trials conducted with pragmatic elements. The tool entails 7 domains with a total of 43 questions. A pooled Kappa statistic (95% CI) using random effects model was estimated using Open Meta (analyst) software. The possible operational challenges were collated and discussed with the trialists that conducted the trials. RESULTS: Agreement in the design choices made for the trial protocols was >50% for all the trials and all teams reached consensus during discussion. The pooled Kappa statistic (95% CI) was 0.236 (0.154-0.318). The GetReal Trial tool highlighted several operational challenges, of which almost half had been experienced previously by the trialists. Out of 25 additional operational challenges mentioned by the trialists, 76% were already highlighted by the tool. The tool was considered helpful to optimize trials right from the design stage. CONCLUSION: The GetReal Trial Tool helps to scrutinize the choice of study design in the light of Real World Evidence generation. The tool identifies most of the operational challenges experienced by trialists to date. The tool serves the intended purpose of facilitating discussion and understanding more pragmatic design choices and their implications.

Development of a claims-based flare algorithm for systemic lupus erythematosus.

OBJECTIVE: To develop a claims-based algorithm identifying systemic lupus erythematosus (SLE) flares using a linked claims-electronic medical record (EMR) dataset. METHODS: This study was a retrospective analysis of linked administrative claims and EMR data spanning 1 January 2003 to 31 March 2019. Included were adult SLE patients with at least 12 months of continuous enrollment in claims data, 12 months of clinical activity in EMR, and an absence of malignancies excluding basal and squamous cell carcinoma. Patient follow-up was divided into 30-day windows, and a proxy SLEDAI-2K score based on the EMR data was calculated for each 30-day period. A flare was defined as an increase of at least 4 from the baseline score. A series of potential flare predictor variables identified in claims were based on a combination of established variables from a previous algorithm, with the addition of other SLE-related indicators based on clinical input. Logistic regression models were built to predict monthly SLE flares. RESULTS: Inclusion criteria identified 2427 patients. Results from a logistic model with forward selection capping the number of variables at 10 performed well with a c-statistic of 0.76 and a Brier score of 0.07. The top five predictors were any inpatient admission (OR = 4.76), outpatient office visit (OR = 3.04), MRI (OR = 2.26), ER visit (OR = 2.25), and number of rheumatology visits (OR = 1.75); p < .01 for all. CONCLUSIONS: The final algorithm shows promise in providing an alternative and more streamlined way for identifying likely flares in administrative claims data that will advance the study of SLE within the context of flares.

The GetReal Trial Tool: design, assess and discuss clinical drug trials in light of Real World Evidence generation.

Methodologies incorporating Real World Elements into clinical trial design (also called pragmatic trials) offer an attractive opportunity to assess the effect of a treatment strategy in routine care and as such guide decision making in practice. Uptake of these methods is slow for several reasons, including uncertainty about acceptability of trial results, lack of experience with the methodology and operational challenges. We developed the "GetReal Trial Tool," an easy-to-use online interface, which allows users to assess the impact of design choices on generalizability to routine clinical practice, while taking into account risk of bias, precision, acceptability and operational feasibility. The tool is grounded in the scientific literature combined with knowledge of experts from academia, pharmaceutical companies, HTA bodies, patient organizations, and regulators. The aim is to help researchers optimize trial design and facilitate translation of evidence from pragmatic trials to clinical practice. In this paper we describe the development, structure and application of the GetReal Trial Tool.

Validation of claims-based indicators used to identify flare-ups in inflammatory bowel disease.

BACKGROUND & AIMS: There are currently no validated claims-based indicators for identifying a worsening of disease in patients with inflammatory bowel disease (IBD). Therefore, we aimed to develop and validate indicators that identify flare-ups of IBD using data from Danish nationwide registries. METHODS: Using Danish nationwide administrative data, we identified all patients with Crohn's disease (CD) or ulcerative colitis (UC) who had at least one measurement of faecal calprotectin between 1 January 2015 and 31 June 2017. We tested several different claims-based indicators of disease flare-ups against levels of faecal (F-)calprotectin (no flare-up: <250 mg/kg; mild flare-up: 250-1000 mg/kg; severe flare-up: ⩾1000 mg/kg). A generalised estimating equation was used to evaluate whether the proposed indicators could predict disease activity. RESULTS: A total of 890 children and 4719 adults with CD, and 592 children and 5467 adults with UC were included in the study. During the observation period, 48-61% and 48-55% of the CD and UC patients, respectively, had no flare-up, 26-29% (CD) and 24-26% (UC) experienced a mild flare-up, and 12-23% (CD) and 21-27% (UC) experienced a severe flare-up. Combinations of indicators that could predict a flare-up in CD and UC adults included hospitalisation, surgery, initiation or switch of biological therapy, treatment with systemic steroids, locally acting steroids or topical 5-aminosalicylates, colonoscopy/sigmoidoscopy, and magnetic resonance imaging/computed tomography. In children, only the number of gastroenterology visits was significant as an indicator among UC patients, and none were seen in children with CD. Overall, the indicator combinations resulted in a predictive ability of 0.62-0.67. CONCLUSION: Administrative claims data can be useful for identifying patients exhibiting (F-calprotectin defined) flare-ups of their IBD. Clinically relevant events captured in the Danish national patient registry are associated with increased levels of calprotectin and hence increased disease activity, and can be used as valid outcomes in future studies.

Follow-up of SARS-CoV-2 positive subgroup from the Asymptomatic novel CORonavirus iNFection study.

A nested longitudinal study within theAsymptomatic novel CORonavirus iNFfection study followed participants with positive nasopharyngeal swab to query for development of symptoms and assess duration of positive reverse transcription-polymerase chain reaction (RT-PCR) test results. Of the 91 participants initially testing positive, 86 participated in follow-up approximately 14 days after study enrollment; of those 86 participants, 19 (22.1%) developed at least one symptom at any time after the initial positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result. The median number of days to symptom development after their initial positive test result was 6 (range 1-29 days). No participants reported a SARS-CoV-2-related hospitalization. The most frequently reported symptoms were fatigue or muscle aches (10.5%), headache (9.3%), fever (5.8%), and shortness of breath (5.8%). Of the 78 participants who submitted a nasopharyngeal swab for repeat RT-PCR testing, 17 (21.8%) remained positive at Day 14, 4 of which continued to test positive at Day 28. These findings reinforce the probable role of silent SARS-CoV-2 infections in community transmission, and that reliance on symptom development will miss a large proportion of infections. Broad testing programs not limited to individuals presenting with symptoms are critical for identifying persons with SARS-CoV-2 infection and ultimately slowing transmission.

A cross-sectional community-based observational study of asymptomatic SARS-CoV-2 prevalence in the greater Indianapolis area.

The Asymptomatic novel CORonavirus iNfection (ACORN) study was designed to investigate the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the asymptomatic adult population of the Indianapolis metropolitan area, to follow individuals testing positive for the development of symptoms, and to understand duration of positive test results. ACORN is a cross-sectional community-based observational study of adult residents presenting asymptomatic for COVID-like illness, defined as the self-reported absence of the following three symptoms in the last 7 days: fever (≥100°F), new-onset or worsening cough, and new-onset or worsening shortness of breath. SARS-CoV-2 infection was determined by real-time reverse transcription-polymerase chain reaction in nasopharyngeal swab samples. SARS-CoV-2 infection prevalence was expressed as a point estimate with 95% confidence interval (CI). Test results are reported for 2953 participants who enrolled and underwent nasopharyngeal swab testing between 7 April 2020 and 16 May 2020. Among tested participants, 91 (3.1%; 95% CI: 2.5%-3.7%) were positive for SARS-CoV-2. Overall, baseline characteristics, medical history, and infection risk factors were comparable between SARS-CoV-2 positive and negative participants. Within the ongoing 14-day follow-up period for positive participants, 58 (71.6%) of 81 assessed participants remained asymptomatic while others (n = 23, 28.4%) reported one or more symptoms. Indiana had "Stay-at-Home" orders in place during nearly the entire test period reported here, yet 3.1% of asymptomatic participants tested positive for SARS-CoV-2. These results indicate screening questions had limited predictive utility for testing in an asymptomatic population and suggest broader testing strategies are needed. Importantly, these findings underscore that more research is needed to understand the viral transmission and the role asymptomatic and presymptomatic individuals play in this global pandemic.

Series: Pragmatic trials and real world evidence: Paper 4. Informed consent.

The GetReal consortium of the Innovative Medicines Initiative aims to develop strategies to incorporate real-world evidence earlier into the drug life cycle to better inform health care decision makers on the comparative risks and benefits of new drugs. Pragmatic trials are currently explored as a means to generate such evidence in routine care settings. The traditional informed consent model for randomized clinical trials has been argued to pose substantial hurdles to the practicability of pragmatic trials: it would lead to recruitment difficulties, reduced generalizability of the results, and selection bias. The present article analyzes these challenges and discusses four proposed alternative informed consent models: integrated consent, targeted consent, broadcast consent, and a waiver of consent. These alternative consent models each aim at overcoming operational and methodological challenges, while still providing patients all the relevant information they need to make informed decisions. Each consent model, however, relies on different attitudes toward the principle of respect for persons and the related duty to inform patients as well as represents different views on whether the common good demands moral duties from patients. Such normative consequences of modifying consent requirements should be at least acknowledged and ought to be assessed in light of the validity of empirical claims.

Series: Pragmatic trials and real world evidence: Paper 6. Outcome measures in the real world.

Results from pragmatic trials should reflect the comparative treatment effects encountered in patients in real-life clinical practice to guide treatment decisions. Therefore, pragmatic trials should focus on outcomes that are relevant to patients, clinical practice, and treatment choices. This sixth article in the series (see Box) discusses different types of outcomes and their suitability for pragmatic trials, design choices for measuring these outcomes, and their implications and challenges. Measuring outcomes in pragmatic trials should not interfere with real-world clinical practice to ensure generalizability of trial results, and routinely collected outcomes should be prioritized. Typical outcomes include mortality, morbidity, functional status, well-being, and resource use. Surrogate endpoints are typically avoided as primary outcome. It is important to measure outcomes over a relevant time horizon and obtain valid and precise results. As pragmatic trials are often open label, a less subjective outcome can reduce bias. Methods that decrease bias or enhance precision of the results, such as standardization and blinding of outcome assessment, should be considered when a high risk of bias or high variability is expected. The selection of outcomes in pragmatic trials should be relevant for decision making and feasible in terms of executing the trial in the context of interest. Therefore, this should be discussed with all stakeholders as early as feasible to ensure the relevance of study results for decision making in clinical practice and the ability to perform the study.

Series: Pragmatic trials and real world evidence: Paper 1. Introduction.

This is the introductory paper in a series of eight papers. In this series, we integrate the theoretical design options with the practice of conducting pragmatic trials. For most new market-approved treatments, the clinical evidence is insufficient to fully guide physicians and policy makers in choosing the optimal treatment for their patients. Pragmatic trials can fill this gap, by providing evidence on the relative effectiveness of a treatment strategy in routine clinical practice, already in an early phase of development, while maintaining the strength of randomized controlled trials. Selecting the setting, study population, mode of intervention, comparator, and outcome are crucial in designing pragmatic trials. In combination with monitoring and data collection that does not change routine care, this will enable appropriate generalization to the target patient group in clinical practice. To benefit from the full potential of pragmatic trials, there is a need for guidance and tools in designing these studies while ensuring operational feasibility. This paper introduces the concept of pragmatic trial design. The complex interplay between pragmatic design options, feasibility, stakeholder acceptability, validity, precision, and generalizability will be clarified. In this way, balanced design choices can be made in pragmatic trials with an optimal chance of success in practice.

The Social Value of Pragmatic Trials.

Pragmatic trials aim to directly inform health care decision-making through the collection of so-called 'real world data' from observations of comparative treatment effects in clinical practice. In order to ensure the applicability and feasibility of a pragmatic trial, design features may be necessary that deviate from standard research ethics requirements. Examples are traditional requirements to seek written informed consent and to perform extensive data and safety monitoring. Proposals for deviations from standard research ethics practice have resulted in controversy about their ethical acceptability. One of the justifications for altered procedures is the allegedly high social value of pragmatic trials. In order to properly operationalize the concept in the ethical assessment of pragmatic trial designs, specification is warranted. We identified three determinants from common claims about a pragmatic trial's social value: (1) the extent to which the research question has real world relevance, (2) the trial design's ability to generate a real world answer and (3) the probability of direct uptake of the results by decision-makers in practice. Subsequently, we discuss how these determinants should be applied to the practice of pragmatic trials, and to what extent they might be applicable to explanatory trials.

Pragmatic trial design elements showed a different impact on trial interpretation and feasibility than explanatory elements.

OBJECTIVES: To illustrate how pragmatic trial design elements or inserting explanatory trial elements in pragmatic trials affect validity, generalizability, precision, and operational feasibility. STUDY DESIGN AND SETTING: From illustrative examples identified through the IMI Get Real Consortium, we selected randomized drug trials with a pragmatic design feature. We searched all publications on these trials for information on how pragmatic trial design features affect validity, generalizability, precision, or feasibility. RESULTS: We present examples from the Salford lung study, International Suicide Prevention Trial, Sequenced Treatment Alternatives to Relieve Depression, and Cluster Randomized Usual care vs. Caduet Investigation Assessing Long-term-risk trial. These examples show that incorporating pragmatic trial design elements in trials may affect generalizability, precision and validity and may lead to operational challenges different from traditional explanatory trials. Inserting explanatory trial elements into pragmatic trials may also affect validity, generalizability, and operational feasibility, especially when these trial elements are incorporated in one arm of the trial only. Design choices that positively affect one of these domains (e.g., generalizability) may negatively affect others (e.g., feasibility). CONCLUSION: Consequences of incorporating pragmatic or explanatory trial design elements in pragmatic trials should be explicitly considered and balanced for all relevant domains, including validity, generalizability, precision, and operational feasibility. Tools are needed to make these consequences more transparent.

Comprehensive review of factors implicated in the heterogeneity of response in depression.

BACKGROUND: Heterogeneity in overall response and outcomes to pharmacological treatment has been reported in several depression studies but with few sources that integrate these results. The goal of this study was to review the literature and attempt to identify nongenetic factors potentially predictive of overall response to depression treatments. METHODS: A comprehensive review of the literature from the last 10 years was performed using three key databases (PubMed, EMBASE, and Cochrane). All relevant studies that met the inclusion criteria were selected and scored for their levels of evidence using the NICE scoring method. A subjective assessment of the strength of evidence for each factor was performed using predefined criteria. RESULTS: Our broad search yielded 76 articles relevant to treatment heterogeneity. Sociodemographic factors, disease characteristics, and comorbidities were the most heavily researched areas. Some of the factors associated with more favorable overall response include being married, other social support, and low levels of baseline depressive symptoms. Evidence relating to baseline disease severity as a factor predictive of antidepressant response was particularly convincing among the factors reviewed. The presence of comorbid anxiety and pain contributed to worse antidepressant treatment outcomes. CONCLUSIONS: Several factors either predictive of or associated with overall response to antidepressant treatment have been identified. Inclusion of factors predictive of response in the design of future trials may help tailor treatments to depression patients presenting to the average clinical practice, resulting in improved outcomes.

Review of treatment response in rheumatoid arthritis: assessment of heterogeneity.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, systemic, progressive, inflammatory disorder. The primary goals of treatment in RA are to reduce the signs and symptoms of disease, prevent progression of joint damage and improve patients' physical function. Patients with different sociodemographic characteristics, varying degrees of severity of illness, and comorbidities tend to exhibit differential response to treatment. The purpose of this review was to identify a broad set of factors that are associated with and/or predictive of RA treatment response and determine those that warrant further research. RESEARCH DESIGN AND METHODS: A comprehensive review of the literature from the last 10 years was performed using three key databases (PubMed, EMBASE, and Cochrane). All relevant articles that met the inclusion/exclusion criteria were selected and scored for their levels of evidence using the National Institute of Clinical Excellence (NICE) scoring method. Data on study design, interventions and treatment outcomes were abstracted using a structured abstraction table. RESULTS: A total of 30 articles were included in the review and data abstraction. Besides gender, baseline clinical variables such as C-reactive protein level, erythrocyte sedimentation rate, measures of disease activity, and Health Assessment Questionnaire scores (based on five patient-centered dimensions) were consistently associated with treatment response over time. CONCLUSIONS: This comprehensive literature review identified several factors associated with treatment response which might be valuable to include as relevant measures in future studies of RA treatment. Inclusion of these factors, particularly those in the clinical and sociodemographic domains, in the design of future trials will further the understanding that ultimately may help clinicians deliver targeted treatment to community practice RA patients, thus resulting in improved patient outcomes.

Stability and treatment outcome of distinct classes of mania.

BACKGROUND: Psychopathological heterogeneity in manic syndromes may in part reflect underlying latent classes with characteristic outcome patterns. Differential treatment course and outcome after 12 weeks of treatment were examined for three distinct classes of patients with acute mania in bipolar disorder. SUBJECTS AND METHODS: Three thousand four hundred and twenty-five patients with acute mania were divided into three distinct mania classes: 'Typical', 'Psychotic' and 'Dual' (i.e. comorbid substance use) mania. Persistence of class differences and social outcomes were examined, using multilevel regression analyses and odds ratios. RESULTS: The three classes showed substantial stability post-baseline in the pattern of associations with class-characteristic variables. Psychotic and Dual mania predicted poorer outcome in terms of psychosis comorbidity and overall bipolar and mania severity, while Dual mania additionally predicted poorer outcome of alcohol and substance abuse. Worse social outcomes were observed for both Dual and Psychotic mania. CONCLUSION: The identified distinct classes are stable and associated with differential treatment outcome. Overall, Dual and Psychotic mania show less favourable outcomes compared to Typical mania. These findings additionally give rise to concern on the generalisability of randomized clinical trials RCTs.

Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study.

BACKGROUND: To evaluate the 12-week outcomes (effectiveness, tolerability, and patterns of medication use) of olanzapine (either in antimanic monotherapy or in combination with other antipsychotics, anticonvulsants, and/or lithium) in patients with bipolar mania or mixed mania. METHOD: EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a 24-month prospective observational study of in- and outpatients with acute mania/mixed mania conducted in 14 European countries. Primary outcome measures included Clinical Global Impressions-Bipolar Disorder scale (overall, mania, and depression); 5-item Hamilton Depression Rating Scale; and Young Mania Rating Scale. Tolerability measures included a questionnaire to assess patients' symptomatic complaints. RESULTS: Overall, 2004 patients received olanzapine (olanzapine monotherapy, n=673; olanzapine combination, n=1331). Concomitant therapy with antidepressants and/or anxiolytics was possible in both groups. The countries significantly differed in the use of olanzapine monotherapy versus olanzapine combination (p<.0001). Baseline-to-endpoint changes on the CGI-BP subscales, YMRS, and HAMD-5 were significant within both treatment groups (p<.0001). Olanzapine monotherapy was generally better tolerated than olanzapine combination, particularly with regard to sedation (12% vs 17%; p<.001), tremor (2% vs 5%; p<.001), and akathisia (3% vs 6%; p<.001). DISCUSSION: The acute-phase EMBLEM results suggest that in naturalistic settings, olanzapine (both as monotherapy and combination) may be effective in treating patients with bipolar mania. The use of olanzapine monotherapy or combination varies significantly across countries, but combination is generally the rule, rather than the exception.

The management of bipolar mania: a national survey of baseline data from the EMBLEM study in Italy.

BACKGROUND: Although a number of studies have assessed the management of mania in routine clinical practice, no studies have so far evaluated the short- and long-term management and outcome of patients affected by bipolar mania in different European countries. The objective of the study is to present, in the context of a large multicenter survey (EMBLEM study), an overview of the baseline data on the acute management of a representative sample of manic bipolar patients treated in the Italian psychiatric hospital and community settings. EMBLEM is a 2-year observational longitudinal study that evaluates across 14 European countries the patterns of the drug prescribed in patients with bipolar mania, their socio-demographic and clinical features and the outcomes of the treatment. METHODS: The study consists of a 12-week acute phase and a < or = 24-month maintenance phase. Bipolar patients were included into the study as in- or out-patients, if they initiated or changed, according to the decision of their psychiatrist, oral antipsychotics, anticonvulsants and/or lithium for the treatment of an episode of mania. Data concerning socio-demographic characteristics, psychiatric and medical history, severity of mania, prescribed medications, functional status and quality of life were collected at baseline and during the follow-up period. RESULTS: In Italy, 563 patients were recruited in 56 sites: 376 were outpatients and 187 inpatients. The mean age was 45.8 years. The mean CGI-BP was 4.4 (+/- 0.9) for overall score and mania, 1.9 (+/- 1.2) for depression and 2.6 (+/- 1.6) for hallucinations/delusions. The YMRS showed that 14.4% had a total score < 12, 25.1% > or = 12 and < 20, and 60.5% > or = 20. At entry, 75 patients (13.7%) were treatment-naïve, 186 (34.1%) were receiving a monotherapy (of which haloperidol [24.2%], valproate [16.7%] and lithium [14.5%] were the most frequently prescribed) while 285 (52.2%) a combined therapy (of which 8.0% were represented by haloperidol/lithium combinations). After a switch to an oral medication, 137 patients (24.8%) were prescribed a monotherapy while the rest (415, 75.2%) received a combination of drugs. CONCLUSION: Data collected at baseline in the Italian cohort of the EMBLEM study represent a relevant source of information to start addressing the short and long-term therapeutic strategies for improving the clinical as well as the socio-economic outcomes of patients affected by bipolar mania. Although it's not an epidemiological investigation and has some limitations, the results show several interesting findings as a relatively late age of onset of bipolar disorder, a low rate of past suicide attempts, a low lifetime rate of alcohol abuse and drug addiction.

The social, psychopathological and consumer context of rate of symptom improvement in acute mania.

BACKGROUND: Knowledge of moderators of symptom improvement over time in acute mania improves predictability of individual patient outcomes. This study attempted to identify such moderators of the rate of symptom improvement. METHODS: In 3459 patients with high levels of mania in whom a change in psychotropic treatment was initiated and who were assessed six times over three months, clinical and social moderators of the rate of response were examined. Additionally, moderators of symptom improvement in individuals with high baseline levels of comorbid depression (n = 815) and psychosis (n = 1849) were identified. RESULTS: Within three months, mania symptoms were reduced by 52%, psychotic symptoms by 56% and depressive symptoms by 36%. High levels of baseline depression, greater illness severity in the past year, lower age of onset and rapid cycling reduced the rate of mania symptom improvement by 5-15%. Social variables indicating disadvantage similarly had negative contributions (5%-14%). Several reasons for change of medication involving patient choice, patient compliance, side effects and lack of effectiveness impacted negatively (reductions of 10%, 6%, 14% and 9% respectively). For the psychosis dimension, both low mania scores (22% reduction) and high depression scores (14% reduction) at baseline impacted negatively, whereas rate of reduction in depression was not conditional on baseline psychopathology. CONCLUSIONS: The rate of symptom improvement in acute mania is to a large extent conditional on the context as provided by the social, psychopathological and consumer environment. Understanding the context of treatment response offers valuable insights into treatment approaches aimed at moderation of traditional pharmacological interventions.

Voluntary vs. involuntary hospital admission in acute mania of bipolar disorder: results from the Swiss sample of the EMBLEM study.

BACKGROUND: Patients with acute mania in bipolar disorder require pharmacological treatment to reduce symptoms. In addition, it is recognised that admission status is a clinically relevant aspect of bipolar disorder. There is, however, a lack of published data assessing the association of admission status with clinical or functional outcomes. The European-Mania-in-Bipolar-Longitudinal-Evaluation-of-Medication (EMBLEM) study has been designed to describe outcomes associated with medication therapies. Baseline data from this study are now available and we used these data to examine the characteristics of patients with acute mania in the Swiss EMBLEM cohort who were admitted involuntary and voluntary, respectively, and their functional and clinical status. METHODS: Ninety-five patients with an acutely manic or mixed episode of bipolar disorder were included in the Swiss cohort of the study. Patients' history, psychosocial functioning, clinical measures of mania and depression, pharmacological and compliance variables were assessed. Statistical methods comprised univariate analyses of variance and logistic regression analyses to elucidate associations between variables of interest. RESULTS: Patients with involuntary hospital admission (n = 55) were more aggressive and had less insight. They had a more frequent history of substance abuse and were less likely to take anticonvulsants or lithium. Furthermore, these patients showed lower compliance, which also guided physicians' decision on pharmacotherapy. LIMITATION: The EMBLEM study had an observational and non-interventional design; therefore it was not possible to compare treatment groups by means of stringent between-group analyses. However, a main target of this study was to gather clinically relevant information on outcomes of acute mania associated with currently available medication therapies. CONCLUSIONS: Involuntary admission status was significantly associated with clinical status, especially aggression and also compliance. Admission status in bipolar patients plays a clinically important role.