Introduction
Delirium affects up to 7 million hospitalized older adults annually1 and is associated with increased risk of mortality, institutionalization, and cognitive and functional impairment.2 There has been a proliferation of pharmacologic and nonpharmacologic clinical trials to reduce incidence and sequelae of delirium.3 For other neuropsychiatric disorders, exclusion criteria disqualify up to 75% of individuals with the condition under study from participating.4 We sought to examine how often common at-risk populations are excluded from clinical trials of interventions for delirium.
Methods
We performed a cross-sectional analysis of data from ClinicalTrials.gov.5 As a publicly available data source that contains only summary data (rather than information on individual participants), use of data from ClinicalTrials.gov does not require institutional review board approval. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We selected all trials in which the study type was listed as interventional and outcome measures included the keyword delirium as a condition studied (N = 89). Two independent reviewers (R.C.M., R.E.K.) manually reviewed study inclusion and exclusion criteria and extracted information on participant age, comorbidities, and setting as exclusion criteria; these data were verified by a third reviewer (Y.Z.). Frequencies were calculated for each type of exclusion criteria, stratified by study start date in 5-year intervals from January 1, 2000, to October 15, 2019. The Fisher exact test was used to examine changes in frequencies over time. P values were considered significant at P < .05 using a Hochberg step-down procedure and were 2-sided. Analyses were conducted using R, version 3.6.1 (R Project for Statistical Computing).
Results
Delirium studies were generally small, with median enrollment of 100 participants (interquartile range, 44–283) (Table 1). Of the 89 studies, 50 (56.2%) primarily focused on prevention and 27 (30.3%) on treatment using pharmacologic interventions (52 [58.4%]). Most studies were randomized, controlled clinical trials (80 [89.9%]). Consistent with the small sample size, most trials (64 [71.9%]) were funded by sources other than the National Institutes of Health or industry.
Table 1.
Characteristics of Clinical Trials on Delirium Registered in ClinicalTrials.gov
| Characteristic | Trialsa (N = 89) |
|---|---|
| Patients enrolled, median (IQR), No. | 100 (44.0–283.0) |
| Recruitment status | |
| Not yet recruiting | 3 (3.37) [0.87–10.22] |
| Recruiting or enrolling | 29 (32.58) [23.26–43.46] |
| Active, not recruiting | 6 (6.74) [2.76–14.64] |
| Completed | 32 (35.96) [26.29–46.93] |
| Withdrawn, suspended, or terminated | 15 (16.85) [10.08–26.65] |
| Unknown | 4 (4.49) [1.45–11.74] |
| Study results | |
| Available | 16 (17.98) [10.95–27.88] |
| Not available | 73 (82.02) [72.12–89.05] |
| Intervention type | |
| Behavioral | 11 (12.36) [6.66–21.50] |
| Device | 12 (13.48) [7.47–22.77] |
| Drug or dietary supplement | 52 (58.43) [47.46–68.60] |
| Procedure | 5 (5.62) [2.09–13.21] |
| Other | 9 (10.11) [5.01–18.78] |
| Study phase | |
| Phase 1 | 1 (1.12) [0.06–6.97] |
| Phase 1 and 2 | 1 (1.12) [0.06–6.97] |
| Phase 2 | 12 (13.48) [7.47–22.77] |
| Phase 3 | 11 (12.36) [6.66–21.50] |
| Phase 3 and 4 | 4 (4.49) [1.45–11.74] |
| Phase 4 | 25 (28.09) [19.33–38.79] |
| Not applicable | 35 (39.33) [29.28–50.25] |
| Study allocation | |
| Randomized | 80 (89.89) [81.21–94.98]b |
| Nonrandomized | 5 (5.62) [2.09–13.22] |
| Not specified | 4 (4.49) [1.45–11.75]b |
| Intervention model | |
| Factorial assignment | 2 (2.25) [0.39–8.65] |
| Parallel assignment | 78 (87.64) [78.50–93.34] |
| Single group assignment | 9 (10.11) [5.01–18.78] |
| Masking | |
| None | 18 (20.22) [12.72–30.31] |
| Single | 13 (14.61) [8.30–24.03] |
| Double | 23 (25.84) [17.37–36.36] |
| Triple | 12 (13.48) [7.47–22.77] |
| Quadruple | 23 (25.84) [17.37–36.36] |
| Primary purpose | |
| Prevention | 50 (56.18) [45.30–66.56] |
| Treatment | 27 (30.34) [21.24–41.08] |
| Other | 12 (13.48) [7.47–22.77] |
| Funding source | |
| Industry | 3 (3.37) [0.87–10.23] |
| Industry and other | 4 (4.49) [1.45–11.74] |
| NIH, industry, and other | 1 (1.12) [0.06–6.97] |
| NIHand other | 17 (19.10) [11.82–29.09] |
| Other | 64 (71.91) [61.21–80.67] |
Abbreviation: NIH, National Institutes of Health.
Data are present as number (percentage) [95% CI] of trials unless otherwise indicated.
Data are based on a sample size of 84.
All 89 studies enrolled only adults, with 41 (46.1%) enrolling only adults 60 years or older (Table 2). Most studies (47 [52.8%]) were restricted to surgical units (primarily elective knee and hip replacement), with a smaller percentage conducted in medical surgical (24 [27.0%]) and medical (13 [14.6%]) units. Only 1 study (1.1%) was conducted in nursing homes, 3 (3.4%) in palliative care units, and 1 (1.1%) in emergency departments. A total of 26 studies (29.2%) were restricted to intensive care units. Neurologic and psychiatric comorbidities were commonly excluded: 46 studies (51.7%) excluded individuals with preexisting dementia; 48 (53.9%), other neurological disorders; 37 (41.6%), psychiatric disorders; and 34 (38.2%), substance use. Patients with advanced or terminal illness were also commonly excluded, usually by specifying individuals with limited life expectancy or supportive care only: 12 (13.5%) excluded nursing home residents, 22 (24.7%) excluded individuals receiving palliative care, and 28 (31.5%) excluded individuals with terminal illness. There were no differences over time in exclusion of neurologic or psychiatric disorders, but exclusions based on advanced or terminal illness decreased over time.
Table 2.
Study Exclusion and Inclusion Criteria in Clinical Trials on Delirium Registered in ClinicalTrials.gov
| Criterion | Trials, No. (%) | Adjusted P valuea | ||||
|---|---|---|---|---|---|---|
| All (N = 89) | 2000–2004 (n = 6) | 2005–2009 (n = 17) | 2009–2014 (n = 21) | 2015–2019 (n = 45) | ||
| Excluded patients aged <18 y | 89 (100) | 6 (100) | 17 (100) | 21 (100) | 45 (100) | NA |
| Excluded patients aged ≥60 y | 41 (46.1) | 2 (33.3) | 9 (52.9) | 6 (28.6) | 24 (53.3) | .95 |
| Excluded based on upper age limit | 14 (15.7) | 1 (16.7) | 0 | 5 (23.8) | 8 (17.8) | .87 |
| Excluded patients with dementia | 46 (51.7) | 4 (66.7) | 12 (70.6) | 13 (61.9) | 17 (37.8) | .82 |
| Excluded patients with other neurologic disorders | 48 (53.9) | 3 (50.0) | 10 (58.8) | 12 (57.1) | 23 (51.1) | .95 |
| Excluded patients wth psychiatric disorders | 37 (41.6) | 3 (50.0) | 10 (58.8) | 11 (52.4) | 13 (28.9) | .87 |
| Excluded patients with drug or alcohol dependency | 34 (38.2) | 3 (50.0) | 7 (41.2) | 8 (38.1) | 16 (35.6) | .95 |
| Type of unit | ||||||
| Medical and surgical | 24 (27.0) | 3 (50.0) | 2 (11.8) | 9 (42.9) | 10 (22.2) | .95 |
| Emergency only | 1 (1.12) | 0 | 0 | 0 | 1 (2.22) | |
| Medical only | 13 (14.6) | 1 (16.7) | 2 (11.8) | 2 (9.52) | 8 (17.8) | |
| Nursing home only | 1 (1.12) | 0 | 0 | 0 | 1 (2.22) | |
| Palliative care only | 3 (3.37) | 0 | 0 | 1 (4.76) | 2 (4.44) | |
| Surgical only | 47 (52.8) | 2 (33.3) | 13 (76.5) | 9 (42.9) | 23 (51.1) | |
| Intensive care unit only | 26 (29.2) | 3 (50.0) | 6 (35.3) | 8 (38.1) | 9 (20.0) | |
| Excludes nursing home | 12 (13.5) | 5 (83.3) | 7 (41.2) | 0 | 0 | .001 |
| Excludes palliative care | 22 (24.7) | 5 (83.3) | 8 (47.1) | 3 (14.3) | 6 (13.3) | .006 |
| Excludes terminal illness | 28 (31.5) | 3 (50.0) | 9 (52.9) | 8 (38.1) | 8 (17.8) | .08 |
Abbreviation: NA, not applicable.
P values were adjusted for multiple comparisons using a Hochberg step-down procedure.
Discussion
The study found that there was an increase in clinical trials for delirium between 2000 and 2019, although the total number of trials remained small. Trials predominantly consisted of pharmacologic interventions for prevention of delirium, with a smaller number focused on treatment.
Limitations are that, although ClinicalTrials.gov captures most trials, other registries may be used. However, small clinical trials on delirium (particularly those not federally or industry funded) may not be reported in any database. Clinicaltrials.gov also does not capture reasons for exclusion criteria. In addition, many exclusion criteria allow considerable discretion on the part of the investigator; thus, actual exclusion rates may be higher than our results indicate.
The study found that most intervention studies for delirium were limited to surgical and intensive care unit populations. Most excluded individuals with neurologic and psychiatric comorbidities, which are common in hospitalized older adults6 and associated with increased delirium risk, with no change over time. Similar to other neuropsychiatric disorders, these findings raise concerns about exclusion of a large number of hospitalized older adults. Further work is still needed to increase inclusion in clinical trials on delirium to maximize generalizability of trial results.
Acknowledgments
Funding/Support: This work was funded by grants R21 AG057982 and R01 AG060993 from the National Institute on Aging, National Institutes of Health (Dr Kennedy).
Role of the Funder/Sponsor: The National Institute on Aging, National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Footnotes
Conflict of Interest Disclosures: Dr Kennedy, Ms DiBlasio, and Ms Fowler reported receiving grants from the National Institute on Aging, National Institutes of Health during the conduct of the study. No other disclosures were reported.
Contributor Information
Roy C. Martin, Department of Neurology, University of Alabama at Birmingham, Birmingham.
Christina A. DiBlasio, Department of Psychology, University of Alabama at Birmingham, Birmingham.
Mackenzie E. Fowler, Department of Epidemiology, University of Alabama at Birmingham, Birmingham.
Yue Zhang, Department of Medicine, University of Alabama at Birmingham, Birmingham.
Richard E. Kennedy, Department of Medicine, University of Alabama at Birmingham, Birmingham.
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