∗ Corresponding author. Sinai Health System, Department of Internal Medicine, 5th Floor Room L255, 60 Murray Street, Toronto, Ontario, Canada M5B 1W8. Tel.: +1 416 586 4800.
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Differences in characteristics were found between patients in the deferred consent and nondeferred consent groups.
Primarily it was found that the patients in the deferred consent group were more likely to be enrolled on weekends and were more likely to be older.
This finding shows that deferred consent, the process of enrolling patients in clinical trials prior to obtaining consent, may allow for the enrollment of a greater number of individuals.
These findings may have implications for obtaining consent when conducting clinical trials in the future.
Deferred consent, the process of enrolling patients in a clinical trial before consent is obtained, is often employed in studies of minimal risk [[1], [2], [3], [4]], or when patients are unable to consent at the time of study enrollment [[5], [6], [7], [8]]. Deferred consent has several possible benefits including decreasing the time to study enrollment, allowing for enrollment when study personnel are unavailable [9,10], and allowing the inclusion of populations less represented in clinical trials [4,11,12]. Multiple studies have identified that deferred consent is considered an acceptable substitute for pre-enrollment consent by both participants and clinicians [13,14]. Our objective was to assess patient-level characteristics, adherence, and rate of withdrawal among participants enrolled with consent obtained before (nondeferred consent) vs. after (deferred consent) randomization in the COVID-PRONE randomized trial (NCT04383613).
We conducted a secondary analysis of the COVID-prone international, pragmatic randomized clinical trial, which assessed prone positioning in patients with COVID-19 [15].
Deferred consent was allowed as the benefit of prone positioning was thought to be greatest when immediately implemented, because patients may be in respiratory distress at the time of enrollment, and because we expected potential harms from prone positioning to be minimal. Deferred consent was allowed at all except two hospitals. The decision on timing of consent was made by the site lead at the time of recruitment.
The primary outcome of this analysis was the difference in patient characteristics, time spent prone, and rate of withdrawal among participants who were enrolled with consent obtained before vs. after randomization. We did not compare the primary outcome between the two groups because our study was stopped for futility and our primary outcome was similar between patients randomized to prone positioning compared to standard of care.
Among 248 total patients, 125 (50.5%) were enrolled after consent, and 123 (49.5%) were enrolled with deferred consent. The median time between randomization and consent was 1 day (interquartile range [IQR] 0–2 days) in the deferred consent group. Patients in the deferred consent group were more likely to be enrolled on weekends (14.6% vs. 9.6%), male (67.5% vs. 60.8%), and older (median age 60 vs. 54 years) Table 1 . The frequency of deferred consent varied significantly by hospital (median 41.5%; range: 0–100%). Patients in the deferred consent group were more likely to require oxygen via face mask (9.8% vs. 2.4%) and less likely to have received remdesivir (27.6% vs. 56%).
| Characteristic | Deferred (N = 123) | Nondeferred (N = 125) |
|---|---|---|
| COVID status | ||
| COVID-19 test result | 120 (97.6%) | 122 (97.6%) |
| Randomization timing | ||
| Number of days between admission and randomization | 1 [1, 1] | 1 [1, 1] |
| Days between randomization and consent | 1 [0, 2] | 0 [0, 0] |
| Randomized on a saturday or sunday | 18 (14.6%) | 12 (9.6%) |
| Age | ||
| Median [IQR] | 60 [49.5, 68] | 54 [39, 61] |
| 31 (25.2%) | 50 (40%) | |
| 50–70 | 69 (56.1%) | 64 (51.2%) |
| >70 | 23 (18.7%) | 11 (8.8%) |
| Sex | ||
| Female | 40 (32.5%) | 49 (39.2%) |
| Date of randomization | ||
| Before Sept 1, 2020 | 6 (4.9%) | 2 (1.6%) |
| Sept 1, 2020 to Feb 28, 2021 | 84 (68.3%) | 60 (48%) |
| After Feb 28, 2021 | 33 (26.8%) | 63 (50.4%) |
| Comorbid conditions | ||
| Diabetes | 35 (28.5%) | 32 (25.6%) |
| Hypertension | 47 (38.2%) | 51 (40.8%) |
| Current smoker | 4 (3.3%) | 3 (2.4%) |
| COPD or asthma | 8 (6.5%) | 19 (15.2%) |
| Heart failure | 3 (2.4%) | 3 (2.4%) |
| Illness severity | ||
| Lymphocyte count | 0.82 [0.6, 1.1] | 0.9 [0.68, 1.2] |
| Creatinine | 81 [66, 100] | 76 [63, 93] |
| Systolic blood pressure | 123 [114, 133] | 122.5 [115, 130] |
| Oxygen saturation | 94 [93, 96] | 94 [93, 95] |
| FiO2 | 32 [28, 36] | 32 [28, 36] |
| S/F ratio | 303 [261, 339] | 305 [264, 337] |
| FiO2 delivery method | ||
| Nasal prong | 109 (88.6%) | 113 (90.4%) |
| High-flow nasal cannula | 1 (0.8%) | 6 (4.8%) |
| Face mask | 12 (9.8%) | 3 (2.4%) |
| Medication | ||
| Dexamethasone | 115 (93.5%) | 121 (96.8%) |
| Remdesivir | 34 (27.6%) | 70 (56%) |
| Tocilizumab | 0 (0%) | 2 (1.6%) |
| Code status | ||
| Full code | 110 (89.4%) | 119 (95.2%) |
| Do not resuscitate | 5 (4.1%) | 0 (0%) |
| Other | 8 (6.5%) | 5 (4%) |
Abbreviations: COPD, chronic obstructive pulmonary disease; FiO2, fraction of inspired oxygen; IQR, interquartile range; S/F ratio, ratio of saturation of oxygen to fraction of inspired oxygen.
Missingness for all variables was
There was no difference in the rates of study withdrawal ([3%] in each group) or median number of hours spent in prone position within the group randomized to prone positioning (nondeferred = 7 [IQR 2.3–16.8], deferred = 4 [IQR 1.3–12.0]). The rate of serious adverse events was 4.9 % in the deferred consent group and 1.6 % in the nondeferred consent group Table 2 .
Secondary outcomes and rate of adverse events among patients enrolled with deferred vs. nondeferred consent
| Outcome | Deferred (N = 123) | Non-deferred (N = 125) |
|---|---|---|
| Secondary outcomes | ||
| S/F ratio after 72 hours | 332 [207, 423] | 345 [260, 446] |
| Change in S/F ratio in first 72 hours (median [IQR]) | 7 [−58, 73] | 60 [−20, 108] |
| Change in FiO2 (%) in first 72 hours (median [IQR]) | 0 [−7, 8] | −4 [−8, 4] |
| Days to discharge (median [IQR]) | 6 [4, 10] | 4 [3, 6] |
| Discharged | 114 (92.7%) | 119 (95.2%) |
| Serious adverse events | ||
| SAE composite | 6 (4.9%) | 2 (1.6%) |
Abbreviations: IQR, interquartile range; SAE, severe adverse event; S/F ratio, ratio of saturation of oxygen to fraction of inspired oxygen.
In this secondary analysis of an international randomized controlled trial of prone positioning for noncritically ill patients with COVID-19, patients who underwent deferred consent were more likely to be male, older, and be enrolled on a weekend. We observed similar rates of both participant withdrawal and protocol adherence.
Our study has several limitations. First, data were unavailable for why deferred consent was chosen. Second, we did not ascertain patients' and providers’ perspectives on deferred consent, though prior literature has shown that both groups find it to be an acceptable alternative [13,14]. Third, this was an exploratory and post-hoc analysis, and thus we did not test for statistical significance and our findings require replication.
Our results suggest that the use of deferred consent may allow for the inclusion of patients who would not otherwise have been enrolled (e.g., patients hospitalized on weekends), potentially improving the external generalizability of randomized trials.
Conflicts of interest: The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests. Michael Fralick is a consultant for ProofDx, a start-up company that has created a point of care device for COVID-19 using CRISPR
Funding: This study was funded by St Michael's Hospital Innovation fund, the Sinai Health Department of Medicine Research fund, and Sunnybrook Health Sciences Center Alternate Funding Plan Innovation Fund. The funders had no role in considering the study design or in the collection, analysis, or interpretation of data, the writing of the report, or the decision to submit the article for publication.
Author Contributions: Understanding how deferred consent affects patient characteristics and outcome: an exploratory analysis of a clinical trial of prone positioning for COVID-19. Study concept and design: All authors; Acquisition of data: All authors; Analysis/interpretation of data: All authors; Drafting of the manuscript: Colacci M, Fralick M; Critical revision of the manuscript: All authors; Statistical analysis: All authors.
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