Characteristics, consent patterns, and challenges of randomized trials using the Trials within Cohorts (TwiCs) design - A scoping review.

OBJECTIVES: Trials within Cohorts (TwiCs) is a pragmatic design approach that may overcome frequent challenges of traditional randomized trials such as slow recruitment, burdensome consent procedures, or limited external validity. This scoping review aims to identify all randomized controlled trials using the TwiCs design and to summarize their design characteristics, ways to obtain informed consent, output, reported challenges and mitigation strategies. STUDY DESIGN AND SETTING: Systematic search of Medline, Embase, Cochrane, trial registries and citation tracking up to December 2022. TwiCs were defined as randomized trials embedded in a cohort with postrandomization consent for the intervention group and no specific postrandomization consent for the usual care control group. Information from identified TwiCs was extracted in duplicate from protocols, publications, and registry entries. We analyzed the information descriptively and qualitatively to highlight methodological challenges and solutions related to nonuptake of interventions and informed consent procedure. RESULTS: We identified a total of 46 TwiCs conducted between 2005 and 2022 in 14 different countries by a handful of research groups. The most common medical fields were oncology (11/46; 24%), infectious diseases (8/46; 17%), and mental health (7/46; 15%). A typical TwiCs was investigator-initiated (46/46; 100%), publicly funded (36/46; 78%), and recruited outpatients (27/46; 59%). Excluding eight pilot trials, only 16/38 (42%) TwiCs adjusted their calculated sample size for nonuptake of the intervention, anticipating a median nonuptake of 25% (interquartile range 10%-32%) in the experimental arm. Seventeen TwiCs (45%) planned analyses to adjust effect estimates for nonuptake. Regarding informed consent, we observed three patterns: 1) three separate consents for cohort participation, randomization, and intervention (17/46; 37%); 2) combined consent for cohort participation and randomization and a separate intervention consent (10/46; 22%); and 3) consent only for cohort participation and intervention (randomization consent not mentioned; 19/46; 41%). CONCLUSION: Existing TwiCs are globally scattered across a few research groups covering a wide range of medical fields and interventions. Despite the potential advantages, the number of TwiCs remains small. The variability in consent procedures and the possibility of substantial nonuptake of the intervention warrants further research to guide the planning, implementation, and analysis of TwiCs.

Antibody and T-Cell Response to Bivalent Booster SARS-CoV-2 Vaccines in People With Compromised Immune Function: COVERALL-3 Study.

BACKGROUND: Bivalent messenger RNA (mRNA) vaccines, designed to combat emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, incorporate ancestral strains and a new variant. Our study assessed the immune response in previously vaccinated individuals of the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS) following bivalent mRNA vaccination. METHODS: Eligible SHCS and STCS participants received approved bivalent mRNA SARS-CoV-2 vaccines (mRNA-1273.214 or BA.1-adapted BNT162b2) within clinical routine. Blood samples were collected at baseline, 4 weeks, 8 weeks, and 6 months postvaccination. We analyzed the proportion of participants with anti-spike protein antibody response ≥1642 units/mL (indicating protection against SARS-CoV-2 infection), and in a subsample T-cell response (including mean concentrations), stratifying results by cohorts and population characteristics. RESULTS: In SHCS participants, baseline anti-spike antibody concentrations ≥1642 units/mL were observed in 87% (96/112), reaching nearly 100% at follow-ups. Among STCS participants, 58% (35/60) had baseline antibodies ≥1642 units/mL, increasing to 80% at 6 months. Except for lung transplant recipients, all participants showed a 5-fold increase in geometric mean antibody concentrations at 4 weeks and a reduction by half at 6 months. At baseline, T-cell responses were positive in 96% (26/27) of SHCS participants and 36% (16/45) of STCS participants (moderate increase to 53% at 6 months). Few participants reported SARS-CoV-2 infections, side-effects, or serious adverse events. CONCLUSIONS: Bivalent mRNA vaccination elicited a robust humoral response in individuals with human immunodeficiency virus (HIV) or solid organ transplants, with delayed responses in lung transplant recipients. Despite a waning effect, antibody levels remained high at 6 months and adverse events were rare. Clinical Trials Registration . NCT04805125.

Antibody Response After the Third SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients and People Living With HIV (COVERALL-2).

Background: After basic immunization with 2 mRNA SARS-CoV-2 vaccine doses, only a small proportion of patients who are severely immunocompromised generate a sufficient antibody response. Hence, we assessed the additional benefit of a third SARS-CoV-2 vaccine in patients with different levels of immunosuppression. Methods: In this observational extension of the COVERALL trial (Corona Vaccine Trial Platform), we recruited patients from the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study (ie, lung and kidney transplant recipients). We collected blood samples before and 8 weeks after the third SARS-CoV-2 vaccination with either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech). The primary outcome was the proportion of participants showing an antibody response (Elecsys Anti-SARS-CoV-2 S test; threshold ≥100 U/mL) 8 weeks after the third SARS-CoV-2 vaccination. We also compared the proportion of patients who reached the primary outcome from basic immunization (the first and second vaccines) to the third vaccination. Results: Nearly all participants (97.2% [95% CI, 95.9%-98.6%], 564/580) had an antibody response. This response was comparable between mRNA-1273 (96.1% [95% CI, 93.7%-98.6%], 245/255) and BNT162b2 (98.2% [95% CI, 96.7%-99.6%], 319/325). Stratification by cohort showed that 99.8% (502/503) of people living with HIV and 80.5% (62/77) of recipients of solid organ transplants achieved the primary endpoint. The proportion of patients with an antibody response in solid organ transplant recipients improved from the second vaccination (22.7%, 15/66) to the third (80.5%, 62/77). Conclusions: People living with HIV had a high antibody response. The third vaccine increased the proportion of solid organ transplant recipients with an antibody response. Clinical Trials Registration. NCT04805125 (ClinicalTrials.gov).

Reminding Peer Reviewers of Reporting Guideline Items to Improve Completeness in Published Articles: Primary Results of 2 Randomized Trials.

Importance: Numerous studies have shown that adherence to reporting guidelines is suboptimal. Objective: To evaluate whether asking peer reviewers to check if specific reporting guideline items were adequately reported would improve adherence to reporting guidelines in published articles. Design, Setting, and Participants: Two parallel-group, superiority randomized trials were performed using manuscripts submitted to 7 biomedical journals (5 from the BMJ Publishing Group and 2 from the Public Library of Science) as the unit of randomization, with peer reviewers allocated to the intervention or control group. Interventions: The first trial (CONSORT-PR) focused on manuscripts that presented randomized clinical trial (RCT) results and reported following the Consolidated Standards of Reporting Trials (CONSORT) guideline, and the second trial (SPIRIT-PR) focused on manuscripts that presented RCT protocols and reported following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. The CONSORT-PR trial included manuscripts that described RCT primary results (submitted July 2019 to July 2021). The SPIRIT-PR trial included manuscripts that contained RCT protocols (submitted June 2020 to May 2021). Manuscripts in both trials were randomized (1:1) to the intervention or control group; the control group received usual journal practice. In the intervention group of both trials, peer reviewers received an email from the journal that asked them to check whether the 10 most important and poorly reported CONSORT (for CONSORT-PR) or SPIRIT (for SPIRIT-PR) items were adequately reported in the manuscript. Peer reviewers and authors were not informed of the purpose of the study, and outcome assessors were blinded. Main Outcomes and Measures: The difference in the mean proportion of adequately reported 10 CONSORT or SPIRIT items between the intervention and control groups in published articles. Results: In the CONSORT-PR trial, 510 manuscripts were randomized. Of those, 243 were published (122 in the intervention group and 121 in the control group). A mean proportion of 69.3% (95% CI, 66.0%-72.7%) of the 10 CONSORT items were adequately reported in the intervention group and 66.6% (95% CI, 62.5%-70.7%) in the control group (mean difference, 2.7%; 95% CI, -2.6% to 8.0%). In the SPIRIT-PR trial, of the 244 randomized manuscripts, 178 were published (90 in the intervention group and 88 in the control group). A mean proportion of 46.1% (95% CI, 41.8%-50.4%) of the 10 SPIRIT items were adequately reported in the intervention group and 45.6% (95% CI, 41.7% to 49.4%) in the control group (mean difference, 0.5%; 95% CI, -5.2% to 6.3%). Conclusions and Relevance: These 2 randomized trials found that it was not useful to implement the tested intervention to increase reporting completeness in published articles. Other interventions should be assessed and considered in the future. Trial Registration: ClinicalTrials.gov Identifiers: NCT05820971 (CONSORT-PR) and NCT05820984 (SPIRIT-PR).

Antibody Response After Third Vaccination With mRNA-1273 or BNT162b2: Extension of a Randomized Controlled SARS-CoV-2 Noninferiority Vaccine Trial in Patients With Different Levels of Immunosuppression (COVERALL-2).

Extension of the COVERALL (COrona VaccinE tRiAL pLatform) randomized trial showed noninferiority in antibody response of the third dose of Moderna mRNA-1273 vaccine (95.3% [95% confidence interval {CI}, 91.9%-98.7%]) compared to Pfizer-BioNTech BNT162b2 vaccine (98.1% [95% CI, 95.9%-100.0%]) in individuals with different levels of immunosuppression (difference, -2.8% [95% CI, -6.8% to 1.3%]).

Prone Positioning as a Potential Risk Factor for Deep Vein Thrombosis in COVID-19 Patients: A Hypothesis Generating Observation.

AIMS OF THE STUDY: Virchow's triad with stasis, activated coagulation, and endothelial damage is common in SARS-CoV2. Therefore, we sought to retrospectively assess whether the duration of prone position may serve as a risk factor for deep vein thrombosis in critically ill patients. METHODS: In this single center retrospective study of a tertiary referral hospital, patients with acute respiratory distress syndrome (ARDS) due to COVID-19 pneumonia admitted to critical care underwent venous ultrasound screening for deep vein thrombosis (DVT). Data on DVT diagnosis, duration of prone positioning, demographic, respiratory, and laboratory parameters were retrospectively collected and compared between DVT and non-DVT patients. RESULTS: 21 patients with ARDS from COVID-19 pneumonia were analyzed. DVT was detected in 11 (52%) patients (76.2% male, median age 64 (58; 68.5) years, median body mass index 31 (27; 33.8) kg/m2). In patients diagnosed with DVT, median prone ventilation had been maintained twice as long as compared to patients without DVT (57 (19; 72) versus 28 (0; 56.3) h, p = 0.227) on ICU day 5 with a trend towards longer prone position time (71 (19; 104) versus 28 (0; 73) h, p = 0.06) on ICU day 7. CONCLUSIONS: Prone ventilation and constitutional factors may constitute an additional risk factor for DVT in COVID-19 patients. Since recent studies have shown that therapeutic anticoagulation does not impact the occurrence of thromboembolic events, it may be worthwhile to consider mechanical factors potentially affecting blood flow stasis in this high-risk population. However, due to the limited number of patients, our observations should only be considered as hypothesis-generating. Future studies, sufficiently powered and preferably prospective, will be needed to confirm our hypothesis.