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Implementing a pragmatic randomised controlled trial in a humanitarian setting: lessons learned from the TISA trial.
N'Diaye, DS, Frison, S, Ba, M, Lê, ML, Cabo, AE, Siroma, F, Devort, A, MacLeod, C, Lapègue, J, Seye, M, et al
Trials. 2024;(1):620
Abstract
INTRODUCTION High-quality evidence is crucial for guiding effective humanitarian responses, yet conducting rigorous research, particularly randomised controlled trials, in humanitarian crises remains challenging. The TISA ("traitement intégré de la sous-nutrition aiguë") trial aimed to evaluate the impact of a Water, Sanitation and Hygiene (WASH) intervention on the standard national treatment of uncomplicated Severe Acute Malnutrition (SAM) in children aged 6-59 months. Implemented in two northern Senegalese regions from December 22, 2021, to February 20, 2023, the trial faced numerous challenges, which this paper explores along with the lessons learned. METHODS The study utilised trial documentation, including field reports, meeting minutes, training plans, operational monitoring data and funding proposals, to retrace the trial timeline, identify challenges and outline implemented solutions. Contributions from all TISA key staff-current and former, field-based and headquarters-were essential for collecting and interpreting information. Challenges were categorised as internal (within the TISA consortium) or external (broader contextual issues). RESULTS The TISA trial, executed by a consortium of academic, operational, and community stakeholders, enrolled over 2000 children with uncomplicated SAM across 86 treatment posts in a 28,000 km2 area. The control group received standard outpatient SAM care, while the intervention group also received a WASH kit and hygiene promotion. Initially planned to start in April 2019 for 12 months, the trial faced a 30-month delay and was extended to 27 months due to challenges like the COVID-19 pandemic, national strikes, health system integration issues and weather-related disruptions. Internal challenges included logistics, staffing, data management, funding and aligning diverse stakeholder priorities. DISCUSSION AND CONCLUSION Despite these obstacles, the trial concluded successfully, underscoring the importance of tailored monitoring, open communication, transparency and community involvement. Producing high-quality evidence in humanitarian contexts demands extensive preparation and strong coordination among local and international researchers, practitioners, communities, decision-makers and funders from the study's inception. TRIAL REGISTRATION Clinicaltrials.gov NCT04667767 .
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Electronic Health Record Population Health Management for Chronic Kidney Disease Care: A Cluster Randomized Clinical Trial.
Jhamb, M, Weltman, MR, Devaraj, SM, Lavenburg, LU, Han, Z, Alghwiri, AA, Fischer, GS, Rollman, BL, Nolin, TD, Yabes, JG
JAMA internal medicine. 2024;(7):737-747
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IMPORTANCE Large gaps in clinical care in patients with chronic kidney disease (CKD) lead to poor outcomes. OBJECTIVE To compare the effectiveness of an electronic health record-based population health management intervention vs usual care for reducing CKD progression and improving evidence-based care in high-risk CKD. DESIGN, SETTING, AND PARTICIPANTS The Kidney Coordinated Health Management Partnership (Kidney CHAMP) was a pragmatic cluster randomized clinical trial conducted between May 2019 and July 2022 in 101 primary care practices in Western Pennsylvania. It included patients aged 18 to 85 years with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2 with high risk of CKD progression and no outpatient nephrology encounter within the previous 12 months. INTERVENTIONS Multifaceted intervention for CKD comanagement with primary care clinicians included a nephrology electronic consultation, pharmacist-led medication management, and CKD education for patients. The usual care group received CKD care from primary care clinicians as usual. MAIN OUTCOMES AND MEASURES The primary outcome was time to 40% or greater reduction in eGFR or end-stage kidney disease. RESULTS Among 1596 patients (754 intervention [47.2%]; 842 control [52.8%]) with a mean (SD) age of 74 (9) years, 928 (58%) were female, 127 (8%) were Black, 9 (0.6%) were Hispanic, and the mean (SD) estimated glomerular filtration rate was 36.8 (7.9) mL/min/1.73m2. Over a median follow-up of 17.0 months, there was no significant difference in rate of primary outcome between the 2 arms (adjusted hazard ratio, 0.96; 95% CI, 0.67-1.38; P = .82). Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker exposure was more frequent in intervention arm compared with the control group (rate ratio, 1.21; 95% CI, 1.02-1.43). There was no difference in the secondary outcomes of hypertension control and exposure to unsafe medications or adverse events between the arms. Several COVID-19-related issues contributed to null findings in the study. CONCLUSION AND RELEVANCE In this study, among patients with moderate-risk to high-risk CKD, a multifaceted electronic health record-based population health management intervention resulted in more exposure days to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers but did not reduce risk of CKD progression or hypertension control vs usual care. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03832595.
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Effect of sodium-glucose co-transporter-2 inhibitors on survival free of organ support in patients hospitalised for COVID-19 (ACTIV-4a): a pragmatic, multicentre, open-label, randomised, controlled, platform trial.
Kosiborod, MN, Windsor, SL, Vardeny, O, Berger, JS, Reynolds, HR, Boumakis, S, Althouse, AD, Solomon, SD, Bhatt, AS, Peikert, A, et al
The lancet. Diabetes & endocrinology. 2024;(10):725-734
Abstract
BACKGROUND Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19. METHODS This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774. FINDINGS The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48-1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58-1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis. INTERPRETATION SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19. FUNDING National Institutes of Health.
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Combination of aspirin and rosuvastatin for reduction of venous thromboembolism in severely injured patients: a double-blind, placebo-controlled, pragmatic randomized phase II clinical trial (The STAT Trial).
Barrett, CD, Moore, HB, Moore, EE, Chandler, J, Sauaia, A
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 2023;(8):499-507
Abstract
INTRODUCTION Venous thromboembolism (VTE) remains a significant source of postinjury morbidity and mortality. Beta-hydroxy beta-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (rosuvastatin) significantly reduced pathologic clotting events in healthy populations in a prior trial. Furthermore, acetylsalicylic acid (ASA) has been shown to be noninferior to prophylactic heparinoids for VTE prevention following orthopedic surgery. We hypothesized that a combination of rosuvastatin/ASA, in addition to standard VTE chemoprophylaxis, would reduce VTE in critically ill trauma patients. METHODS This was a double-blind, placebo-controlled, randomized trial, evaluating VTE rates in two groups: ASA + statin (Experimental) and identical placebos (Control). Injured adults, 18-65 years old, admitted to the surgical intensive care unit without contraindications for VTE prophylaxis were eligible. Upon initiation of routine VTE chemoprophylaxis (i.e. heparin/heparin-derivatives), they were randomized to the Experimental or Control group. VTE was the primary outcome. RESULTS Of 112 potentially eligible patients, 33% (n = 37, median new injury severity scale = 27) were successfully randomized, of whom 11% had VTEs. The Experimental group had no VTEs, while the Control group had 6 VTEs (4 PEs and 2 DVTs) in 4 (22%) patients (P = 0.046). The Experimental treatment was not associated with any serious adverse events. Due to the COVID-19 pandemic, the study was interrupted at the second interim analysis at <10% of the planned enrollment, with significance declared at P < 0.012 at that stage. DISCUSSION The combination of ASA and rosuvastatin with standard VTE prophylaxis showed a favorable trend toward reducing VTEs with no serious adverse events. An appropriately powered phase III multicenter trial is needed to further investigate this therapeutic approach. LEVEL OF EVIDENCE Level II, Therapeutic.
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Healthcare Costs and Healthcare Utilization Outcomes of Vitamin D3 Supplementation at 5000 IU Daily during a 10.9 Month Observation Period within a Pragmatic Randomized Clinical Trial.
LaRiccia, PJ, Cafaro, T, John, D, van Helmond, N, Mitrev, LV, Bandomer, B, Brobyn, TL, Hunter, K, Roy, S, Ng, KQ, et al
Nutrients. 2023;(20)
Abstract
Vitamin D insufficiency has been linked to multiple conditions including bone disease, respiratory disease, cardiovascular disease, diabetes, and cancer. Observational studies indicate lower healthcare costs and healthcare utilization with sufficient vitamin D levels. The secondary aims of our previously published pragmatic clinical trial of vitamin D3 supplementation were comparisons of healthcare costs and healthcare utilization. Comparisons were made between the vitamin D3 at 5000 IU supplementation group and a non-supplemented control group. Costs of care between the groups differed but were not statistically significant. Vitamin D3 supplementation reduced healthcare utilization in four major categories: hospitalizations for any reason (rate difference: -0.19 per 1000 person-days, 95%-CI: -0.21 to -0.17 per 1000 person-days, p < 0.0001); ICU admissions for any reason (rate difference: -0.06 per 1000 person-days, 95%-CI: -0.08 to -0.04 per 1000 person-days, p < 0.0001); emergency room visits for any reason (rate difference: -0.26 per 1000 person-days, 95%-CI: -0.46 to -0.05 per 1000 person-days, p = 0.0131; and hospitalizations due to COVID-19 (rate difference: -8.47 × 10-3 per 1000 person-days, 95%-CI: -0.02 to -1.05 × 10-3 per 1000 person-days, p = 0.0253). Appropriately powered studies of longer duration are recommended for replication of these utilization findings and analysis of cost differences.
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The impact of COVID-19 on a large pragmatic clinical trial embedded in primary care.
Leatherman, SM, Hau, C, Klint, A, Glassman, PA, Taylor, AA, Ferguson, RE, Cushman, WC, Ishani, A
Contemporary clinical trials. 2023;:107179
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INTRODUCTION The COVID-19 pandemic had significant impact on clinical care and clinical trial operations, but the impact on decentralized pragmatic trials is unclear. The Diuretic Comparison Project (DCP) is a Point-of Care (POC) pragmatic trial testing whether chlorthalidone is superior to hydrochlorothiazide in preventing major cardiovascular (CV) events and non-cancer death. DCP utilized telephone consent, data collection from the electronic health record and Medicare, forwent study visits, and limited provider commitment beyond usual care. We assessed the impact of COVID-19 on recruitment, follow-up, data collection, and outcome ascertainment in DCP. METHODS We compared data from two 8-month periods: Pre-Pandemic (July 2019-February 2020) and Mid-Pandemic (July 2020-February 2021). Consent and randomization rates, diuretic adherence, blood pressure (BP) and electrolyte follow-up rates, records of CV events, hospitalization, and death rates were compared. RESULTS Providers participated at a lower rate mid-pandemic (65%) than pre-pandemic (71%), but more patients were contacted (7622 vs. 5363) and consented (3718 vs. 3048) mid-pandemic than pre-pandemic. Patients refilled medications and remained on their randomized diuretic equally (90%) in both periods. Overall, rates of BP, electrolyte measurements, and hospitalizations decreased mid-pandemic while deaths increased. CONCLUSIONS While recruitment, enrollment, and adherence did not suffer during the pandemic, documented blood pressure checks and laboratory evaluations decreased, likely due to fewer in-person visits. VA hospitalizations decreased, despite a considerable number of COVID-related hospitalizations. This suggests changes in clinical care during the pandemic, but the limited impact on DCP's operations during a global pandemic is an important strength of POC trials. CLINICAL TRIAL REGISTRATION NCT02185417.
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Patient Engagement Using Telemedicine in Primary Care during COVID-19 Pandemic: A Trial Study.
Vicente, MA, Fernández, C, Guilabert, M, Carrillo, I, Martín-Delgado, J, Mira, JJ, Prometeo Working Group,
International journal of environmental research and public health. 2022;(22)
Abstract
The correct treatment of most non-transmissible diseases requires, in addition to adequate medication, adherence to physical activity and diet guidelines, as well as health data monitoring and patient motivation. The restrictions caused by the COVID-19 pandemic made telemedicine tools and mobile apps the best choice for monitoring patient compliance. The objective of this study was to analyze the benefits of an m-Health solution designed specifically for chronic patients during the COVID-19 pandemic. A pragmatic clinical trial with pre-post measurements of a single group was carried out with 70 patients (aged 40+) with one or more chronic conditions. Patients were provided with an ad hoc mobile app and health data measuring devices according to their diseases. The health status of the patients was monitored remotely by health professionals who could also modify the patient's objectives according to their evolution. The results obtained show an average fulfillment of objectives of 77%. Higher fulfillment values: medication adherence (98%) and oxygen saturation (82%); lower fulfillment values: weight (48%), glucose (57%), and distance walked (57%). Globally, the ad hoc app was rated 8.72 points out of 10 (standard deviation 1.10). Concerning the pre-post analysis, there were significant improvements vs. prior apps used by the participants in the following items: improved physical activation and better control of blood pressure, diet, weight, glucose, and oxygen saturation. In conclusion, the telemedicine tool developed was useful in increasing patient engagement and adherence to treatment.
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Recruitment and Baseline Characteristics of Participants in the AgeWell.de Study-A Pragmatic Cluster-Randomized Controlled Lifestyle Trial against Cognitive Decline.
Röhr, S, Zülke, A, Luppa, M, Brettschneider, C, Weißenborn, M, Kühne, F, Zöllinger, I, Samos, FZ, Bauer, A, Döhring, J, et al
International journal of environmental research and public health. 2021;(2)
Abstract
Targeting dementia prevention, first trials addressing multiple modifiable risk factors showed promising results in at-risk populations. In Germany, AgeWell.de is the first large-scale initiative investigating the effectiveness of a multi-component lifestyle intervention against cognitive decline. We aimed to investigate the recruitment process and baseline characteristics of the AgeWell.de participants to gain an understanding of the at-risk population and who engages in the intervention. General practitioners across five study sites recruited participants (aged 60-77 years, Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE dementia risk score ≥ 9). Structured face-to-face interviews were conducted with eligible participants, including neuropsychological assessments. We analyzed group differences between (1) eligible vs. non-eligible participants, (2) participants vs. non-participants, and (3) between intervention groups. Of 1176 eligible participants, 146 (12.5%) dropped out before baseline; the study population was thus 1030 individuals. Non-participants did not differ from participants in key sociodemographic factors and dementia risk. Study participants were M = 69.0 (SD = 4.9) years old, and 52.1% were women. The average Montreal Cognitive Assessment/MoCA score was 24.5 (SD = 3.1), indicating a rather mildly cognitively impaired study population; however, 39.4% scored ≥ 26, thus being cognitively unimpaired. The bandwidth of cognitive states bears the interesting potential for differential trial outcome analyses. However, trial conduction is impacted by the COVID-19 pandemic, requiring adjustments to the study protocol with yet unclear methodological consequences.
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A pragmatic outreach pilot to understand and overcome barriers to COVID-19 vaccination in abdominal organ transplant.
Serper, M, Liu, CH, Blumberg, EA, Burdzy, AE, Veasey, S, Halpern, S, Lander, E, Sigafus, MR, Bloom, RD, Dunn, TB, et al
Transplant infectious disease : an official journal of the Transplantation Society. 2021;(5):e13722
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BACKGROUND Solid organ transplant recipients (SOTRs) are at increased risk for adverse outcomes with coronavirus disease 19 (COVID-19). Early data show a lower severe acute respiratory syndrome virus 2 (SARS-CoV-2) spike antibody immune response among SOTRs leading to patient concerns about vaccine efficacy. Public health messaging has largely left out immunocompromized individuals leading to a higher risk of vaccine misinformation. The American Society of Transplantation recommends COVID-19 vaccination for all SOTRs; however, patient concerns and beliefs about vaccination are largely unknown. METHODS We conducted a transplant-center-based, pragmatic pilot trial to encourage COVID-19 vaccination among 103 unvaccinated SOTRs. We assessed vaccine concerns, barriers to vaccination, answered questions about efficacy, side effects, and clinical recommendations. RESULTS A total of 24% (n = 25) of SOTRs reported that they will schedule COVID-19 vaccination after the study call, 46% reported that they will consider vaccination in the future, and 30% said they will not consider vaccination. Older age and White race were associated with lower willingness to schedule the vaccine, whereas Black race and longer time from transplant were associated with higher willingness. Common vaccine concerns included lack of long-term data, inconsistent messaging from providers, scheduling inconvenience, and insufficient resources. Follow-up approximately 1 month after the initial outreach found 52% (n = 13) of liver transplant recipients, and 10% (n = 3) of kidney transplant recipients subsequently received COVID-19 vaccines for a vaccination rate of 29% among respondents. CONCLUSION Transplant center-based vaccine outreach efforts can decrease misinformation and increase vaccination uptake; however, vaccine-related mistrust remains high.
