Browsing by Subject "Clinical trials"
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Item Advances in the area of cardiorenal medicine: clinical research highlights from selected papers published in NDT(Oxford University Press, 2022) Georgianos, Panagiotis I.; Agarwal, Rajiv; Medicine, School of MedicineItem An ethics framework for consolidating and prioritizing COVID-19 clinical trials(Sage, 2021) Meyer, Michelle N.; Gelinas, Luke; Bierer, Barbara E.; Chandros Hull, Sara; Joffe, Steven; Magnus, David; Mohapatra, Seema; Sharp, Richard R.; Spector-Bagdady, Kayte; Sugarman, Jeremy; Wilfond, Benjamin S.; Fernandez Lynch, Holly; Robert H. McKinney School of LawGiven the dearth of established safe and effective interventions to respond to COVID-19, there is an urgent ethical imperative to conduct meaningful clinical research. The good news is that interventions to be tested are not in short supply. Unfortunately, the human and material resources needed to conduct these trials are finite. It is essential that trials be robust and meet enrollment targets and that lower-quality studies not be permitted to displace higher-quality studies, delaying answers to critical questions. Yet, with few exceptions, existing research review bodies and processes are not designed to ensure these conditions are satisfied. To meet this challenge, we offer guidance for research institutions about how to ethically consolidate and prioritize COVID-19 clinical trials, while recognizing that consolidation and prioritization should also take place upstream (among manufacturers and funders) and at a higher level (e.g., nationally). In our proposed three-stage process, trials must first meet threshold criteria. Those that do are evaluated in a second stage to determine whether the institution has sufficient capacity to support all proposed trials. If it does not, the third stage entails evaluating studies against two additional sets of comparative prioritization criteria: those specific to the study and those that aim to advance diversification of an institution’s research portfolio. To implement these criteria fairly, we propose that research institutions form COVID-19 research prioritization committees. We briefly discuss some important attributes of these committees, drawing on the authors’ experiences at our respective institutions. Although we focus on clinical trials of COVID-19 therapeutics, our guidance should prove useful for other kinds of COVID-19 research, as well as non-pandemic research, which can raise similar challenges due to the scarcity of research resources.Item Association of site of treatment with clinical outcomes following intravenous antimicrobial treatment of a pulmonary exacerbation(Elsevier, 2022) Sanders, D. B.; Khan, U.; Heltshe, S. L.; Skalland, M.; West, N. E.; VanDevanter, D. R.; Goss, C. H.; Flume, P. A.; Pediatrics, School of MedicineBackground: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital. Methods: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location. Results: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only. Conclusions: Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home.Item Avoid or Embrace? Practice Effects in Alzheimer’s Disease Prevention Trials(Frontiers Media, 2022-06-16) Aschenbrenner, Andrew J.; Hassenstab, Jason; Wang, Guoqiao; Li, Yan; Xiong, Chengjie; McDade, Eric; Clifford, David B.; Salloway, Stephen; Farlow, Martin; Yaari, Roy; Cheng, Eden Y. J.; Holdridge, Karen C.; Mummery, Catherine J.; Masters, Colin L.; Hsiung, Ging-Yuek; Surti, Ghulam; Day, Gregory S.; Weintraub, Sandra; Honig, Lawrence S.; Galvin, James E.; Ringman, John M.; Brooks, William S.; Fox, Nick C.; Snyder, Peter J.; Suzuki, Kazushi; Shimada, Hiroyuki; Gräber, Susanne; Bateman, Randall J.; Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU); Neurology, School of MedicineDemonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer's disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed "practice effects"). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies.Item Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: a randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF)(Oxford University Press, 2017-08-07) Pang, Peter S.; Butler, Javed; Collins, Sean P.; Cotter, Gad; Davison, Beth A.; Ezekowitz, Justin A.; Filippatos, Gerasimos; Levy, Phillip D.; Metra, Marco; Ponikowski, Piotr; Teerlink, John R.; Voors, Adriaan A.; Bharucha, David; Goin, Kathleen; Soergel, David G.; Felker, G. Michael; Emergency Medicine, School of MedicineAims: Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies. Methods and results: BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25 mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5 mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027. Conclusion: In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.Item Black vs African American: Why are communication and clinical researchers not paying attention to what descendants of the African Diaspora want to be called, and why is that a problem?(Indiana Medical Student Program for Research and Scholarship (IMPRS), 2020) Owusu, Raiven; Ridley-Merriweather, Katherine; Hoffmann-Longtin, KristaProblem: Descendants of African Diaspora (DADs) in the U.S. experience greater health disparities than other racial or ethnic minority groups. Many factors play a role, including their lack of participation in clinical trials. By refusing to participate, DADs cannot benefit from medical research. The barriers to recruiting DADs is well discussed in literature, but we found no research suggesting that mislabeling participants could be creating another barrier. This essay delves into the history of labeling DADs to illuminate the existing tensions between the use of “Black” and “African American” and the impact they may have on recruitment. Processes: Communication Theory of Identity and Critical Race Theory shaped our analysis of this mislabeling issue and its possible implications. Both theories offer insight into how an individual shapes and is simultaneously shaped by communication. We reviewed, summarized, and coded literature in the academic and popular press to answer the research question: How can mislabeling DADs possibly deter them from participating in clinical trials? Findings: Within DADs, there are several subgroups with different cultural heritages that contribute to how people identify. Therefore, no “catch-all” label can be used to accurately describe DADs. Academic and popular press literature indicate that preferences exist amongst this group for how they wish to be identified. Researchers should realize that “Black” and “African American” are not perceived the same by many DADs and should refrain from using them interchangeably. Conclusion: Given the current Black Lives Matter movement, it is imperative that health communication scholars and health researchers consider how language shapes participation and research outcomes for DADs. More research is needed to determine if the use of “Black” and “African American” interchangeably creates another barrier to the recruitment of DADs. However, if possible, researchers should take time to note the preferences of their target populations prior to recruitment.Item Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force(Springer, 2022) Angioni, D.; Delrieu, J.; Hansson, O.; Fillit, H.; Aisen, P.; Cummings, J.; Sim, J. R.; Braunstein, J. B.; Sabbagh, M.; Bittner, T.; Pontecorvo, M.; Bozeat, S.; Dage, J. L.; Largent, E.; Mattke, S.; Correa, O.; Gutierrez Robledo, L. M.; Baldivieso, V.; Willis, D. R.; Atri, A.; Bateman, R. J.; Ousset, P-J.; Vellas, B.; Weiner, M.; Neurology, School of MedicineTimely and accurate diagnosis of Alzheimer’s disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.Item Burosumab for the Treatment of Tumor‐Induced Osteomalacia(Wiley, 2021-04) Jan de Beur, Suzanne M.; Miller, Paul D.; Weber, Thomas J.; Peacock, Munro; Insogna, Karl; Kumar, Rajiv; Rauch, Frank; Luca, Diana; Cimms, Tricia; Scott Roberts, Mary; Martin, Javier San; Carpenter, Thomas O.; Medicine, School of MedicineTumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia.Item Canagliflozin, Blood Pressure Variability, and Risk of Cardiovascular, Kidney, and Mortality Outcomes: Pooled Individual Participant Data From the CANVAS and CREDENCE Trials(American Heart Association, 2023) Fletcher, Robert A.; Arnott, Clare; Rockenschaub, Patrick; Schutte, Aletta E.; Carpenter, Lewis; Vaduganathan, Muthiah; Agarwal, Rajiv; Bakris, George; Chang, Tara I.; Heerspink, Hiddo J. L.; Jardine, Meg J.; Mahaffey, Kenneth W.; Neal, Bruce; Pollock, Carol; Jun, Min; Rodgers, Anthony; Perkovic, Vlado; Neuen, Brendon L.; Medicine, School of MedicineBackground: Sodium glucose cotransporter‐2 inhibitors reduce systolic blood pressure (SBP), but whether they affect SBP variability is unknown. There also remains uncertainty regarding the prognostic value of SBP variability for different clinical outcomes. Methods and Results: Using individual participant data from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, we assessed the effect of canagliflozin on SBP variability in people with type 2 diabetes across 4 study visits over 1.5 years as measured by standard deviation, coefficient of variation, and variability independent of the mean. We used multivariable Cox regression models to estimate associations of SBP variability with cardiovascular, kidney, and mortality outcomes. In 11 551 trial participants, canagliflozin modestly lowered the standard deviation of SBP variability (−0.25 mm Hg [95% CI, –0.44 to −0.06]), but there was no effect on coefficient of variation (0.02% [95% CI, –0.12 to 0.16]) or variability independent of the mean (0.08 U [95% CI, –0.11 to 0.26]) when adjusting for correlation with mean SBP. Each 1 standard deviation increase in standard deviation of SBP variability was independently associated with higher risk of hospitalization for heart failure (hazard ratio [HR], 1.19 [95% CI, 1.02–1.38]) and all‐cause mortality (HR, 1.12 [95% CI, 1.01–1.25]), with consistent results observed for coefficient of variation and variability independent of the mean. Increases in SBP variability were not associated with kidney outcomes. Conclusions: In people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease, higher visit‐to‐visit SBP variability is independently associated with risks of hospitalization for heart failure and all‐cause mortality. Canagliflozin has little to no effect on SBP variability, independent of its established SBP‐lowering effect.Item Changes in symptom scores as a potential clinical endpoint for studies of cystic fibrosis pulmonary exacerbation treatment(Elsevier, 2021) VanDevanter, D.R.; Heltshe, S.L.; Sanders, D.B.; West, N.E.; Skalland, M.; Flume, P.A.; Goss, C.H.; Pediatrics, School of MedicineIntroduction: Symptom improvement was assessed as changes in the Chronic Respiratory Infection Symptom Score (CRISS) during intravenous antimicrobial exacerbation treatments among subjects from study NCT02109822. Methods: Median daily CRISS reduction (i.e., improvement) and covariates associated with CRISS reduction by Day 14 were assessed by logistic regression. Results: Among 173 subjects, median baseline CRISS was 49 [IQR 41, 56]; 93.6% had a CRISS reduction of ≥11 (minimal clinically important difference); median time to -11 reduction was 2 days [95% CI 2, 3]. The greatest median CRISS difference from baseline, on Day 17, was -26 [-29, -23]. Odds of -26 CRISS change by Day 14 were greater in subjects with higher baseline CRISS (P=.006) and younger ages (P=.041). Conclusions: CRISS response has good dynamic range and may be a useful efficacy endpoint for PEx interventional trials. The optimal use of CRISS change as an endpoint remains uncharacterized.