Browsing by Subject "Randomized clinical trial"
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Item Adjudicating Mild Cognitive Impairment Due to Alzheimer's Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial(Springer, 2022) Schneider, Lon S.; Bennett, David A.; Farlow, Martin R.; Peskind, Elaine R.; Raskind, Murray A.; Sano, Mary; Stern, Yaakov; Haneline, Stephen; Welsh-Bohmer, Kathleen A.; O’Neil, Janet; Walter, Ryan; Maresca, Sylvia; Culp, Meredith; Alexander, Robert; Saunders, Ann M.; Burns, Daniel K.; Chiang, Carl; Neurology, School of MedicineBackground: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. Methods: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. Results: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. Conclusions: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.Item Challenges and Opportunities in Developing an Oncology Clinical Trial Network in the United States Veterans Affairs Health Care System: The VA STARPORT Experience(MDPI, 2024-08-21) Solanki, Abhishek A.; Zheng, Kevin; Skipworth, Alicia N.; Robin, Lisa M.; Leparski, Ryan F.; Henry, Elizabeth; Rettig, Matthew; Salama, Joseph K.; Ritter, Timothy; Jones, Jeffrey; Quek, Marcus; Chang, Michael; Block, Alec M.; Welsh, James S.; Kumar, Aryavarta; Chao, Hann-Hsiang; Chen, Albert C.; Shapiro, Ronald; Bitting, Rhonda L.; Kwon, Robert; Stross, William; Puckett, Lindsay; Wong, Yu-Ning; Nickols, Nicholas G.; Carlson, Kimberly; VA STARPORT Investigators Group; Radiation Oncology, School of MedicineThe United States Veterans Affairs (VA) Health Care System has a strong history of conducting impactful oncology randomized clinical trials (RCTs). We developed a phase II/III RCT to test the use of metastasis-directed therapy in Veterans with oligometastatic prostate cancer (OMPC)-the first VA RCT in OMPC that leverages novel imaging and advanced radiotherapy techniques. To accomplish this, we developed a clinical trial network to conduct the study. In this manuscript, we describe several challenges we encountered in study development/conduct and our strategies to address them, with the goal of helping investigators establish robust study networks to conduct clinical trials. In the study start-up, we encountered challenges in timely site activation, and leveraged project management to maximize efficiency. Additionally, there were several changes in the clinical paradigms in imaging and treatment that led to protocol amendments to ensure maximum equipoise, recruitment, and impact of the study. Specifically, we amended the trial to add de novo OMPC patients (from initially only recurrent OMPC) and expanded the study to allow up to 10 metastases (from initially five). Finally, in order to maintain local study team engagement, we developed initiatives to maximize collaboration and add value to the overall clinical program through study participation.Item Correction: Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age(Springer Nature, 2024-04-25) Shorey‑Kendrick, Lyndsey E.; McEvoy, Cindy T.; Milner, Kristin; Harris, Julia; Brownsberger, Julie; Tepper, Robert S.; Park, Byung; Gao, Lina; Vu, Annette; Morris, Cynthia D.; Spindel, Eliot R.; Pediatrics, School of MedicineCorrection to: Clinical Epigenetics (2024) 16:35 10.1186/s13148-024-01644-8 Following publication of the original article [1], the authors noticed that the NCBI Gene Expression Omnibus (GEO) accession series has been incorrectly listed as GSE253158 within the “Availability of data and materials section”. The correct GEO series for this work is GSE252169.Item Design and baseline characteristics of the Cognitive and Aerobic Resilience for the Brain (CARB) study(Elsevier, 2023-08) Tam, Joyce W.; Khurshid, Kiran; Sprague, Briana; Clark, Daniel O.; Xu, Huiping; Moser, Lyndsi R.; Miller, Douglas K.; Considine, Robert; Callahan, Christopher M.; Garringer, Holly J.; Rexroth, Daniel; Unverzagt, Frederick W.; Pathology and Laboratory Medicine, School of MedicineBackground Treatments that delay progression of cognitive impairment in older adults are of great public health significance. This manuscript outlines the protocol, recruitment, baseline characteristics, and retention for a randomized controlled trial of cognitive and aerobic physical training to improve cognition in individuals with subjective cognitive dysfunction, the “Cognitive and Aerobic Resilience for the Brain” (CARB) study. Methods Community-dwelling, older adults with self-reported memory loss were randomly assigned to receive either computer-based cognitive training, aerobic physical training, combined cognitive and physical training, or education control. Treatment was delivered 2- to 3-times per week in 45- to 90-min sessions for 12 weeks by trained facilitators videoconferencing into subject's home. Outcome assessments of were taken at the baseline, immediately following training, and 3-months after training. Results 191 subjects were randomized into the trial (mean age, 75.5 years; 68% female; 20% non-white; mean education, 15.1 years; 30% with 1+ APOE e4 allele). The sample was generally obese, hypertensive, and many were diabetic, while cognition, self-reported mood, and activities of daily living were in the normal range. There was excellent retention throughout the trial. Interventions were completed at high rates, participants found the treatments acceptable and enjoyable, and outcome assessments were completed at high rates. Conclusions This study was designed to determine the feasibility of recruiting, intervening, and documenting response to treatment in a population at risk for progressive cognitive decline. Older adults with self-reported memory loss were enrolled in high numbers and were well engaged with the intervention and outcome assessments.Item Evaluation of electronic recruitment efforts of primary care providers as research subjects during the COVID-19 pandemic(BMC, 2022-04-28) Mazurenko, Olena; Sanner, Lindsey; Apathy, Nate C.; Mamlin, Burke W.; Menachemi, Nir; Adams, Meredith C.B.; Hurley, Robert W.; Fortin Erazo, Saura; Harle, Christopher A.; Medicine, School of MedicineBackground: Recruiting healthcare providers as research subjects often rely on in-person recruitment strategies. Little is known about recruiting provider participants via electronic recruitment methods. In this study, conducted during the COVID-19 pandemic, we describe and evaluate a primarily electronic approach to recruiting primary care providers (PCPs) as subjects in a pragmatic randomized controlled trial (RCT) of a decision support intervention. Methods: We adapted an existing framework for healthcare provider research recruitment, employing an electronic consent form and a mix of brief synchronous video presentations, email, and phone calls to recruit PCPs into the RCT. To evaluate the success of each electronic strategy, we estimated the number of consented PCPs associated with each strategy, the number of days to recruit each PCP and recruitment costs. Results: We recruited 45 of 63 eligible PCPs practicing at ten primary care clinic locations over 55 days. On average, it took 17 business days to recruit a PCP (range 0-48) and required three attempts (range 1-7). Email communication from the clinic leaders led to the most successful recruitments, followed by brief synchronous video presentations at regularly scheduled clinic meetings. We spent approximately $89 per recruited PCP. We faced challenges of low email responsiveness and limited opportunities to forge relationships. Conclusion: PCPs can be efficiently recruited at low costs as research subjects using primarily electronic communications, even during a time of high workload and stress. Electronic peer leader outreach and synchronous video presentations may be particularly useful recruitment strategies.Item Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes(BMC, 2021-09-19) Shorey‑Kendrick, Lyndsey E.; McEvoy, Cindy T.; O’Sullivan, Shannon M.; Milner, Kristin; Vuylsteke, Brittany; Tepper, Robert S.; Haas, David M.; Park, Byung; Gao, Lina; Vu, Annette; Morris, Cynthia D.; Spindel, Eliot R.; Pediatrics, School of MedicineBackground: Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes. Results: DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate "restored CpGs" for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers. Conclusions: Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP.Item Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age(Springer Nature, 2024-02-27) Shorey‑Kendrick, Lyndsey E.; McEvoy, Cindy T.; Milner, Kristin; Harris, Julia; Brownsberger, Julie; Tepper, Robert S.; Park, Byung; Gao, Lina; Vu, Annette; Morris, Cynthia D.; Spindel, Eliot R.; Pediatrics, School of MedicineBackground: We previously reported in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" randomized clinical trial (RCT) that vitamin C (500 mg/day) supplementation to pregnant smokers is associated with improved respiratory outcomes that persist through 5 years of age. The objective of this study was to assess whether buccal cell DNA methylation (DNAm), as a surrogate for airway epithelium, is associated with vitamin C supplementation, improved lung function, and decreased occurrence of wheeze. Methods: We conducted epigenome-wide association studies (EWAS) using Infinium MethylationEPIC arrays and buccal DNAm from 158 subjects (80 placebo; 78 vitamin C) with pulmonary function testing (PFT) performed at the 5-year visit. EWAS were performed on (1) vitamin C treatment, (2) forced expiratory flow between 25 and 75% of expired volume (FEF25-75), and (3) offspring wheeze. Models were adjusted for sex, race, study site, gestational age at randomization (≤ OR > 18 weeks), proportion of epithelial cells, and latent covariates in addition to child length at PFT in EWAS for FEF25-75. We considered FDR p < 0.05 as genome-wide significant and nominal p < 0.001 as candidates for downstream analyses. Buccal DNAm measured in a subset of subjects at birth and near 1 year of age was used to determine whether DNAm signatures originated in utero, or emerged with age. Results: Vitamin C treatment was associated with 457 FDR significant (q < 0.05) differentially methylated CpGs (DMCs; 236 hypermethylated; 221 hypomethylated) and 53 differentially methylated regions (DMRs; 26 hyper; 27 hypo) at 5 years of age. FEF25-75 was associated with one FDR significant DMC (cg05814800), 1,468 candidate DMCs (p < 0.001), and 44 DMRs. Current wheeze was associated with 0 FDR-DMCs, 782 candidate DMCs, and 19 DMRs (p < 0.001). In 365/457 vitamin C FDR significant DMCs at 5 years of age, there was no significant interaction between time and treatment. Conclusions: Vitamin C supplementation to pregnant smokers is associated with buccal DNA methylation in offspring at 5 years of age, and most methylation signatures appear to be persistent from the prenatal period. Buccal methylation at 5 years was also associated with current lung function and occurrence of wheeze, and these functionally associated loci are enriched for vitamin C associated loci.Item A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS(Taylor & Francis, 2021-05) Shefner, Jeremy M.; Andrews, Jinsy A.; Genge, Angela; Jackson, Carlayne; Lechtzin, Noah; Miller, Timothy M.; Cockroft, Bettina M.; Meng, Lisa; Wei, Jenny; Wolff, Andrew A.; Malik, Fady I.; Bodkin, Cynthia; Brooks, Benjamin R.; Caress, James; Dionne, Annie; Fee, Dominic; Goutman, Stephen A.; Goyal, Namita A.; Hardiman, Orla; Hayat, Ghazala; Heiman-Patterson, Terry; Heitzman, Daragh; Henderson, Robert D.; Johnston, Wendy; Karam, Chafic; Kiernan, Matthew C.; Kolb, Stephen J.; Korngut, Lawrence; Ladha, Shafeeq; Matte, Genevieve; Mora, Jesus S.; Needham, Merrilee; Oskarsson, Bjorn; Pattee, Gary L.; Pioro, Erik P.; Pulley, Michael; Quan, Dianna; Rezania, Kourosh; Schellenberg, Kerri L.; Schultz, David; Shoesmith, Christen; Simmons, Zachary; Statland, Jeffrey; Sultan, Shumaila; Swenson, Andrea; Van Den Berg, Leonard H.; Vu, Tuan; Vucic, Steve; Weiss, Michael; Whyte-Rayson, Ashley; Wymer, James; Zinman, Lorne; Rudnicki, Stacy A.; Neurology, School of MedicineTo evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).Item A randomized clinical trial of a group cognitive-behavioral therapy to reduce alcohol use among human immunodeficiency virus-infected outpatients in western Kenya(Wiley, 2021) Papas, Rebecca K.; Gakinya, Benson N.; Mwaniki, Michael M.; Lee, Hana; Keter, Alfred K.; Martino, Steve; Klein, Debra A.; Liu, Tao; Loxley, Michelle P.; Sidle, John E.; Schlaudt, Kathryn; Nafula, Tobista; Omodi, Victor M.; Baliddawa, Joyce B.; Kinyanjui, Daniel W.; Maisto, Stephen A.; Medicine, School of MedicineBackground and aims: Culturally relevant and feasible interventions are needed to address limited professional resources in sub-Saharan Africa for behaviorally treating the dual epidemics of HIV and alcohol use disorder. This study tested the efficacy of a cognitive-behavioral therapy (CBT) intervention to reduce alcohol use among HIV-infected outpatients in Eldoret, Kenya. Design: Randomized clinical trial. Setting: A large HIV outpatient clinic in Eldoret, Kenya, affiliated with the Academic Model Providing Access to Healthcare collaboration. Participants: A total of 614 HIV-infected outpatients [312 CBT; 302 healthy life-styles (HL); 48.5% male; mean age: 38.9 years; mean education 7.7 years] who reported a minimum of hazardous or binge drinking. Intervention and comparator: A culturally adapted six-session gender-stratified group CBT intervention compared with HL education, each delivered by paraprofessionals over six weekly 90-minute sessions with a 9-month follow-up. Measurements: Primary outcome measures were percentage of drinking days (PDD) and mean drinks per drinking day (DDD) computed from retrospective daily number of drinks data obtained by use of the time-line follow-back from baseline to 9 months post-intervention. Exploratory analyses examined unprotected sex and number of partners. Findings: Median attendance was six sessions across condition. Retention at 9 months post-intervention was high and similar by condition: CBT 86% and HL 83%. PDD and DDD marginal means were significantly lower in CBT than HL at all three study phases. Maintenance period, PDD - CBT = 3.64 (0.696), HL = 5.72 (0.71), mean difference 2.08, 95% confidence interval (CI) = 0.13 - 4.04; DDD - CBT = 0.66 (0.96), HL = 0.98 (0.098), mean difference = 0.31, 95% CI = 0.05 - 0.58. Risky sex decreased over time in both conditions, with a temporary effect for CBT at the 1-month follow-up. Conclusions: A cognitive-behavioral therapy intervention was more efficacious than healthy lifestyles education in reducing alcohol use among HIV-infected Kenyan outpatient drinkers.Item The Pain Outcomes Comparing Yoga vs. Structured Exercise (POYSE) Trial in Veterans With Fibromyalgia: Study Design and Methods(Frontiers Media, 2022-07-07) Allsop, Vivianne L.; Schmid, Arlene A.; Miller, Kristine K.; Slaven, James E.; Daggy, Joanne K.; Froman, Amanda; Kline, Matthew; Sargent, Christy; French, Dustin D.; Ang, Dennis; Van Puymbroeck, Marieke; Schalk, Nancy L.; Bair, Matthew J.; Medicine, School of MedicineBackground: Fibromyalgia is a common pain condition that often leads to significant disability. Unfortunately, the effectiveness of most medications for fibromyalgia is limited, and there is a need for alternative, non-pharmacological therapies. Yoga and aerobic exercise are both evidence-based non-pharmacological treatments for fibromyalgia. However, no prior studies have directly compared the effectiveness of yoga vs. exercise. Objective: This article describes the study design and recruitment outcomes of the Pain Outcomes comparing Yoga vs. Structured Exercise (POYSE) Trial, a two-arm randomized comparative effectiveness trial. Methods: Veterans with fibromyalgia, defined by the 2010 American College of Rheumatology diagnostic criteria, who also experienced at least moderate pain severity were enrolled. The participants were randomized to a 12-week yoga-based or a structured exercise program (SEP) and will undergo comprehensive outcome assessments at baseline, 1, 3, 6, and 9 months by interviewers blinded to treatment assignment. The primary outcome will be the overall severity of fibromyalgia as measured by the total Fibromyalgia Impact Questionnaire-Revised. Secondary outcomes included depression, anxiety, health-related quality of life, pain beliefs, fatigue, sleep, and self-efficacy. Results: A total of 2,671 recruitment letters were sent to potential participants with fibromyalgia. Of the potential participants, 623 (23.3%) were able to be contacted by telephone and had their eligibility assessed. Three hundred seventy-one of those interviewed were found to be eligible (59.6%) and 256 (69.0%) agreed to participate and were randomized to the YOGA (n = 129) or the SEP (n = 127) arm of the trial. Conclusions: Clinicians are faced with numerous challenges in treating patients with fibromyalgia. The interventions being tested in the POYSE trial have the potential to provide primary care and other care settings with new treatment options for clinicians while simultaneously providing a much needed relief for patients suffering from fibromyalgia.