Factorial Randomized Clinical Trial Research Articles

Tobacco Quitline Retreatment Interventions Among Adults With Socioeconomic Disadvantage

A single round of standard tobacco quitline treatment may not be sufficient to sustain abstinence, particularly among people experiencing socioeconomic disadvantage. Adaptive retreatment may help more individuals with socioeconomic disadvantage achieve abstinence and reduce disparities in smoking cessation outcomes. To evaluate 4 evidence-based strategies for adults with limited education, no insurance, or Medicaid eligibility who continued smoking after quitline treatment. A factorial randomized clinical trial with 4 factors adapting quitline strategies was conducted for participants enrolled from June 7, 2018, to January 25, 2023, with 6-month follow-up. Adults using the Wisconsin Tobacco Quit Line who were smoking cigarettes 3 to 6 months after prior quitline treatment who were uninsured, Medicaid insured, or had no more than a high school education were included. Quitline retreatment strategies were (1) increased counseling intensity (4 calls vs 1 call), (2) increased nicotine replacement therapy intensity (4 weeks of combination nicotine patch plus nicotine lozenge vs 2 weeks of nicotine patch), (3) text-message support (National Cancer Institute SmokefreeTXT program vs none), and (4) financial incentives for engagement in counseling and SmokefreeTXT ($30/call and/or 6-week SmokefreeTXT retention vs no incentives). Primary outcome was 7-day point-prevalence biochemically confirmed abstinence 26 weeks after the target quit day. Intention-to-treat analysis was performed. Of 6019 people assessed for eligibility, 1316 (21.9%) participants were randomized (mean [SD] age, 53.1 [11.9] years; 760 [57.8%] women), and 919 (69.8%) provided final follow-up. Intention-to-treat analyses showed 162 participants (12.3%) had biochemically confirmed abstinence at 26 weeks (368 [28.0% self-reported abstinence]). There were no significant main effects for the primary outcome: 1 call (11.6% [77 of 662]) vs 4 calls (13.0% [85 of 654]) (odds ratio [OR], 1.04; 95% CI, 0.88-1.24), 2-week patch (11.2% [73 of 654]) vs 4-week combination nicotine replacement therapy (13.4% [89 of 662]) (OR, 1.12; 95% CI, 0.94-1.34), no SmokefreeTXT (13.4% [88 of 657]) vs SmokefreeTXT (11.2% [74 of 659]) (OR, 0.88; 95% CI, 0.74-1.05), and no financial incentives (12.8% [85 of 662]) vs financial incentives (11.8% [77 of 654]) (OR, 0.94; 95% CI, 0.78-1.11). In this randomized clinical trial evaluating enhancements to tobacco quitlines for adults with socioeconomic disadvantage who were smoking after quitline treatment, none of the adaptive treatment strategies robustly improved long-term abstinence. Strategies are needed to enhance quitline retreatment effectiveness for adults with socioeconomic disadvantage. ClinicalTrials.gov Identifier: NCT03538938.

Tissue Plasminogen Activator or Perfluoropropane for Submacular Hemorrhage in Age-Related Macular Degeneration

Evidence is limited to support therapies to treat submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (AMD) as an adjunct to anti-vascular endothelial growth factor therapy (anti-VEGF). To determine if intravitreal tissue plasminogen activator (TPA) or gas improves visual acuity or promotes resolution of SMH secondary to neovascular AMD in eyes treated with ranibizumab. This was a double-masked, sham-controlled, factorial randomized clinical trial and feasibility study that recruited participants from June 2014 to March 2019, with 12 months' follow-up. Included in the trial were patients from 4 UK vitreoretinal units who had fovea-involving SMH of at least 1 disc area secondary to neovascular AMD and were evaluated within 14 days of onset. Study eyes received baseline ranibizumab and were then randomized 2:1:1:1 to 1 of 4 intravitreal treatments: sham injection, perfluoropropane (C3F8), TPA, or combined C3F8 and TPA (C3F8 + TPA). All eyes received monthly pro re nata ranibizumab therapy over 12 months. Outcome assessors were masked to intervention assignment. Best-corrected visual acuity (BCVA) at month 3. Fifty-three of 56 participants (95%; mean [SD] age, 81.5 [8.1] years; 33 female [59%]) reached the primary end point. Study eyes were randomized to the following intravitreal treatments: sham injection (n = 23), C3F8 (n = 11), TPA (n = 11), or C3F8 + TPA (n = 11). On factorial analysis, the combined TPA groups had significantly better month 3 mean logMAR BCVA than those not receiving TPA: 0.66 vs 0.98 (μd = -0.32; 95% CI, -0.58 to -0.07; P = .02). There was no statistically significant difference comparing groups that did vs did not receive C3F8: 0.80 vs 0.90 (μd = -0.11; 95% CI, -0.37 to 0.16; P = .43). The combined TPA groups were less likely to have SMH present at month 1 (10 of 18 [55.6%] vs 21 of 24 [87.5%]; P = .03), a benefit not evident in the combined gas groups. The mean logMAR BCVA at 3 months was not significantly different between the groups: monotherapy control, 0.99; C3F8, 0.97 (vs control μd = -0.02; 95% CI, -0.48 to 0.44); TPA, 0.70 (vs control μd = -0.29; 95% CI, -0.79 to 0.21); combined C3F8 and TPA, 0.71 (vs control μd = -0.36; 95% CI, -0.82 to 0.11); P = .11. No safety differences were identified across the treatment groups. Results of this randomized clinical trial suggest that TPA may increase the chance of visual acuity gain when added to ranibizumab therapy for neovascular AMD in eyes with SMH, warranting consideration of additional clinical trials. ClinicalTrials.gov Identifier: NCT01835067.

Mandibular overdenture retained by four one-piece titanium-zirconium mini implants: A 2-year RCT on patient-reported outcomes

AimThe positive impact of implant interventions on dental patient-reported outcomes is an essential parameter of treatment effectiveness. This study assessed the 2-year changes in patient satisfaction and oral health-related quality of life (OHRQoL) of edentulous patients treated with a four mini implant mandibular overdenture (IOD) MethodsThe study was planned as a 2 × 2 factorial randomized clinical trial that tested two surgical approaches (flapped or flapless) and two loading protocols (immediate and delayed) using a titanium-zirconium mini implant (Straumann Mini Implant System®) and a PEEK retentive system (Straumann® Optiloc® Retentive System). Outcome measures (OHIP-Edent scores and the McGill Denture Satisfaction questionnaire) were assessed before treatment and at the 3-, 6-, 12-, and 24-month follow-ups. The Friedman test and multiple regression using Generalized Estimating Equations (GEE) were used for data analysis, considering the per-protocol (PP) and intention-to-treat (ITT) approaches ResultsSeventy-four patients were randomized to the study groups. No implant failure occurred during the study period. Marked improvement in all post-treatment periods compared to baseline were observed for the two outcomes. No significant effect of patient's gender, age, and surgical protocol on the study outcomes. The effect of treatment provision was significant for the two outcomes in the PP and ITT approaches (p < 0.001). A barely significant positive effect of the immediate loading was observed for OHIP-Edent in the PP approach (p = 0.020) ConclusionIOD treatment significantly improved patient-reported outcomes measures, with sustained benefits over the two years of overdenture use, and can be considered a promising treatment option in for the edentulous mandible.

Study Protocol for Pain Self-Management and Patient-Oriented Buprenorphine Dosing for Pain and Retention in Office-Based Opioid Treatment: A Hybrid Type 1, 2 × 2 Factorial Randomized Controlled Trial.

Chronic pain is a significant factor for patients with opioid use disorder (OUD) contributing to suboptimal retention in buprenorphine treatment, which is a crucial predictor of long-term health outcomes. This study aims to address the critical need for effective interventions targeting chronic pain management within office-based opioid treatment (OBOT) programs. We are conducting a multisite, hybrid type 1, 2 × 2 factorial randomized clinical trial to determine the effectiveness of 2 novel interventions, pain self-management (PSM) and patient-oriented buprenorphine dosing (POD), to decrease pain interference and improve retention in buprenorphine treatment. PSM, a manualized and customizable approach delivered through individual and peer-led group sessions, aims to decrease pain-related symptoms and quality of life. POD involves split dosing of buprenorphine to extend the duration of analgesia to better match its duration of efficacy at managing OUD symptoms, leading to improved retention in buprenorphine treatment. Eligible participants will be randomized into 1 of 4 groups: (1) PSM + POD, (2) PSM + Standard Buprenorphine Dosing, (3) Usual Care + POD, or (4) Usual Care + Standard Buprenorphine Dosing. Usual Care refers to usual care for chronic pain and Standard Buprenorphine Dosing refers to the participant's current dosing regimen. Secondary objectives encompass overall pain reduction, decreased opioid use, improved pain symptom management, and exploration of implementation strategies. The supplemental approved protocol provides comprehensive insights into the procedures and variables being investigated. As part of the HEAL Initiative®-funded Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR) network, this study aims to fill gaps in behavioral and medication treatments for individuals with co-occurring chronic pain and OUDs, improving pain management and retention in care. Successful outcomes from this trial may inform future larger trials, offering essential evidence for implementation considerations and reimbursement decisions.

Effect of Intrapersonal and Interpersonal Behavior Change Strategies on Physical Activity Among Older Adults

Despite guidelines that recommend physical activity (PA), little is known about which types of behavior change strategies (BCSs) effectively promote sustained increases in PA in older adults who are insufficiently active. To determine whether intrapersonal BCSs (eg, goal setting) or interpersonal BCSs (eg, peer-to-peer sharing or learning) combined with the Otago Exercise Program (17 strength and balance exercises and a walking program that are learned and individually tailored, with instruction to perform 3 times per week at home or location of choice) and a wearable PA monitor help older adults sustain increases in their PA. This 2 × 2 factorial randomized clinical trial (Community-Based Intervention Effects on Older Adults' Physical Activity) of community-dwelling older adults 70 years or older with PA levels below minimum national PA guidelines was conducted in urban community centers. Dates of enrollment were from November 17, 2017, to June 15, 2021, with final follow-up assessments completed on September 2, 2022. Participants were randomized to intrapersonal (eg, goal setting) BCSs, interpersonal (eg, problem-solving with peer-to-peer sharing and learning) BCSs, intrapersonal and interpersonal BCSs, or an attention control group. All interventions included a PA monitor and 8 weekly small-group meetings with discussion, practice, and instructions to implement the exercise program and relevant BCSs independently between meetings and after the intervention. The primary outcome was daily minutes of objectively measured total PA (light, moderate, or vigorous intensities) averaged over 7 to 10 days, measured at baseline and after the intervention at 1 week, 6 months, and 12 months. Among 309 participants (mean [SD] age, 77.4 [5.0] years; 240 women [77.7%]), 305 (98.7%) completed the intervention, and 302 (97.7%) had complete data. Participants receiving PA interventions with interpersonal BCS components exhibited greater increases in total PA than did those who did not at 1 week (204 vs 177 PA minutes per day; adjusted difference, 27.1 [95% CI, 17.2-37.0]; P < .001), 6 months (195 vs 175 PA minutes per day; adjusted difference, 20.8 [95% CI, 10.0-31.6]; P < .001), and 12 months (195 vs 168 PA minutes per day; adjusted difference, 27.5 [95% CI, 16.2-38.8]; P < .001) after the intervention. Compared with participants who did not receive interventions with intrapersonal BCS components, participants who received intrapersonal BCSs exhibited no significant changes in total PA at 1 week (192 vs 190 PA minutes per day; adjusted difference, 1.8 [95% CI, -8.6 to 12.2]; P = .73), 6 months (183 vs 187 PA minutes per day; adjusted difference, -3.9 [95% CI, -15.0 to 7.1]; P = .49), or 12 months (177 vs 186 PA minutes per day; adjusted difference, -8.8 [95% CI, -20.5 to 2.9]; P = .14) after the intervention. Interactions between intrapersonal and interpersonal BCSs were not significant. In this randomized clinical trial, older adults with low levels of PA who received interpersonal BCSs, the exercise program, and a PA monitor exhibited significant increases in their PA for up to 12 months after the intervention. Intrapersonal BCSs elicited no significant PA changes and did not interact with interpersonal BCSs. Our findings suggest that because effects of a PA intervention on sustained increases in older adults' PA were augmented with interpersonal but not intrapersonal BCSs, approaches to disseminating and implementing the intervention should be considered. ClinicalTrials.gov Identifier: NCT03326141.

Impact of multiple-session home-based transcranial direct current stimulation (M-HB-tDCS) on eating behavior in fibromyalgia: A factorial randomized clinical trial

BackgroundMultiple-session home-based self-applied transcranial direct current stimulation (M-HB-self-applied-tDCS) has previously been found to effectively reduce chronic pain and enhance cognitive function. However, the effectiveness of this method for disordered eating behavior still needs to be studied. ObjectiveThis study aimed to assess whether 20 sessions of M-HB-self-applied-tDCS, administered over four weeks to either the left dorsolateral prefrontal cortex (L-DLPFC) or primary motor cortex (M1), could improve various aspects of eating behavior, anthropometric measures, and adherence. MethodsWe randomly assigned 102 fibromyalgia patients between the ages of 30 and 65 to one of four tDCS groups: L-DLPFC (anodal-(a)-tDCS, n = 34; sham-(s)-tDCS, n = 17) or M1 (a-tDCS, n = 34; s-tDCS, n = 17). Patients self-administered 20-min tDCS sessions daily with 2 mA under remote supervision following in-person training. ResultsGeneralized linear models revealed significant effects of M-HB-self-applied-tDCS compared to s-tDCS on uncontrolled eating (UE) (Wald χ2 = 5.62; df = 1; P = 0.018; effect size, ES = 0.55), and food craving (Wald χ2 = 5.62; df = 1; P = 0.018; ES = 0.57). Regarding fibromyalgia symptoms, we found a differentiated impact of a-tDCS on M1 compared to DLPFC in reducing food cravings. Additionally, M-HB-a-tDCS significantly reduced emotional eating and waist size. In contrast, M1 stimulation was more effective in improving fibromyalgia symptoms. The global adherence rate was high, at 88.94%. ConclusionThese findings demonstrate that M-HB-self-applied-tDCS is a suitable approach for reducing uncontrolled and emotional eating, with greater efficacy in L-DLPFC. Furthermore, these results revealed the influence of fibromyalgia symptoms on M-HB-self-applied-tDCS's, with M1 being particularly effective in mitigating food cravings and reducing fibromyalgia symptoms.

Effect of Automated and Personalized Outreach Messages on Well-Child Visit Catch Up: A Randomized Clinical Trial

ObjectiveTo determine the effectiveness of text/telephone outreach messages and personal contact attempts on well-child care (WCC) scheduling and completion and measles, mumps, and rubella (MMR) vaccine receipt. MethodsWe conducted an intent-to-treat, 2 × 2 factorial randomized clinical trial with 3 replications at 3 academic pediatric primary care practices from September 27, 2020 to August 6, 2021. We randomized participants to 1 of 4 groups: 1 automated message (group 1), 2 automated messages (group 2), 1 automated message plus personal contact attempts (group 3), or 2 automated messages plus personal contact attempts (group 4). Outcomes included: 1) scheduled WCC within 2 weeks (secondary outcome), 2) completed WCC within 8 weeks (secondary outcome), 3) receipt of first MMR by 15 months of age or second MMR within 3 months of first message for 4-year-olds (primary outcome). ResultsWe randomized 1312 patients (mean [SD] age = 38.8 [19.3] months, 53.5% male, 72.8% non-Hispanic Black, 86.9% Medicaid-enrolled). Scheduling rates were significantly higher in groups with personal contact attempts compared to those without (1 = 15.2%, 2 = 12.5%, 3 = 29.3%, and 4 = 31.5%). WCC completion rates also differed across groups: 1 = 27.4%, 2 = 22.3%, 3 = 32.0%, and 4 = 29.4%, with groups 3 and 4 having significantly higher rates than group 2. Similarly, groups 3 (30.2%) and 4 (31.8%) had significantly higher rates of receiving the MMR vaccine compared to group 2 (23.5%) but not group 1 (28.0%). ConclusionsOutreach messages that were followed by personal contact attempts increased the rates of scheduling and completing WCCs and receiving the MMR vaccine, providing a useful tool to re-engage at-risk populations.

Selenium and Vitamin E for Prevention of Non–Muscle-Invasive Bladder Cancer Recurrence and Progression

Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer. To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC. This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK. A total of 755 patients were screened for inclusion; 484 did not meet the inclusion criteria, and 1 declined to participate. A total of 270 patients were randomly assigned to 4 groups (selenium plus placebo, vitamin E plus placebo, selenium plus vitamin E, and placebo plus placebo) in a double-blind fashion between July 17, 2007, and October 10, 2011. Eligibility included initial diagnosis of NMIBC (stages Ta, T1, or Tis); randomization within 12 months of first transurethral resection was required. Oral selenium (200 μg/d of high-selenium yeast) and matched vitamin E placebo, vitamin E (200 IU/d of d-alfa-tocopherol) and matched selenium placebo, selenium and vitamin E, or placebo and placebo. Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022). The study randomized 270 patients (mean [SD] age, 68.9 [10.4] years; median [IQR] age, 69 [63-77] years; 202 male [75%]), with 65 receiving selenium and vitamin E placebo, 71 receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos. Median overall follow-up was 5.5 years (IQR, 5.1-6.1 years); 228 patients (84%) were followed up for more than 5 years. Median treatment duration was 1.5 years (IQR, 0.9-2.5 years). The study was halted because of slow accrual. For selenium (n = 134) vs no selenium (n = 136), there was no difference in RFI (hazard ratio, 0.92; 95% CI, 0.65-1.31; P = .65). For vitamin E (n = 140) vs no vitamin E (n = 130), there was a statistically significant detriment to RFI (hazard ratio, 1.46; 95% CI, 1.02-2.09; P = .04). No significant differences were observed for progression-free interval or overall survival time with either supplement. Results were unchanged after Cox proportional hazards regression modeling to adjust for known prognostic factors. In total, 1957 adverse events were reported; 85 were serious adverse events, and all were considered unrelated to trial treatment. In this randomized clinical trial of selenium and vitamin E, selenium supplementation did not reduce the risk of recurrence in patients with NMIBC, but vitamin E supplementation was associated with an increased risk of recurrence. Neither selenium nor vitamin E influenced progression or overall survival. Vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required. isrctn.org Identifier: ISRCTN13889738.

Effects of a Polypill, Aspirin, and the Combination of Both on Cognitive and Functional Outcomes

Vascular risk factors are associated with cognitive decline but studies addressing individual risk factors have not demonstrated an effect of risk factor management on the preservation of cognition. Few trials have examined the effect of vascular risk factor management on function. To determine if a polypill could reduce cognitive and functional decline in people with risk factors but without manifest cardiovascular disease. The International Polycap Study 3 (TIPS-3) was a 2 × 2 × 2 factorial randomized clinical trial. Hospital and community-based centers in 8 countries recruited and followed up participants between July 30, 2012, and September 30, 2020. A total of 5713 individuals were randomly assigned to treatment groups, and 2098 people 65 years or older at intermediate risk of cardiovascular disease completed a cognitive assessment and were included in the analyses. Polypill (antihypertensives and a statin), aspirin, or a combination of both treatments. Cognitive and functional assessments completed at baseline, 2 years, and study end. The primary outcome was the effect of a polypill compared with placebo and a polypill plus aspirin compared with double placebo on the composite outcome of the proportion of participants in each group who experienced a substantive decrease (>1.5 SD change) in cognitive or functional abilities. Of the 2389 study participants older than 65 years, a total of 2098 (88%; mean [SD] age, 70.1 [4.5] years; 1266 female individuals [60%]) completed the baseline and follow-up assessment. A total of 1796 participants (86%) had hypertension, and 680 participants (32%) had impaired fasting plasma glucose levels. Mean (SD) baseline systolic blood pressure was 146.1 (17.7) mm Hg, and mean (SD) low-density lipoprotein cholesterol (LDL-C) level was 124.3 (40.7) mg/dL and decreased by 5.7 mm Hg and 24 mg/dL, respectively, among those assigned to the polypill group. During a 5-year follow-up, there were no significant differences between treatment groups in the number of participants who experienced substantive cognitive decline (356 assigned polypill, 328 assigned placebo) or dementia (2 assigned polypill, 4 assigned placebo). Functional decline was reduced during follow-up for those assigned to polypill compared with placebo (mean [SD] country-standardized adjusted follow-up Standard Assessment of Global Everyday Activities [SAGEA] scores, 0.06 [0.03] vs 0.15 [0.03]; P = .01) and polypill plus aspirin compared with double placebo (mean [SD] country-standardized adjusted follow-up SAGEA scores, 0.01 [0.04] vs 0.14 [0.04]; P = .01). In this randomized clinical trial of patients 65 years or older with vascular risk factors, a polypill, with or without aspirin, was not associated with reduced cognitive outcomes but was associated with reduced functional decline.

Effect of a Machine Learning Recommender System and Viral Peer Marketing Intervention on Smoking Cessation

Novel data science and marketing methods of smoking-cessation intervention have not been adequately evaluated. To compare machine learning recommender (ML recommender) computer tailoring of motivational text messages vs a standard motivational text-based intervention (standard messaging) and a viral peer-recruitment tool kit (viral tool kit) for recruiting friends and family vs no tool kit in a smoking-cessation intervention. This 2 ×2 factorial randomized clinical trial with partial allocation, conducted between July 2017 and September 2019 within an online tobacco intervention, recruited current smokers aged 18 years and older who spoke English from the US via the internet and peer referral. Data were analyzed from March through May 2022. Participants registering for the online intervention were randomly assigned to the ML recommender or standard messaging groups followed by partially random allocation to access to viral tool kit or no viral tool kit groups. The ML recommender provided ongoing refinement of message selection based on user feedback and comparison with a growing database of other users, while the standard system selected messages based on participant baseline readiness to quit. Our primary outcome was self-reported 7-day point prevalence smoking cessation at 6 months. Of 1487 participants who smoked (444 aged 19-34 years [29.9%], 508 aged 35-54 years [34.1%], 535 aged ≥55 years [36.0%]; 1101 [74.0%] females; 189 Black [12.7%] and 1101 White [78.5%]; 106 Hispanic [7.1%]), 741 individuals were randomly assigned to the ML recommender group and 746 individuals to the standard messaging group; viral tool kit access was provided to 745 participants, and 742 participants received no such access. There was no significant difference in 6-month smoking cessation between ML recommender (146 of 412 participants [35.4%] with outcome data) and standard messaging (156 of 389 participants [40.1%] with outcome data) groups (adjusted odds ratio, 0.81; 95% CI, 0.61-1.08). Smoking cessation was significantly higher in viral tool kit (177 of 395 participants [44.8%] with outcome data) vs no viral tool kit (125 of 406 participants [30.8%] with outcome data) groups (adjusted odds ratio, 1.48; 95% CI, 1.11-1.98). In this study, machine learning-based selection did not improve performance compared with standard message selection, while viral marketing did improve cessation outcomes. These results suggest that in addition to increasing dissemination, viral recruitment may have important implications for improving effectiveness of smoking-cessation interventions. ClinicalTrials.gov Identifier: NCT03224520.

Effects of Mindfulness Training and Exercise on Cognitive Function in Older Adults

Episodic memory and executive function are essential aspects of cognitive functioning that decline with aging. This decline may be ameliorable with lifestyle interventions. To determine whether mindfulness-based stress reduction (MBSR), exercise, or a combination of both improve cognitive function in older adults. This 2 × 2 factorial randomized clinical trial was conducted at 2 US sites (Washington University in St Louis and University of California, San Diego). A total of 585 older adults (aged 65-84 y) with subjective cognitive concerns, but not dementia, were randomized (enrollment from November 19, 2015, to January 23, 2019; final follow-up on March 16, 2020). Participants were randomized to undergo the following interventions: MBSR with a target of 60 minutes daily of meditation (n = 150); exercise with aerobic, strength, and functional components with a target of at least 300 minutes weekly (n = 138); combined MBSR and exercise (n = 144); or a health education control group (n = 153). Interventions lasted 18 months and consisted of group-based classes and home practice. The 2 primary outcomes were composites of episodic memory and executive function (standardized to a mean [SD] of 0 [1]; higher composite scores indicate better cognitive performance) from neuropsychological testing; the primary end point was 6 months and the secondary end point was 18 months. There were 5 reported secondary outcomes: hippocampal volume and dorsolateral prefrontal cortex thickness and surface area from structural magnetic resonance imaging and functional cognitive capacity and self-reported cognitive concerns. Among 585 randomized participants (mean age, 71.5 years; 424 [72.5%] women), 568 (97.1%) completed 6 months in the trial and 475 (81.2%) completed 18 months. At 6 months, there was no significant effect of mindfulness training or exercise on episodic memory (MBSR vs no MBSR: 0.44 vs 0.48; mean difference, -0.04 points [95% CI, -0.15 to 0.07]; P = .50; exercise vs no exercise: 0.49 vs 0.42; difference, 0.07 [95% CI, -0.04 to 0.17]; P = .23) or executive function (MBSR vs no MBSR: 0.39 vs 0.31; mean difference, 0.08 points [95% CI, -0.02 to 0.19]; P = .12; exercise vs no exercise: 0.39 vs 0.32; difference, 0.07 [95% CI, -0.03 to 0.18]; P = .17) and there were no intervention effects at the secondary end point of 18 months. There was no significant interaction between mindfulness training and exercise (P = .93 for memory and P = .29 for executive function) at 6 months. Of the 5 prespecified secondary outcomes, none showed a significant improvement with either intervention compared with those not receiving the intervention. Among older adults with subjective cognitive concerns, mindfulness training, exercise, or both did not result in significant differences in improvement in episodic memory or executive function at 6 months. The findings do not support the use of these interventions for improving cognition in older adults with subjective cognitive concerns. ClinicalTrials.gov Identifier: NCT02665481.

Interactions in the 2×2×2 factorial randomised clinical STEPCARE trial and the potential effects on conclusions: a protocol for a simulation study

BackgroundRandomised clinical trials with a factorial design may assess the effects of multiple interventions in the same population. Factorial trials are carried out under the assumption that the trial interventions have no interactions on outcomes. Here, we present a protocol for a simulation study investigating the consequences of different levels of interactions between the trial interventions on outcomes for the future 2×2×2 factorial designed randomised clinical Sedation, TEmperature, and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial in comatose patients after out-of-hospital cardiac arrest.MethodsBy simulating a multisite trial with 50 sites and 3278 participants, and a presumed six-month all-cause mortality of 60% in the control population, we will investigate the validity of the trial results with different levels of interaction effects on the outcome. The primary simulation outcome of the study is the risks of type-1 and type-2 errors in the simulated scenarios, i.e. at what level of interaction is the desired alpha and beta level exceeded. When keeping the overall risk of type-1 errors ≤ 5% and the risk of type-2 errors ≤ 10%, we will quantify the maximum interaction effect we can accept if the planned sample size is increased by 5% to take into account possible interaction between the trial interventions. Secondly, we will assess how interaction effects influence the minimal detectable difference we may confirm or reject to take into account 5% (small interaction effect), 10% (moderate), or 15% (large) positive interactions in simulations with no ‘true’ intervention effect (type-1 errors) and small (5%), moderate (10%), or large negative interactions (15%) in simulations with ‘true’ intervention effects (type-2 errors). Moreover, we will investigate how much the sample size must be increased to account for a small, moderate, or large interaction effects.DiscussionThis protocol for a simulation study will inform the design of a 2×2×2 factorial randomised clinical trial of how potential interactions between the assessed interventions might affect conclusions. Protocolising this simulation study is important to ensure valid and unbiased results.Trial registrationNot relevant

Effect of Vitamin D3 and Omega-3 Fatty Acid Supplementation on Risk of Frailty

Preventive strategies for frailty are needed. Whether supplements with anti-inflammatory properties, such as vitamin D3 or marine omega-3 fatty acids, are useful for frailty prevention is unknown. To test the effects of vitamin D3 and omega-3 supplements on change in frailty in older individuals. This study was conducted in 2021, as a prespecified ancillary to the Vitamin D and Omega-3 (VITAL) trial, a 2 × 2 factorial randomized clinical trial. A total of 25 871 individuals (men aged ≥50 years and women aged ≥55 years), without cancer or cardiovascular disease and with data on frailty, were recruited across all 50 US states from November 2011 to March 2014 and followed up through December 31, 2017. Data analysis for the ancillary study was conducted from December 1, 2019, to March 30, 2022. Vitamin D3, 2000 IU/d, and marine omega-3 fatty acids, 1 g/d. Frailty was measured using a validated 36-item frailty index that includes measures of function, cognition, mood, and comorbidities from annual questionnaires. Change in frailty score from baseline to year 5, according to randomization, using an intention-to-treat protocol, was assessed using repeated measures. Cox proportional hazards regression models assessed incident frailty. In subgroup analysis, an alternative frailty definition, the physical phenotype, was used as a sensitivity analysis. Of 25 871 VITAL trial participants randomized, 25 057 had sufficient data to calculate a frailty index. Baseline mean (SD) age was 67.2 (7.0) years, and 12 698 (50.7.%) were women. Mean (SD) frailty score was 0.109 (0.090) (range, 0.00-0.685), and 3174 individuals (12.7%) were frail. During a median 5-year follow-up, mean (SD) frailty scores increased to 0.121 (0.099) (range, 0.00-0.792). Neither vitamin D3 nor omega-3 fatty acid supplementation affected mean frailty scores over time (mean difference at year 5: vitamin D3, -0.0002; P = .85; omega-3 fatty acid, -0.0001; P = .90) or rate of change in mean frailty score (interaction with time: vitamin D3; P = .98; omega-3 fatty acid; P = .13) Incident frailty remained similar over time (interaction with time: vitamin D3, P = .90; omega-3 fatty acid; P = .32). Results were unchanged using the frailty physical phenotype. In this ancillary study of the VITAL randomized clinical trial, treatment with vitamin D3 or omega-3 fatty acid supplementation, compared with placebo, did not affect the rate of frailty change or incidence over time. These results do not support routine use of either vitamin D3 or omega-3 fatty acid supplementation for frailty prevention in generally healthy community-dwelling older adults not selected for vitamin D3 deficiency. ClinicalTrials.gov Identifier: NCT01169259.

Protocol for a multi-center randomized controlled trial to evaluate the benefits of exercise incentives and corticosteroid injections in osteoarthritis of the knee (MOVE-OK)

BackgroundKnee osteoarthritis (KOA) is a high-priority problem among the aging population. While exercise has been shown to be beneficial in management of the disease, scalable and low-cost interventions to improve exercise in this population are lacking. Recent controversy over the value of corticosteroid injections for palliation has also arisen. Therefore, we designed a randomized, double-blind, placebo-controlled clinical trial with a 2-period crossover design to study (1) behavioral incentives to promote exercise and (2) corticosteroid injections to reduce pain and improve function in patients with KOA when compared to lidocaine only.MethodsThe study design is a pragmatic factorial and crossover randomized clinical trial. Patients with KOA who are deemed eligible by their provider to receive knee injections and are able to walk without assistive devices will be recruited from clinical practices at four sites within the Veterans Affairs (VA) Health System in the USA. In total, 220 participants will be randomized to receive social incentives with gamification (i.e., incorporation of game elements) to promote exercise and compared to controls that receive a Fitbit but no incentive. Each patient will also be assigned to receive a blinded corticosteroid injection and a lidocaine-only injection in random order. The primary outcomes are the change in average daily step counts from baseline and the change in Knee Osteoarthritis Outcome Score (KOOS) from baseline. The study team will continuously collect step count, heart rate, and sleep data using activity monitors and patient-reported outcomes using the Way to Health (WTH) platform at two four-week intervals over eight months of follow-up. Mixed effects regression incorporating all available data points will be used for analysis.DiscussionThe “Marching on for Veterans with Osteoarthritis of the Knee” (MOVE-OK) trial will take a pragmatic approach to evaluate (1) whether incentives based on behaviorally enhanced gamification can improve physical activity in this patient population and (2) whether corticosteroids injections reduce pain and disability in patients with KOA. Results of this trial will help to direct clinical practice and inform management guidelines.Trial registrationClinicalTrials.gov NCT05035810. Registered on 5 September 2021.

Flapped versus flapless surgery and delayed versus immediate loading for a four mini implant mandibular overdenture: A RCT on post-surgical symptoms and short-term clinical outcomes.

This factorial randomized clinical trial (RCT) tested the effects of the surgical approach (flapped-FPS vs. flapless-FLS surgery) and loading protocol (delayed-DL vs. immediate-IL) for treatment with a four mini implant mandibular overdenture. A total of 296 one-piece titanium-zirconium mini-implants were inserted in 74 patients (IL/FLS=17; IL/FPS=18; DL/FLS=20; and DL/FPS=19). Outcomes included patient's perceived surgical burdens, clinical time, implant survival, and post-surgical symptoms and complications, assessed immediately after surgery, in the 7-day and 6-week follow-ups. Perceived surgical burdens were relatively low, higher for females, and no difference was found between FPS and FLS surgery. Surgical time was lower for FLS surgery. Overall symptoms were mild after 24 h, and higher for females. Less symptoms were recorded for the FLS surgery compared to the FPS for the delayed loading patients, and FLS surgery was associated with a lower risk of bleeding. No early implant failure was observed until the 6-week follow-up. Delayed was associated with discontinuous use of the prosthesis and poor function. Lower complaint rates were observed for immediate loading regardless of the surgery protocol. Mini implants for mandibular overdenture are a feasible option regardless of surgical access and loading protocol, with high safety and predictable survival rates, and low incidence of post-insertion complications. FLS surgery requires less clinical time and results in easier intraoral prosthetic incorporation of attachments compared to FPS surgeries. Immediate loading did not increase the risk of early implant failure when satisfactory primary stability was achieved.

Effects of Vitamin D, Omega-3 Fatty Acids and a Home Exercise Program on Prevention of Pre-Frailty in Older Adults: The DO-HEALTH Randomized Clinical Trial

BackgroundThe benefits of supplemental vitamin D3, marine omega-3 fatty acids, and a simple home exercise program (SHEP) on frailty prevention in generally healthy community-dwelling older adults are unclear.ObjectiveTo test the effect of vitamin D3, omega-3s, and a SHEP, alone or in combination on incident pre-frailty and frailty in robust older adults over a follow-up of 36 months.MethodsDO-HEALTH is a multi-center, double-blind, placebo-controlled, 2x2x2 factorial randomized clinical trial among generally healthy European adults aged 70 years or older, who had no major health events in the 5 years prior to enrollment, sufficient mobility and intact cognitive function. As a secondary outcome of the DO-HEALTH trial, among the subset of participants who were robust at baseline, we tested the individual and combined benefits of supplemental 2,000 IU/day of vitamin D3, 1 g/day of marine omega-3s, and a SHEP on the odds of being pre-frail and frail over 3 years of follow-up.ResultsAt baseline, 1,137 out of 2,157 participants were robust (mean age 74.3 years, 56.5% women, mean gait speed 1.18 m/s). Over a median follow-up time of 2.9 years, 696 (61.2%) became pre-frail and 29 (2.6%) frail. Odds ratios for becoming pre-frail were not significantly lower for vitamin D3, or omega 3-s, or SHEP, individually, compared to control (placebo for the supplements and control exercise). However, the three treatments combined showed significantly decreased odds (OR 0.61 [95% CI 0.38–0.98; p=0.04) of becoming pre-frail compared to control. None of the individual treatments or their combination significantly reduced the odds of becoming frail.ConclusionRobust, generally healthy and active older adults without major comorbidities, may benefit from a combination of high-dose, supplemental vitamin D3, marine omega-3s, and SHEP with regard to the risk of becoming pre-frail over 3 years.

Effects of Dental Implants and Nutrition on Elderly Edentulous Subjects: Protocol for a Factorial Randomized Clinical Trial.

BackgroundLoss of masticatory function consequent to tooth loss has been associated with changes in food choices and insufficient nutritional intake. To date, interventions based on dental prostheses alone did not significantly improve nutrient intake. Pilot studies have shown positive impacts of interventions combining implant-supported fixed dental prosthesis with brief dietary advice. The relative contribution and the potential synergy of the components of such interventions need to be determined as it has major public health implications for the community-dwelling aging population that continues to disproportionately suffer from tooth loss and its consequences.ObjectiveTo assess the effect of rehabilitation of masticatory function with fixed implant supported dentures and nutrition education in older subjects with terminal dentition (stage IV periodontitis) or full edentulism.MethodsA 2 × 2 factorial randomized controlled trial with 16-month follow-up of eligible adults (≥60 years) with loss of masticatory function consequent to full arch edentulism or terminal dentition (n = 120) will be conducted to test whether the rehabilitation of masticatory function with fixed implant supported dentures, nutrition education and/or their combination improves intake of fresh fruits and vegetables for aging subjects. The study has been designed to detect changes in fresh fruits and fresh vegetables intake at 4 months using the 24-h dietary recall method. Changes in protein as percentage of total energy, nutritional biomarkers, plasma metabolomics, oral and gut microbiome, quality of life and masticatory function will also be assessed.DiscussionWe hypothesize that receiving rehabilitation of masticatory function with fixed implant dentures together with nutrition education is the most effective intervention for improving nutrient intake in aging community-dwelling subjects with extensive tooth loss. The results of this study will assist in designing better treatment regimens, guide medical care for individual subjects, and inform public health and policy.Clinical Trials RegistrationNCT05334407.

COVID-19 Trials: Who Participates and Who Benefits?

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately afflicted vulnerable populations. Older adults, particularly residents of nursing facilities, represent a small percentage of the population but account for 40% of mortality from COVID-19 in the United States. Racial and ethnic minority individuals, particularly Black, Hispanic, and Indigenous Americans have experienced higher rates of infection and death than the White population. Although there has been an unprecedented explosion of clinical trials to examine potential therapies, participation by members of these vulnerable communities is crucial to obtaining data generalizable to those communities. We undertook an open-label, factorial randomized clinical trial examining hydroxychloroquine and/or azithromycin for hospitalized patients. Of 53 screened patients, 11 (21%) were enrolled. Ten percent (3/31) of Black patients were enrolled, 33% (7/21) of White patients, and 50% (6/12) of Hispanic patients. Forty-seven percent (25/53) of patients declined participation despite eligibility; 58%(18/31) of Black patients declined participation. Forty percent (21/53) of screened patients were from a nursing facility and 10% (2/21) were enrolled. Enrolled patients had fewer comorbidities than nonenrolled patients: median modified Charlson comorbidity score 2.0 (interquartile range 0-2.5), versus 4.0 (interquartile range 2-6) for nonenrolled patients (P = 0.006). The limitations of the study were the low participation rate and the multiple treatment trials concurrently recruiting at our institution. The high rate of nonparticipation in our trial of nursing facility residents and Black people emphasizes the concern that clinical trials for therapeutics may not target key populations with high mortality rates.

Effect of Lidocaine 2% Versus Bupivacaine 0.5% and 1 Versus 2 Dual Separate Injections on Onset and Duration of Ultrasound-Guided Wrist Blocks: A Blinded 2 × 2 Factorial Randomized Clinical Trial.

Local anesthetics are often selected or mixed to accomplish faster onset of anesthesia. However, with ultrasound guidance, local anesthetics are delivered with greater precision, which may shorten the onset time with all classes of local anesthetics. In this study, we compared onset time and duration of ultrasound-guided wrist blocks with a fast onset versus a longer lasting local anesthetic administered via single or dual (spatially separate) injections at the level of the midforearm. In this randomized clinical trial, 36 subjects scheduled for carpal tunnel release were randomly assigned to receive ultrasound-guided median and ulnar nerve blocks with lidocaine 2% or bupivacaine 0.5% via single or dual injections (n = 9 in each group). Subjects fulfilled the study requirements. The main outcome variables were onset and duration of sensory blockade, which were tested separately in 2 (drug) × 2 (injection) analysis of variances (ANOVAs) with interaction terms. Sensory block onset time did not differ significantly between subjects given lidocaine 2% (9.2 ± 3.4 minutes) or bupivacaine 0.5% (9.5 ± 3.1 minutes) (P = .76; mean difference, -0.3 ± 1.1 minutes [95% confidence interval {CI}, -2.5 to 1.9]) or between the single- (9.6 ± 2.8 minutes) and dual- (9.1 ± 3.6 minutes) injection groups (P = .69; mean difference, -0.4 ± 1.1 minutes [95% CI, -1.8 to 2.6]). Sensory duration was longer for subjects in the bupivacaine 0.5% group (27.3 ± 11.6 hours) than for subjects in the lidocaine 2% group (8.4 ± 4.1 hours) (P < .001; 95% CI, 12.7-25.1). However, sensory duration in the single- (15.7 ± 12.5 hours) and dual- (19.4 ± 13.1 hours) injection groups did not differ significantly (P = .28; mean difference, -3.7 ± 4.3 hours [95% CI, -12.6 to 5.1]). No significant effect was found for onset time between lidocaine 2% and bupivacaine 0.5% used in ultrasound-guided wrist blocks. Dual injections did not shorten onset time. Since mean nerve block duration was longer with bupivacaine 0.5%, our results suggest that the selection of local anesthetic for the median and ulnar nerves at the level of the midforearm should be based on the desired duration of the block and not on its speed of onset.

Does Menopausal Hormone Therapy, Exercise, or Both Improve Pain and Function in Postmenopausal Women With Greater Trochanteric Pain Syndrome? A 2 × 2 Factorial Randomized Clinical Trial

Background: Greater trochanteric pain syndrome (GTPS) is a debilitating chronic condition, most prevalent in postmenopausal women. A positive association between high estrogen levels and tendon health may exist, and postmenopausal women have reduced estrogen. Menopausal hormone therapy (MHT) may reduce the incidence of tendon abnormality, particularly when combined with exercise. Purpose: To determine the effect of MHT and exercise on tendon pain and function in postmenopausal women with GTPS. Study Design: Randomized controlled clinical trial; Level of evidence, 1. Methods: Postmenopausal women (N = 132; n = 12, lost to follow-up) with GTPS were randomized into MHT and placebo transdermal cream groups combined with tendon-specific or sham exercise. All groups received education about avoiding gluteal tendon compression and load management throughout 12 weeks of intervention. The primary outcome was the Victorian Institute of Sport Assessment for gluteal tendinopathy (VISA-G), and secondary outcomes were measured at baseline and at 12 and 52 weeks. The Global Rating of Change was assessed at 12 and 52 weeks. A linear mixed-effects model was used to assess differences. Body mass index (BMI) was included as a covariate. Results: All participant groups improved over time (baseline vs 12 weeks, P < .001; baseline vs 52 weeks, P < .001). There was no difference among exercise groups measured by all outcomes (VISA-G: baseline, P = .97, mean difference [MD] = 0.10; 12 weeks, P = .49, MD = 2.15; 52 weeks, P = .32, MD = −3.08). There was a significant interaction effect between cream and BMI; therefore, the population was stratified by BMI levels (<25, <30, ≥30). The MHT groups (with exercise and education) had significantly better VISA-G outcomes (baseline, P = .04, MD = −11.20, 95% CI = −21.70 to −0.70; 12 weeks, P < .001, MD = −20.72, 95% CI = −31.22 to −10.22; 52 weeks, P = .002, MD = −16.71, 95% CI = −27.21 to −6.22) and secondary measure scores as compared with placebo at all time points when BMI was <25. Conclusion: MHT or placebo combined with tendon-specific or sham exercise plus education reduced pain and increased function for this population. For women with a BMI <25, MHT with any exercise plus education was better than placebo. A targeted exercise or sham exercise strategy is effective when prescribed with education about avoiding gluteal tendon compression and load management. Registration: ACTRN12614001157662 (Australian New Zealand Clinical Trials Registry).