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Background Patient outcomes can depend on the treating centre, or health professional, delivering the intervention. A health professional’s skill in delivery improves with experience, meaning that outcomes may be associated with learning. Considering differences in intervention delivery at trial design will ensure that any appropriate adjustments can be made during analysis. This work aimed to establish practice for the allowance of clustering and learning effects in the design and analysis of randomised multicentre trials. Methods A survey that drew upon quotes from existing guidelines, references to relevant publications and example trial scenarios was delivered. Registered UK Clinical Research Collaboration Registered Clinical Trials Units were invited to participate. Results Forty-four Units participated ( N  = 50). Clustering was managed through design by stratification, more commonly by centre than by treatment provider. Managing learning by design through defining a minimum expertise level for treatment provider was common (89%). One-third reported experience in expertise-based designs. The majority of Units had adjusted for clustering during analysis, although approaches varied. Analysis of learning was rarely performed for the main analysis ( n  = 1), although it was explored by other means. The insight behind the approaches used within and reasons for, or against, alternative approaches were provided. Conclusions Widespread awareness of challenges in designing and analysing multicentre trials is identified. Approaches used, and opinions on these, vary both across and within Units, indicating that approaches are dependent on the type of trial. Agreeing principles to guide trial design and analysis across a range of realistic clinical scenarios should be considered.

Even today, patients with schizophrenia often have an unfavorable outcome. Negative symptoms and cognitive deficits are common features in many patients and prevent recovery. In recent years, aerobic endurance training has emerged as a therapeutic approach with positive effects on several domains of patients’ health. However, appropriately sized, multicenter randomized controlled trials that would allow better generalization of results are lacking. The exercise study presented here is a multicenter, rater-blind, two-armed, parallel-group randomized clinical trial in patients with clinically stable schizophrenia being conducted at five German tertiary hospitals. The intervention group performs aerobic endurance training on bicycle ergometers three times per week for 40–50 min/session (depending on the intervention week) for a total of 26 weeks, and the control group performs balance and tone training for the same amount of time. Participants are subsequently followed up for 26 weeks. The primary endpoint is all-cause discontinuation; secondary endpoints include psychopathology, cognition, daily functioning, cardiovascular risk factors, and explorative biological measures regarding the underlying mechanisms of exercise. A total of 180 patients will be randomized. With currently 162 randomized participants, our study is the largest trial to date to investigate endurance training in patients with schizophrenia. We hypothesize that aerobic endurance training has beneficial effects on patients’ mental and physical health, leading to lower treatment discontinuation rates and improving disease outcomes. The study results will provide a basis for recommending exercise interventions as an add-on therapy in patients with schizophrenia.The study is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Background Acne vulgaris adversely impacts quality of life, requiring safer alternatives to conventional treatments. This study explores a facial mask combining Bentonite's detoxifying and Alcea sulphurea's anti‐inflammatory properties, rooted in Traditional Persian Medicine (TPM). It aims to evaluate its efficacy in reducing acne severity and enhancing patient satisfaction, integrating traditional and modern therapeutic approaches. Methods This add‐on randomized, controlled clinical trial included 60 patients with moderate acne, recruited through purposive sampling in Sari from October 2022 to November 2023. Participants were randomly allocated into intervention (Bentonite‐Alcea mask + Azithromycin 250 mg) and placebo (placebo + Azithromycin 250 mg). Outcomes, including lesion count, acne severity, and satisfaction, were assessed at baseline, 4 weeks, and 8 weeks. Data analysis was conducted using SPSS version 16. Results Sixty people completed the study (30 persons in both group). The mean and standard deviation of the age in control group was 24 ± 8.03 years and in placebo group was 19.03 ± 7.03 and 46 subjects (76.7%) were female. TLC and ASI in the fourth and eighth weeks in control group were significantly less than in placebo group (p < 0.001). The percentage of relatively satisfied and very satisfied participants in the intervention group was significantly higher than the control group (p < 0.001). Bentonite‐based facial mask with Alcea sulphurea extract had no serious side effects. The intervention group exhibited significant reductions in TLC (total lesion count) (55.45% ± 21.74%) and ASI (Acne Severity Index) (66.33% ± 27.15%) from baseline to 8 weeks (p < 0.001), outperforming the placebo group. Patient satisfaction was notably higher in the intervention group, with 43.3% being very satisfied compared to 3.3% in the placebo group (p < 0.001). Conclusion A facial mask based on Bentonite and A. sulphurea extract effectively reduces acne severity and enhances patient satisfaction. These findings suggest its potential as a natural alternative or adjunct to conventional acne treatments. Trial Registration Iranian registry: IRCT20220403054395N1

Muscle Stem Cells (MuSCs) drive muscle regeneration and slow pathological progression of muscle diseases. In preclinical models, nicotinamide (NAM) and pyridoxine (PN) synergistically increased MuSC proliferation and differentiation, and accelerated muscle regeneration. Herein we tested if NAM/PN could enhance MuSC activity and muscle regeneration in a randomized, placebo‐controlled clinical trial. Men aged 18–49 years were supplemented daily with 714 mg NAM and 19 mg PN, or placebo, for 9 days following one session of damaging unilateral eccentric muscle contractions. The primary endpoint was MuSC activity via immunohistofluorescence on biopsy sections from the vastus lateralis muscle. Histological markers of muscle regeneration constituted secondary outcomes, and muscle damage was validated with clinical markers. 39 out of 43 enrolled participants completed the study. Supplementation of NAM/PN was well tolerated and increased blood concentrations of NAM and PN vitamers. 8 days after the contraction protocol, the number of Pax7, MyoD, and myogenin positive cells per damaged fiber was significantly higher in NAM/PN vs placebo groups (+29%–67%). NAM/PN also increased the proportion of regenerating fibers (+37%). Daily oral NAM/PN supplementation after high intensity muscle contractions enhances MuSC activity and accelerates muscle regeneration and repair, providing new opportunities for therapeutic applications in muscle recovery and muscle wasting disorders. In a randomized clinical trial, we test the potential of combined nicotinamide (NAM) and pyridoxine (PN) to improve muscle recovery through muscle stem cell (MuSC) activity. Daily oral NAM and PN supplementation after high intensity muscle contractions enhances MuSC activation and differentiation, and accelerates muscle regeneration, providing new opportunities for therapeutic applications in muscle recovery and muscle wasting disorders.

Background Phase-3 clinical trials provide the highest level of evidence on drug safety and effectiveness needed for market approval by implementing large randomized controlled trials (RCTs). However, 30–40% of these trials fail mainly because such studies have inadequate sample sizes, stemming from the inability to obtain accurate initial estimates of average treatment effect parameters. Methods To remove this obstacle from the drug development cycle, we present a new algorithm called Trend-Adaptive Design with a Synthetic-Intervention-Based Estimator (TAD-SIE) that powers a parallel-group trial, a standard RCT design, by leveraging a state-of-the-art hypothesis testing strategy and a novel trend-adaptive design (TAD). Specifically, TAD-SIE uses synthetic intervention (SI) to estimate individual treatment effects and thereby simulate a cross-over design, which makes it easier for a trial to reach target power within trial constraints (e.g., sample size limits). To estimate sample sizes, TAD-SIE implements a new TAD tailored to SI given that using it violates assumptions under standard TADs. In addition, our TAD overcomes the ineffectiveness of standard TADs by allowing sample sizes to be increased across iterations without any condition while controlling significance level with futility stopping. Our TAD also introduces a hyperparameter that enables trial designers to trade off between accuracy and efficiency (sample size and number of iterations) of the solution. Results On a real-world Phase-3 clinical RCT (i.e., a two-arm parallel-group superiority trial with an equal number of subjects per arm), TAD-SIE obtains operating points ranging between 63% to 84% power and 3% to 6% significance level in contrast to baseline algorithms that get at best 49% power and 6% significance level. Conclusion TAD-SIE is a superior TAD that can be used to reach typical target operating points but only for trials with rapidly measurable primary outcomes due to its sequential nature. The framework is useful to practitioners interested in leveraging the SI algorithm for their study design.

Purpose of Review This review integrates recent findings from randomized controlled clinical trial (RCT) research examining the impacts of physical exercise activities on various aspects and areas of functioning for autistic individuals. Recent Findings Recent meta-analytic and clinical trials research indicates physical exercise intervention programs improve social and communication skills for autistic children and adolescents, improve executive functioning skills for autistic children, improve sleep-related behavior for autistic children and adolescents, and may be helpful for improving physical health for autistic children. There is very limited RCT research evidence on exercise intervention approaches or impacts for autistic adults, for autistic girls or women, for autistic people with co-occurring intellectual disability, and for reducing negative emotional symptoms (e.g., anxiety, depression) for any autistic population. Summary The extant clinical trials research provides convincing, consistent evidence for positive impacts of physical exercise programs on multiple areas of functioning for autistic children and adolescents. Additional research is needed to determine and ensure potential impacts of physical exercise activity programs for important autistic sub-populations, including adults.

Noninferiority trials test whether a new experimental treatment is not unacceptably less efficacious than an active control treatment already in use. With continuous improvements in health technologies, standard care, and clinical outcomes, the incremental benefits of newly developed treatments may be only marginal over existing treatments. Sometimes assigning patients to a placebo is unethical. In such circumstances, there has been increasing emphasis on the use of noninferiority trial designs. Noninferiority trials are more complex to design, conduct, and interpret than typical superiority trials. This paper reviews the concept of noninferiority trials and discusses some important issues related to them.

To describe the characteristics of Covid-19 randomized clinical trials (RCTs) and examine the association between trial characteristics and the likelihood of finding a significant effect. We conducted a systematic review to identify RCTs (up to October 21, 2020) evaluating drugs or blood products to treat or prevent Covid-19. We extracted trial characteristics (number of centers, funding sources, and sample size) and assessed risk of bias (RoB) using the Cochrane RoB 2.0 tool. We performed logistic regressions to evaluate the association between RoB due to randomization, single vs. multicentre, funding source, and sample size, and finding a statistically significant effect. We included 91 RCTs (n = 46,802); 40 (44%) were single-center, 23 (25.3%) enrolled <50 patients, 28 (30.8%) received industry funding, and 75 (82.4%) had high or probably high RoB. Thirty-eight trials (41.8%) reported a statistically significant effect. RoB due to randomization and being a single-center trial were associated with increased odds of finding a statistically significant effect. There is high variability in RoB among Covid-19 trials. Researchers, funders, and knowledge-users should be cognizant of the impact of RoB due to randomization and single-center trial status in designing, evaluating, and interpreting the results of RCTs. CRD42020192095

Background Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5–21 years) with ASD. Methods We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and Δ9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and Δ9-tetrahydrocannabinol at the same ratio. Participants ( N  = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI). Results Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract ( n  = 45) versus 21% on placebo ( n  = 47; p  = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract ( n  = 34) versus 3.6 points after placebo ( n  = 36); p  = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively ( n  = 95); 23% and 21% on pure-cannabinoids ( n  = 93), and 8% and 15% on placebo ( n  = 94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results. Conclusions This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226

Violet light (VL), 360–400 nm wavelength, is contained in the sunlight and is an effective element for myopia suppression. This study is to investigate the safety and efficacy of novel eyeglasses that emit VL from the frames. This is a double-masked, randomized, pilot clinical trial conducted in a clinic in Japan. Forty-three children with myopia were enrolled. Participants were randomly assigned to two groups, wearing VL-emitting eyeglass frames (VLf) that emitted VL of 310 μW/cm2 (VLf group, n = 22) or pseudo-placebo eyeglass frames with a minimal emission of VL (<10 μW/cm2) (control group, n = 21). The exposure time was 3 h per day. The primary outcomes were visual acuity, tear film break-up time, corneal endothelial cell density, and the slit-lamp/fundus examinations. The secondary outcome was the 6-month changes in the axial lengths and cycloplegic refractions. Forty-one (95%) participants were included; twenty-one in the VLf group and twenty in the control group. No significant differences were seen in any safety evaluation. Significant changes were seen in axial elongation, choroidal thickness, and cycloplegic refractions in the subgroup analysis of 8- to 10-year-old children (p < 0.05), but otherwise no significant differences were seen. The VLf showed short-term safety and effectiveness against myopia progression.