Placebo-controlled Randomized Clinical Trial Research Articles

Immunogenicity and reactogenicity following MMR vaccination in 5–7-month-old infants: a double-blind placebo-controlled randomized clinical trial in 6540 Danish infants

Measles is a highly contagious viral disease. Vaccinated mothers transfer fewer antibodies during pregnancy, resulting in shortened infant immunity. Earlier primary vaccination might avert the gap in protection. Healthy 5-7-month-old Danish infants were assigned in a 1:1 ratio to M-M-RVaxPro or placebo (solvent) in a double-blind, randomized trial between April 15, 2019 and November 1, 2021 (ClinicalTrials.govNCT03780179, EudraCT 2016-001901-18). Eligibility criteria were birth weight >1000g and gestational age ≥32 weeks.Immunogenicity was measured by plaque reduction neutralization test (PRNT) and IgG ELISA before intervention, four weeks after intervention and routine MMR. Reactogenicity data were collected for six weeks and measured by hazard ratios (HR). 647 and 6540 infants participated in the immunogenicity and reactogenicity study, respectively; 87% and 99% completed follow-up. After early MMR, seroprotection rates (SPRs) were 47% (13%) in measles PRNT; 28% (2%), 57% (8%) in mumps and rubella IgG (placebo). For measles PRNT, geometric mean ratio was 4.3 (95% CI: 3.4-5.3) between randomization groups after intervention and 1.5 (95% CI: 1.3-1.9) after routine MMR.Reactogenicity was independent of randomization (HR, 1.0; 95% CI: 0.9-1.1). Severe adverse events occurred in 25 infants (HR, 1.8; 95% CI: 0.8-4.0); none deemed vaccine related. Early MMR elicited low SPRs but did not negatively impact short-term responses to a subsequent MMR. MMR at 5-7 months was safe and not associated with higher rates of reactogenicity than placebo. Innovation Fund Denmark.

Preoperative Midazolam and Patient-Centered Outcomes of Older Patients

The effect of oral midazolam premedication on patient satisfaction in older patients undergoing surgery is unclear, despite its widespread use. To determine the differences in global perioperative satisfaction in patients with preoperative administration of oral midazolam compared with placebo. This double-blind, parallel-group, placebo-controlled randomized clinical trial was conducted in 9 German hospitals between October 2017 and May 2019 (last follow-up, June 24, 2019). Eligible patients aged 65 to 80 years who were scheduled for elective inpatient surgery for at least 30 minutes under general anesthesia and with planned extubation were enrolled. Data were analyzed from November 2019 to December 2020. Patients were randomized to receive oral midazolam, 3.75 mg (n = 309), or placebo (n = 307) 30 to 45 minutes prior to anesthesia induction. The primary outcome was global patient satisfaction evaluated using the self-reported Evaluation du Vécu de l'Anesthésie Generale (EVAN-G) questionnaire on the first postoperative day. Key secondary outcomes included sensitivity and subgroup analyses of the primary outcome, perioperative patient vital data, adverse events, serious complications, and cognitive and functional recovery up to 30 days postoperatively. Among 616 randomized patients, 607 were included in the primary analysis. Of these, 377 (62.1%) were male, and the mean (SD) age was 71.9 (4.4) years. The mean (SD) global index of patient satisfaction did not differ between the midazolam and placebo groups (69.5 [10.7] vs 69.6 [10.8], respectively; mean difference, -0.2; 95% CI, -1.9 to 1.6; P = .85). Sensitivity (per-protocol population, multiple imputation) and subgroup analyses (anxiety, frailty, sex, and previous surgical experience) did not alter the primary results. Secondary outcomes did not differ, except for a higher proportion of patients with hypertension (systolic blood pressure ≥160 mm Hg) at anesthesia induction in the placebo group. A single low dose of oral midazolam premedication did not alter the global perioperative patient satisfaction of older patients undergoing surgery or that of patients with anxiety. These results may be affected by the low dose of oral midazolam. Further trials-including a wider population with commonplace low-dose intravenous midazolam and plasma level measurements-are needed. ClinicalTrials.gov Identifier: NCT03052660.

Effect of Esketamine Added to Propofol Sedation on Desaturation and Hypotension in Bidirectional Endoscopy

Propofol sedation is widely used for endoscopic procedures, but it poses risks of hemodynamic and respiratory depression. The addition of esketamine as an adjuvant may reduce propofol requirements and associated adverse events. To evaluate the effects of low-dose esketamine added to propofol-based sedation on desaturation and hypotension during same-visit bidirectional endoscopy. This multicenter, double-blind, placebo-controlled randomized clinical trial assessed patients from 3 teaching hospitals in China who were scheduled for same-visit bidirectional endoscopy between February 8 and November 30, 2022, and randomly assigned to receive esketamine or normal saline (placebo). After induction of sedation with 0.1 μg/kg of sufentanil and 0.5 mg/kg of propofol, patients in the esketamine group received 0.15 mg/kg of intravenous esketamine, whereas patients in the placebo group received an equivalent volume of saline. Sedation was achieved through propofol titration. The primary outcome was the composite of desaturation and hypotension during the procedures. Secondary outcomes included desaturation, hypotension, propofol requirements, postprocedure pain and fatigue, nausea or vomiting, dizziness or headache, hallucination or nightmare, endoscopist satisfaction, and patient satisfaction. Among the 663 initially enrolled patients, 660 completed the study (median [IQR] age, 48 [36-57] years; 355 [53.8%] female), with 331 randomized to the esketamine group and 329 to the placebo group. The administration of esketamine compared with placebo significantly reduced the incidence of the composite outcome of desaturation and hypotension (8.2% vs 21.0%; difference, -12.8 percentage points; odds ratio [OR], 0.34; 95% CI, 0.21-0.54; P < .001). Additionally, esketamine led to significantly lower incidences of desaturation (OR, 0.36; 95% CI, 0.18-0.72; false discovery rate q = .01) and hypotension (OR, 0.33; 95% CI, 0.18-0.60; q < .001) and reduced propofol requirements (difference, -58.9 mg; 95% CI, -65.7 to -52.2 mg; q < .001), without significant effects on other secondary outcomes. In this randomized clinical trial of patients undergoing same-visit bidirectional endoscopy, the administration of low-dose esketamine resulted in an approximately 61% reduction in the incidence of desaturation and hypotension, accompanied by decreased propofol requirements. These findings support the use of esketamine as an adjuvant to propofol-based sedation in endoscopic procedures. Chinese Clinical Trial Registry Identifier: ChiCTR2200055938.

Ketamine for postoperative avoidance of depressive symptoms: the K-PASS feasibility randomised trial

BackgroundSurgical patients with previous depression frequently experience postoperative depressive symptoms. This study's objective was to determine the feasibility of a placebo-controlled trial testing the impact of a sustained ketamine infusion on postoperative depressive symptoms. MethodsThis single-centre, triple-blind, placebo-controlled randomised clinical trial included adult patients with depression scheduled for inpatient surgery. After surgery, patients were randomly allocated to receive ketamine (0.5 mg kg−1 over 10 min followed by 0.3 mg kg−1 h−1 for 3 h) or an equal volume of normal saline. Depressive symptoms were measured using the Montgomery–Asberg Depression Rating Scale. On post-infusion day 1, participants guessed which intervention they received. Feasibility endpoints included the fraction of patients approached who were randomised, the fraction of randomised patients who completed the study infusion, and the fraction of scheduled depression assessments that were completed. ResultsIn total, 32 patients were allocated a treatment, including 31/101 patients approached after a protocol change (31%, 1.5 patients per week). The study infusion was completed without interruption in 30/32 patients (94%). In each group, 7/16 participants correctly guessed which intervention they received. Depression assessments were completed at 170/192 scheduled time points (89%). Between baseline and post-infusion day 4 (pre-specified time point of interest), median depressive symptoms decreased in both groups, with difference-in-differences of −1.00 point (95% confidence interval −3.23 to 1.73) with ketamine compared with placebo. However, the between-group difference did not persist at other time points. ConclusionsPatient recruitment, medication administration, and clinical outcome measurement appear to be highly feasible, with blinding maintained. A fully powered trial may be warranted. Clinical trial registrationNCT05233566.

Oral Acitretin Plus Topical Triamcinolone vs Topical Triamcinolone Monotherapy in Patients With Symptomatic Oral Lichen Planus

Symptomatic oral lichen planus (OLP) can be challenging to treat. To compare the efficacy of oral acitretin plus topical triamcinolone acetonide (TAC), 0.1%, with TAC monotherapy in patients with symptomatic OLP. This monocentric, investigator-initiated, placebo-controlled, investigator- and patient-blinded randomized clinical trial was conducted from December 2018 to June 2020 at the Postgraduate Institute of Medical Education and Research, a tertiary referral center in Chandigarh, India. Sixty-four patients 18 years or older with symptomatic OLP were recruited by consecutive sampling. Data were analyzed from July to December 2020. The patients were randomized to receive either a combination of oral acitretin (25-35 mg/d) and TAC (treatment group) or TAC in combination with placebo (placebo group) for 28 weeks, with an additional 8 weeks of treatment-free follow-up after the end of treatment (36 weeks of total study duration). The disease severity and treatment response were assessed using Oral Disease Severity Score (ODSS), Oral Health Impact Profile 14 (OHIP-14), and visual analog scale (VAS). The primary aim was to assess the number of patients achieving ODSS-75 (75% reduction in ODSS compared with baseline) in both groups at 28 weeks and at the end of 36 weeks. Among 64 patients, 31 in the treatment group and 30 in the placebo group completed the study (mean [SD] age, 50.6 [15.2] years vs 49.2 [14.4] years; male-female ratio, 13:19 vs 16:16). Baseline ODSS, visual analog scale, and Oral Health Impact Profile 14 scores were comparable in both groups. In the intention-to-treat analysis, there was a statistically significant higher number of patients achieving 75% or higher reduction in ODSS in the treatment group compared with the placebo group at the end of 28 weeks (28 [88%] vs 15 [47%], a 41 [95% CI, 20-61] percentage point difference between groups; P < .001; Cramér V = 0.47) and 36 weeks (27 [84%] vs 13 [41%], a 43 [95% CI, 23-67] percentage point difference between groups; P < .001; Cramér V = 0.47). Relapses during the posttreatment follow-up of 8 weeks were low among patients in both treatment and placebo groups (1 [3%] vs 2 [6%], a 3 [95% CI, -13 to 7] percentage point difference between groups; P > .99; Cramér V = 0.07). In this randomized clinical trial, the combination of oral acitretin and TAC was more effective than TAC monotherapy in patients with symptomatic OLP. Clinical Trial Registry of India Identifier: CTRI/2018/11/016448.

Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa

Hidradenitis suppurativa is a painful immune-mediated disorder with limited treatment options; hence, a need exists for new treatments. To evaluate the feasibility of heat shock protein 90 inhibition by RGRN-305 as a novel mechanism of action in treating moderate to severe hidradenitis suppurativa. This was a parallel-design, double-blind, proof-of-concept, placebo-controlled randomized clinical trial conducted between September 22, 2021, and August 29, 2022, at the Department of Dermatology, Aarhus University Hospital in Denmark. The study included a 1- to 30-day screening period, a 16-week treatment period, and a 4-week follow-up period. Eligibility criteria included age 18 years or older and moderate to severe hidradenitis suppurativa with 6 or more inflammatory nodules or abscesses in at least 2 distinct anatomic regions. Of 19 patients screened, 15 patients were enrolled in the study. Intention-to-treat analysis was performed. Patients were randomly assigned (2:1) to receive oral RGRN-305, 250-mg tablet, or matching placebo once daily for 16 weeks. The primary efficacy end point was the percentage of patients achieving Hidradenitis Suppurativa Clinical Response 50 (HiSCR-50) at week 16. Secondary efficacy end points included HiSCR-75 or HiSCR-90, Hidradenitis Suppurativa Physician's Global Assessment, Dermatology Life Quality Index scores, and a pain numeric rating scale. Safety was assessed by adverse events, physical examinations, clinical laboratory measurements, and electrocardiograms. A total of 15 patients were enrolled, completed the study, and were included in all analyses (10 [67%] female; median age, 29 [IQR, 23-41] years). The primary end point HiSCR-50 at week 16 was achieved by a higher percentage in the RGRN-305 group (60% [6 of 10]) than in the placebo group (20% [1 of 5]). Improvements were also observed across all secondary end points at week 16, including higher rates of the harder-to-reach HiSCR levels; 50% (5 of 10) achieved HiSCR-75 and 30% (3 of 10) achieved HiSCR-90, whereas none of the placebo-treated patients achieved HiSCR-75 or HiSCR-90. RGRN-305 was well tolerated, with no deaths or serious adverse events, and treatment-emergent adverse events were similarly frequent between the RGRN-305 and placebo groups. The findings of this trial suggest that heat shock protein 90 inhibition by RGRN-305 offers a novel mechanism of action in treating hidradenitis suppurativa, warranting further evaluation in larger trials. ClinicalTrials.gov Identifier: NCT05286567.

Simvastatin induces degradation of the extracellular matrix in human leiomyomata: novel in vitro, in vivo, and patient level evidence of matrix metalloproteinase involvement

ObjectivesTo assess the effect of simvastatin on uterine leiomyoma growth and extracellular matrix (ECM) deposition. DesignLaboratory analysis of human leiomyoma cell culture, xenograft in a mouse model, and patient tissue from a clinical trial. SettingAcademic research center. Patient(s)Tissue culture from human leiomyoma tissue and surgical leiomyoma tissue sections from a placebo-controlled randomized clinical trial. Intervention(s)Simvastatin treatment. Main Outcome Measure(s)Serum concentrations, xenograft volumes, and protein expression. ResultsMice xenografted with 3-dimensional human leiomyoma cultures were divided as follows: 7 untreated controls, 12 treated with activated simvastatin at 10 mg/kg body weight, and 15 at 20 mg/kg body weight. Simvastatin was detected in serum from mice injected at the highest dose. Xenograft volumes were significantly smaller (mean 53% smaller at the highest concentration, p < 0.05). There was dissolution of compact ECM, decreased ECM formation, and lower collagen protein expression in xenografts. Membrane type 1 matrix metalloproteinase (MT1-MMP) was increased in vitro and in vivo. Matrix metalloproteinase 2 (MMP2) and low density lipoprotein receptor related protein 1 (LRP1) were increased in vitro. ConclusionsSimvastatin exhibited antitumoral activity, with extracellular matrix degradation and decreased leiomyoma tumor volume in vivo. Activation of the MMP2/MT1-MMP/LRP1 pathway may explain these findings.

Implications of ARIA for trial design and monitoring

AbstractBackgroundSide‐effects of therapy with monoclonal antibodies against Alzheimer’s disease are common, which has important consequences for treatment monitoring. Moreover, adverse effects may affect trial validity through unblinding of participants, but impact on trial results is uncertain.MethodLiterature review, and simulation modelling using observations from published randomised placebo‐controlled clinical trials (RCTs) of monoclonal antibodies against amyloid‐β.ResultIn analysis of simulated trial data, we demonstrate the impact of disclosure of treatment status on cognitive and functional endpoints in RCTs. These analyses show the likelihood that placebo effects after unblinding contribute to the observed treatment effects. We define the most prudent targets for safeguarding causal inference from RCTs, and suggest mitigation strategies for future trial conduct. Furthermore, we consider best practice for treatment selection and monitoring in light of amyloid‐related imaging abnormalities (ARIA). Specifically, we discuss i) the implications of interaction with other, concurrently used medication (e.g. antithrombotic drugs) on treatment safety, and ii) challenges in treatment monitoring on the basis of observed rates of ARIA with monoclonal antibody treatment, as well as background risk of hemorrhagic ARIA in the general population and in placebo‐groups of published RCTs. We end with recommendations for future research on the most pressing ARIA‐related questions for implementation of monoclonal antibodies in routine practice.ConclusionSimulated trial data can offer valuable insight in the interpretation and design of RCTs against Alzheimer’s disease. Better understanding of ARIA in different patient groups is needed to guide treatment indication and monitoring.

Intermittent Sargramostim Administration Expands Proliferating Naïve T Cells, Tregs, HLA-DR+ PD-L1+ Monocytes and Myeloid-Derived Suppressor Cells: Results from a Randomized Placebo-Controlled Clinical Trial of GM-CSF in Patients with Peripheral Artery Disease

Introduction: Sargramostim (rhuGM-CSF; Leukine ®) is an FDA-approved drug known for mobilizing hematopoietic progenitor cells and expediting hematopoietic reconstitution in patients with acute myeloid leukemia (AML) as well as after autologous and allogeneic bone marrow transplantation. While GM-CSF has been explored as an adjuvant for cancer vaccines due to its ability to promote dendritic cell differentiation and maturation, continuous daily administration of sargramostim has been associated with leukocytosis and adverse side effects. To validate and expand upon our previously published findings that thrice-weekly sargramostim administration in patients with severe peripheral artery disease (PAD) is both well-tolerated and beneficial for claudication symptoms, we conducted a placebo-controlled randomized clinical trial to assess the efficacy of an extended dosing regimen of sargramostim in PAD patients. Data regarding progenitor mobilization kinetics and claudication symptoms will be presented elsewhere. In this analysis, we investigated the impact of intermittent sargramostim dosing on immune cell subsets in the bloodstream, aiming to support the use of this dosing schedule for enhancing adaptive immunity. Methods: Symptomatic atherosclerotic PAD patients were enrolled and randomly assigned to receive either 500 μg/day of sargramostim or placebo via self-administered subcutaneous injections thrice weekly for 3 weeks, for two separate courses 3 months apart. The study was IRB-approved with adverse events and safety signals monitored by an independent Data Safety Monitoring Board. A total of 61 patients (40 receiving sargramostim and 21 receiving placebo) participated in the immune-monitoring sub-study. Blood mononuclear cells were collected at various time points and cryopreserved. Thawed peripheral blood mononuclear cells (PBMCs) were stained using immune cell-specific antibody cocktails, and analyzed by flow cytometry. Statistical significance was determined using the Student's t-test. Results: No dose-limiting leukocytosis or drug-related side effects were observed. As expected, the numbers of white blood cells (WBCs) increased by an average of 68% in the blood of sargramostim-treated patients compared to placebo-treated patients, with peak values reached after 3 weeks of intermittent study drug administration, followed by return to baseline before the next treatment course. Absolute counts of CD3+, CD4+, and CD8+ T cells, B cells, and CD14+ monocytes significantly increased one and two weeks after starting intermittent sargramostim treatment compared to the control group. Notably, sargramostim-treated patients exhibited higher levels of proliferating naïve, Ki-67+ CD4+ T cells (106.83/uL ± 70.28) compared to placebo-treated patients (44.94/uL ± 33.84, p=0.001), as well as increased numbers of naïve Ki-67+ CD8+ T cells (33.05/uL ± 25.43 after sargramostim versus 15.77/uL ± 15.73 for placebo, p=0.01) (Fig. 1, A). However, sargramostim treatment did not influence the quantities of central memory CD4+ and CD8+ T cells. Besides the heightened proliferation of naïve T cells, sargramostim treatment also resulted in a significant increase in the numbers of CD3+CD4+CD25+FoxP3+ Tregs (Fig. 1, A), as well as PD-1-expressing CD4+ and CD8+ T cells, compared to the control group. Moreover, sargramostim treatment led to elevated levels of CD14+HLA-DR+ and CD14+PDL-1+ monocytes, as well as myeloid-derived suppressor cells, 2 and 3 weeks after initiation of treatment, when compared to the control group (Fig. 1, B). Conversely, sargramostim treatment had no impact on the levels of gamma-delta T cells, natural killer (NK) cells, plasmacytoid dendritic cells, or classical dendritic cells. Conclusions: Our findings demonstrate that intermittent dosing with sargramostim is well-tolerated and induces significant but transient increases in the numbers and activation status of T cells in the bloodstream. Sargramostim treatment also increased numbers of proliferating naïve T cells, Tregs, and certain subsets of myelo-monocytic cells with immunosuppressive phenotypes. These results support the use of intermittent sargramostim dosing to avoid excessive leukocytosis and associated adverse effects. Further investigation is warranted to elucidate the clinical implications of these findings in the context of immune modulation.

Efficacy of conditioned autologous serum therapy (Orthokine®) on the dorsal root ganglion in patients with chronic radiculalgia: study protocol for a prospective randomized placebo-controlled double-blind clinical trial (RADISAC trial)

BackgroundPulsed radiofrequency (PRF) treatment on the dorsal root ganglion (DRG) has been proposed as a good option for the treatment of persistent radicular pain based on its effect of neuromodulation on neuropathic pain. Autologous conditioned serum (ACS) therapy is a conservative treatment based on the patient’s own blood. The aim of this manuscript is to develop a study protocol using ACS on the DRG as a target for its molecular modulation.MethodsWe plan to conduct a randomized controlled study to compare the efficacy of PRF therapy plus ACS versus PRF therapy plus physiological saline 0.9% (PhS) on the DRG to reduce neuropathic pain in patients with persistent lower limb radiculalgia (LLR) and to contribute to the functional improvement and quality of life of these patients.Study participants will include patients who meet study the inclusion/exclusion criteria. Eligible patients will be randomized in a 1:1 ratio to one of treatment with PRF plus ACS (experimental group) or PRF plus PhS (placebo group). The study group will consist of 70 patients (35 per group) who have experienced radicular pain symptoms for ≥ 6 months’ duration who have failed to respond to any therapy. Both groups will receive PRF on the DRG treatment before the injection of the sample (control or placebo). Patient assessments will occur at baseline, 1 month, 3 months, 6 months, and 12 months after therapy.The primary efficacy outcome measure is Numeric Pain Rating Scale (NPRS) responders from baseline to 12 months of follow-up using validated minimal important change (MIC) thresholds. A reduction of ≥ 2 points in NPRS is considered a clinically significant pain relief.The secondary efficacy outcome measure is the proportion of Oswestry Low Back Pain Disability Scale (ODS) responders from baseline to 12 months of follow-up in the experimental group (PRF plus ACS) versus the placebo group (PRF plus PhS). ODS responders are defined as those patients achieving the validated MIC of ≥ 10-point improvement in ODS from baseline to 12 months of follow-up as a clinically significant efficacy threshold.DiscussionThis prospective, double-blind, randomized placebo-controlled study will provide level I evidence of the safety and effectiveness of ACS on neuropathic symptoms in LLR patients.Trial registration {2a}{2b}EUDRACT number: 2021–005124-38. Validation date: 13 November 2021. Protocol version {3}: This manuscript presents the 2nd protocol version.

Relaxin as a biological marker and therapeutic target in heart failure

An important task of modern cardiology is the search and study of new cardiovascular biological markers that can help in the early diagnosis of heart diseases, serve as a tool to assess the effectiveness of treatment, and act as a prognostic marker and risk stratification criterion. This literature review aimed to consider relaxin (RLN) as a new diagnostic and prognostic cardiovascular biological marker. RLN is a natural peptide hormone with a molecular weight of approximately 6000 daltons. RLN2 is the main circulating form of RLN in the blood. Although human RLN2 was originally discovered as a hormone mainly secreted by the corpus luteum of the ovary, it is also synthesized in various tissues in non-pregnant women and men and is considered one of the most pleiotropic hormones of the human body, which perform various activities beyond reproduction.&#x0D; The availability of serelaxin (a recombinant molecule identical to human RLN2) has made it possible to study the effects of RLN2 on the cardiovascular system, kidneys, liver, and brain and to evaluate it in several randomized placebo-controlled clinical trials. RLN2 exerts many cardioprotective effects on the heart and vessels and has been proposed as a therapeutic target for cardiovascular diseases such as heart failure, atrial fibrillation, coronary heart disease, myocardial infarction, and arterial hypertension. Through the activation of its cognate receptor and subsequent flow of several molecular signaling pathways in the cardiovascular system, RLN2 can induce vasodilation and angiogenesis, increase arterial compliance and cardiac output, reduce vascular resistance, exert antifibrotic effects through regulation and remodeling of extracellular matrix turnover, reduce inflammation and apoptosis, inhibit oxidative stress, induce chronotropic and inotropic effects, and inhibit ventricular and atrial ectopic activity.&#x0D; Further studies are needed to demonstrate the potential use of RLN as an additional laboratory tool for diagnosis, risk stratification, and prediction of cardiovascular events in patients with heart failure. The effects of relaxin on morbidity and mortality in patients with heart failure have yet to be evaluated in more detail.

2 Cognitive Processing Speed Training in Individuals with Multiple Sclerosis

Objective:Cognitive impairment is observed in up to two-thirds of persons with Multiple Sclerosis (MS). Impairments in cognitive processing speed (PS) is the most prevalent cognitive disturbance, occurs early in the course of disease and is strongly associated with disease progression, various brain parameters and everyday life functional activities. As such, cognitive rehabilitation for PS impairments should be an integral part of MS treatment and management. The current study examines the efficacy of Speed of Processing Training (SOPT) to improve processing speed (PS) in individuals with Multiple Sclerosis (MS). SOPT was chosen because of its significant positive results in the aging populations.Participants and Methods:This double-blind, placebo-controlled randomized clinical trial included 84 participants with clinically definite MS and impaired PS, 43 in the treatment group and 41 in the placebo control group. Outcomes included changes in the Useful Field of View (UFOV) and neuropsychological evaluation (NPE) including measure of PS (e.g., Pattern Comparison and Letter Comparison). Participants completed a baseline NPE and a repeat NPE post-treatment. Treatment consisted of 10 sessions delivered twice per week for 5 weeks. After the 5 weeks, the treatment group was randomized to booster sessions or no contact. Long-term follow-up assessments were completed 6 months after completion of treatment. The primary outcome were tests of PS including UFOV and neuropsychological testing.Results:A significant effect of SOPT was observed on both the UFOV (large effect) and Pattern Comparison with a similar pattern of results noted on Letter Comparison, albeit at a trend level. The treatment effect was maintained 6-months later. The impact of booster sessions was not significant. Correlations between degree of improvement on the UFOV and the number of levels completed within each training task were significant for both Speed and Divided Attention indicating that completion of more levels of training correlated with greater benefit.Conclusions:SOPT is effective for treating PS deficits in MS with benefit documented on both the UFOV and a neuropsychological measure of PS. Less benefit was observed as the outcome measures became more distinct in cognitive demands from the treatment. Long-term maintenance was observed. The number of training levels completed within the 10-sessions exerted a significant impact on treatment benefit, with more levels completed resulting in greater benefit.

Stratified analysis in comparative effectiveness studies that emulate randomized trials.

For observational cohort studies that employ matching by propensity scores (PS), preliminary stratification by consequential predictors of outcome better emulates stratified randomization and potentially reduces variance and bias through relaxed dependence on modeling assumptions. We assessed the impact of pre-stratification in two real-life examples. For both, prior evidence from placebo-controlled randomized clinical trials (RCTs) suggested small or no risk reduction, but observational analysis suggested protection, presumably the result of confounding bias. The study populations consisted of Medicare beneficiaries (2014-18) with type 2 diabetes initiating either (i) empagliflozin versus dipeptidyl peptidase-4 inhibitors (DPP-4i) or (ii) empagliflozin versus glucagon-like peptide-1 receptor agonists (GLP-1RA). The outcome was myocardial infarction or stroke. We estimated hazard ratios (HR) and rate differences (RD) after controlling for 143 pre-exposure covariates via 1:1 PS matching after (1) PS estimation in the total cohort (total-cohort PS-matching) and (2) PS estimation separately by baseline cardiovascular disease (stratified PS matching). Stratified PS matching resulted in HRs that exceeded those from total-cohort PS-matching by 13% and 9%, respectively, for the comparisons of empagliflozin to DPP-4i and GLP-1RA. Against both comparators, HRs and RDs after stratified PS matching were closer to the null, with slightly higher variances (2%-3%) than those after total-cohort PS matching. Stratified PS matching produced effect estimates closer to the expected trial findings than total-cohort PS matching. The price paid in increased variance was minimal.

Acute effects of a chewable beetroot-based supplement on cognitive performance: a double-blind randomized placebo-controlled crossover clinical trial

BackgroundDietary nitrate (NO3−) has been shown to be useful as an ergogenic aid with potential applications in health and disease (e.g., blood pressure control). However, there is no consensus about the effects of dietary NO3− or beetroot (BR) juice supplementation on cognitive function.ObjectiveThe aim of this study was to evaluate the effects of a single dose of a chewable BR-based supplement on cognitive performance.MethodsA double-blind randomized placebo-controlled two-period crossover clinical trial was carried out based on the extension of the CONSORT guidelines for randomized crossover trials. A total of 44 participants (24 F; 20 M; 32.7 [12.5] years; 66.3 [9.0] kg; 170 [9.2] cm; 22.8 [1.4] kg/m2) were randomly allocated to receive first either four BR-based chewable tablets (BR-CT) containing 3 g of a Beta vulgaris extract (RedNite®) or four tablets of a placebo (maltodextrin). A 4-day washout period was used before crossover. Ninety minutes after ingestion of the treatments, a neuropsychological testing battery was administered in each period. The trial was registered at clinicaltrials.gov NCT05509075.ResultsSignificant improvements with moderate effect size were found on memory consolidation at the short and long term only after BR-CT supplementation via the Rey Auditory Verbal Learning Test immediate (+ 20.69%) and delayed (+ 12.34%) recalls. Likewise, enhancement on both frontal lobe functions (+ 2.57%) and cognitive flexibility (+ 11.16%) were detected after BR-CT. There was no significant change (p < 0.05) on verbal memory of short-term digits, working memory and information processing speed. Mixed results were found on mood and anxiety through the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI-Y1 and STAI-Y2); however, sequence and period effects were seen on STAI-Y2.ConclusionsThe acute administration of a chewable BR-based supplement improves certain aspects of cognitive function in healthy females and males, particularly memory capacity and frontal skills.

Mind games in dentistry: confounded evidence suggests a substantial nocebo response in dental impaction pain model.

A systematic review and metaanalysis of randomized clinical trials (RCTs). Electronic search was conducted in PubMed, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL), on 22 May 2021. Eligibility criteria included parallel-group placebo-controlled RCTs assessing analgesics after third molar (M3) surgery in healthy patients, reporting the number of patients with at least one drug-related adverse event (AE), and being published in English. Two reviewers independently screened all identified articles against the eligibility criteria, and performed quality assessment and data extraction. Any disagreements were resolved by discussion involving a third reviewer. The primary outcome was the pooled rate of drug-related AEs in placebo and active arms of RCTs assessing analgesic treatment following M3 surgery. Secondary outcome was the drug-related dropout rates in the same setting. A total of 50 RCTs in 47 articles were included in the analyses. The pooled rates of patients with AE ≥ 1 in the placebo and active arms were 22.8% and 20.6%, respectively. The pooled drug-related dropout rates in the placebo and active arms were 0.24% and 0.08%, respectively. There were no significant risk differences in patients with AE ≥ 1 and drug-related dropouts (p = 0.61 and p = 0.94; respectively). High statistical heterogeneity was found for the proportion of patients with AE ≥ 1 (I2 = 79.7%, p < 0.001), but not for drug-related dropout rates (I2 = 0%, p = 1.00). Patients in the placebo arm reported AEs at a similar frequency as patients receiving active treatment, suggesting that most analgesic-related AEs after M3 surgery may be attributed to the nocebo phenomenon.

Janus Kinase Inhibitors and Adverse Events of Acne

Janus kinase (JAK) inhibitors are increasingly used across a range of dermatologic conditions. Adverse events of acne have been noted in some studies in clinical practice, but the scope of this outcome across JAK inhibitors has not been established. To systematically analyze all published phase 2 and 3 placebo-controlled randomized clinical trials (RCTs) of JAK inhibitors for the risk of acne as an adverse effect of these medications. Comprehensive search of Ovid MEDLINE and PubMed databases through January 31, 2023. Inclusion criteria were phase 2 and 3 placebo-controlled RCTs of JAK inhibitors published in English with reported adverse events of acne. Two reviewers independently reviewed and extracted information from all included studies. The primary outcome of interest was the incidence of acne following JAK inhibitor use. A meta-analysis was conducted using random-effects models. A total of 25 unique studies (10 839 unique participants; 54% male and 46% female) were included in the final analysis. The pooled odds ratio (OR) was calculated to be 3.83 (95% CI, 2.76-5.32) with increased ORs for abrocitinib (13.47 [95% CI, 3.25-55.91]), baricitinib (4.96 [95% CI, 2.52-9.78]), upadacitinib (4.79 [95% CI, 3.61-6.37]), deucravacitinib (2.64 [95% CI, 1.44-4.86]), and deuruxolitinib (3.30 [95% CI, 1.22-8.93]). Estimated ORs were higher across studies investigating the use of JAK inhibitors for the management of dermatologic compared with nondermatologic conditions (4.67 [95% CI, 3.10-7.05]) as well as for JAK1-specific inhibitors (4.69 [95% CI, 3.56-6.18]), combined JAK1 and JAK2 inhibitors (3.43 [95% CI, 2.14-5.49]), and tyrosine kinase 2 inhibitors (2.64 [95% CI, 1.44-4.86]). In this systematic review and meta-analysis, JAK inhibitor use was associated with an elevated odds of acne. Patients should be properly counseled on this potential adverse effect of these medications before treatment initiation. Future studies are needed to further elucidate the pathophysiology of this association.

Participant Safety in Multisite, Randomized, Double-Blind, Placebo-Controlled Clinical Trials in Hospice/Palliative Care: Data from the Contracted Studies of the Australian National Palliative Care Clinical Studies Collaborative.

Objective: To describe the harms in all arms of six consecutive multi-site, double-blind, placebo-controlled randomised clinical trials. Background: Controversies surround conduct of phase III clinical trials in palliative care. Concerns include risks to participants' safety, use of placebo arms, participants' burden, and justification when therapies are already widely used. Methods: This study collates safety data of the first six studies of the Australian national Palliative Care Clinical Studies Collaborative. On an intention-to-treat basis, all harms are described using standard international definitions, their severity, outcomes, and level of attribution. Results: Studies recruited 1,232 participants: 65/1,232 (5.3%) participants had serious adverse events of which none had a definite (blinded) attribution, all of which settled with ceasing the intervention; 49/1,232 (4.0%) participants had adverse events. No participants on placebo arms had adverse or serious adverse events with definite (blinded) attribution. Discussion: These studies are safe for participants and generate knowledge to support informed patient decision making.

Radiotherapy Plus Cisplatin With or Without Lapatinib for Non–Human Papillomavirus Head and Neck Carcinoma

Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC. To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS). This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020. Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo). The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS. Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84). In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis. ClinicalTrials.gov Identifier: NCT01711658.

Effect of Coccinia grandis (Linn.) Voigt extract on glucose metabolism markers in a prediabetic population: A double-blind randomised clinical trial

BackgroundThere is increasing interest in the use of herbal medicines to prevent and manage the symptoms of type 2 diabetes mellitus (T2DM). Coccinia grandis has been traditionally used for blood glucose regulation and has shown promise in clinical trials for T2DM although it has not yet been assessed as an anti-glycaemic agent in a prediabetic population. ObjectiveThis study aimed to assess the safety as well as the efficacy of a C. grandis extract in reducing blood glucose levels in a non-medicated prediabetic cohort over 12 weeks. MethodsThe study was a single-site, double-blind, placebo-controlled randomised clinical trial conducted in 48 medically diagnosed prediabetic adults aged 27 to 73 years. Participants received either 1000 mg of a dried C. grandis hydroalcoholic extract per day (equivalent to 15 g/day of dried herb) or placebo (control) for 12 weeks. The primary outcome measure was group change scores in fasting blood glucose (FBG) levels measured at baseline, week 6 and week 12. Secondary outcome measures were 2 h post-prandial blood glucose (PPBG), fasting and 2 h post-prandial insulin (FI and PPI), glycated haemoglobin (HbA1c), c-peptide, full blood count (FBC), lipids (triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), emotional states of depression, anxiety and stress (DASS-21), adverse reactions and tolerability. ResultsAt 12 weeks there was a significant difference between the C. grandis and control groups in the change between their pre and post treatment measurements of FBG (p = 0.019, CI -1.272 to -0.105), 2 h PPBG (p = 0.039, CI 0.212 to 1.392) and TG (p= 0.046). Additionally, although non-significant, the difference between the change in PPI levels (p = 0.061) is worthy of further exploration to provide an understanding of the mechanisms of action of C. grandis extract in managing glucose dysregulation. There were no changes in HbA1c, lipids or biochemical markers in either group after treatment. The C. grandis extract was well tolerated and no adverse events were reported over the 12 weeks. ConclusionC. grandis may be a suitable candidate for managing blood glucose dysregulation in those with prediabetes and further studies are warranted.

Daily consumption of galactooligosaccharide gummies ameliorates constipation symptoms, gut dysbiosis, degree of depression and quality of life among sedentary university teaching staff: A double-blind randomized placebo control clinical trial.

Functional constipation affects approximately 10% of the Indian population and may reduce the quality of life (QOL)and increase gut dysbiosis. PURPOSEOF STUDY: The study aimed at assessing the impact of galactooligosaccharide (GOS) gummy supplementation on gut health, depression status and QOL of constipated subjects. A double-blind placebo control clinical trial (CTRI/2021/10/037474) was conducted on sedentary constipated adults (n = 35), who were split into an experimental group (n = 17) and a control group (n = 18), supplemented with 10g GOS and sugar gummies, respectively, for 30days. Relative abundance of fecal gut microbes, including Bifidobacterium, Lactobacillus, Clostridium and Bacteroides and phyla Bacteroidetes and Firmicutes using real-time polymerase chain reaction and short-chain fatty acids, was analyzed pre and post supplementation. Constipation profile was studied using Rome IV criteria and the Bristol stool chart. Depression status was studied using the Becks Depression Inventory. TheQOL was assessed using patient assessment of constipation. GOS gummy supplementation increased Bifidobacterium and Lactobacillus by 1230% and 322%, respectively, (p < 0.001; p < 0.01) with reduced Clostridium by 63%, phylum Firmicutes by 73% and Bacteroidetes by 85% (p < 0.01). The GOS-supplemented group demonstrated a higher F/B ratio (4.2) indicating improved gut health (p < 0.01) with reduced gut dysbiosis and constipation severity. GOS gummies enhanced acetic acid and butyric acid levels compared to the control group (p < 0.01; p < 0.001). Post supplementation, there was 40% reduction in depression (p < 0.01) and 22% improvement in QOL (p < 0.05). This research validates the predicted beneficial benefits of short-term GOS consumption on constipation profile, gut microflora, depression status and quality of life of constipated subjects.