Placebo-controlled Randomized Controlled Trials Research Articles

A 12 week double-blind randomised controlled trial investigating the effect of dietary supplementation with 5000 IU/day (125 µg/day) vitamin D in adults with asthma, led to an improvement in the lung function parameter - FEV1:FVC ratio.

Vitamin D deficiency has previously been linked to higher rates of exacerbation and reduced lung function in asthmatics. Previous randomised controlled trials (RCT) investigating the effect of vitamin D supplementation have mainly focussed on children with asthma. Trials involving adults have typically used bolus dosing regimes and the main outcomes have been patient focussed without investigating underlying inflammation. The present study aimed to conduct a 12-week placebo-controlled RCT administering a daily 5000 IU (125 µg) vitamin D3 supplement to adults with mild to moderate asthma. A total of 32 participants were randomised to receive either the 5000 IU vitamin D3 supplement or an identical matching placebo. The primary outcome of the study was lung function measured by ratio of FEV1:FVC (effect size 2.5) with secondary outcomes including asthma symptoms and inflammatory biomarkers. There was a small but statistically significant higher increase in the mean (± SD) ratio of FEV1: FVC from baseline to post-intervention in the vitamin D group (+ 0.05 ± 0.06) compared to the placebo group (+ 0.006 ± 0.04, p = 0.04). There was no effect of the intervention on asthma control test scores, or the inflammatory biomarkers measured. There was a moderate, significant association between baseline plasma 25(OH)D concentration and baseline plasma IL-10 (r = 0.527, p = 0.005) and TNF-α (r = -0.498. p = 0.008) concentrations. A daily vitamin D3 supplement led to slightly improved lung function in adult asthmatics and may be a useful adjunct to existing asthma control strategies, particularly for individuals with suboptimal vitamin D status.

Antidepressant treatment in inflammatory bowel disease: a systematic review and meta-analysis.

Around 25% of patients with inflammatory bowel disease (IBD) have depressive symptoms, yet antidepressants have been poorly studied in IBD. We systematically searched IBD studies testing antidepressants in four databases. Outcomes were depressive symptoms, anxiety, IBD disease activity, quality of life (QoL) and adverse events. For randomized controlled trials (RCTs), we performed random-effects meta-analysis of the standardized mean difference (SMD) in posttreatment scores between antidepressant and placebo groups. Risk of bias was assessed using the Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group tool (clinical trials) and Newcastle-Ottawa scale (cohort studies). We included 11 studies ( n = 327): three placebo-controlled RCTs, two nonrandomized trials, and six other study types. In the pooled analysis, antidepressants improved depressive symptoms [SMD = -0.71 (95% confidence interval (CI) -1.32 to -0.10), P = 0.02, I2 = 51%] and QoL [SMD = 0.88 (95% CI 0.30-1.45), P = 0.003, I2 = 44%] more than placebo. Serotonin and noradrenaline reuptake inhibitors (SNRIs) alone improved depressive symptoms [SMD = -0.95 (95% CI -1.45 to -0.45, P < 0.001, I2 = 11%], anxiety [SMD = -0.92 (95% CI 1.72 to -0.13), P = 0.023, I2 = 65%] and QoL [SMD = 1.14 (95% CI 0.66-1.62), P < 0.001, I2 = 0%]. The three RCTs were of good quality. In conclusion, based on three small but good-quality studies, antidepressants improve depressive symptoms and QoL compared to placebo in IBD. SNRI antidepressants may also improve anxiety. A fully powered study of antidepressants in IBD is needed.

Psychostimulant Medications for Physical Function and Spasticity in Children With Cerebral Palsy: Protocol for a Randomized Controlled Trial.

Cerebral palsy (CP) is a prevalent nonprogressive disorder that leads to impaired movement (ie, spasticity), posture, and balance, which affects functions such as walking and upper extremity tasks. Current medical treatments show efficacy in improving motor performance but have considerable side effects. Emerging off-label use of central nervous system (CNS) medications for improving motor performance has shown promising results in children with CP and other populations. The aim of this study is to describe a protocol for a pilot randomized controlled trial (RCT) to examine the safety, tolerability, and efficacy of methylphenidate (MPH) and modafinil on spasticity and motor performance in children with CP. This will be a protocol study for a pilot, triple-masked, placebo-controlled RCT (a class I trial following the American Academy of Neurology criteria) with blinded patients, outcome assessors, and intervention delivery team. Eligible children should be diagnosed with CP levels I or II based on the Gross Motor Function Classification System and be aged between 7 and 12 years. Thirty-six children with CP will be randomized into 3 groups to receive (1) MPH (2.5 mg of MPH + 100 mg placebo), (2) modafinil (100 mg modafinil + 2.5 mg placebo), or (3) a placebo (2.5 mg placebo + 100 mg placebo), in addition to physical therapy for 12 weeks. Primary outcomes include the Gross Motor Function Measure-66 and the Modified Ashworth Scale. Secondary outcomes include the Timed Up and Go test, 5 Time Sit to Stand test, Modified Clinical Test for Sensory Interaction of Balance, and 10-Meter Walk Test. The protocol has been accepted by Kuwait University (VDR/EC-225) and the Ministry of Health of Kuwait (2022/2157). The inclusion of participants will start in June 2024. The combination of CNS stimulant medications and controlling for rehabilitation has not been studied yet. The findings of this study may determine if using CNS stimulant medications is beneficial for the reduction of spasticity and improvement of physical function in children with spastic CP. ClinicalTrials.gov NCT05675098; https://clinicaltrials.gov/study/NCT05675098. PRR1-10.2196/53728.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ibogaine.

Ibogaine is a plant-derived alkaloid that has been used for thousands of years in rites of passage and spiritual ceremonies in West-Central Africa. In the West, it has primarily been used and studied for its anti-addictive properties and more recently for other neuropsychiatric indications, including post-traumatic stress disorder, depression, anxiety, and traumatic brain injury. Ibogaine requires careful patient screening and monitoring because of significant safety issues. There is potential for cardiotoxicity (prolonged QT interval); without rigorous screening, fatal arrhythmias may occur. However, preliminary research suggests that co-administration of ibogaine with magnesium may mitigate cardiotoxicity. Additionally, ibogaine may have dangerous interactions with opiates, so patients who receive ibogaine treatment for opioid use disorder must withdraw from long-acting opioids. Other potential concerning effects of ibogaine include rare incidences of mania or psychosis. Anticipated transient effects during ibogaine treatment can include ataxia, tremors, and gastrointestinal symptoms. Robust effects after a single treatment with ibogaine have been reported. In open-label and randomized controlled trials (RCTs), ibogaine reduces heroin and opioid cravings by upwards of 50%, up to 24 weeks after the treatment. An observational study of 30 Special Operations Forces veterans with mild traumatic brain injury reported that 86% were in remission from post-traumatic stress disorder, 83% from depression, and 83% from anxiety, one month after a single-dose ibogaine treatment. Although there are several observational and open-label studies, there is only a single double-blind, placebo-controlled RCT on ibogaine. More RCTs with large sample sizes must be conducted to support ibogaine's safety and efficacy. Given the promising preliminary findings, ibogaine could potentially fill a much-needed gap in treatments for challenging conditions, including opioid dependence. Ibogaine's remarkable effects in traditionally treatment-resistant, combat-exposed individuals hints at its potential in broader populations with physical and psychological trauma.

Effect of SGLT-2 inhibitors on arrhythmia events: insight from an updated secondary analysis of > 80,000 patients (the SGLT2i—Arrhythmias and Sudden Cardiac Death)

ObjectiveWe aimed to assess the effect of SGLT2i on arrhythmias by conducting a meta-analysis using data from randomized controlled trials(RCTs).BackgroundSodium-glucose co-transporter 2 inhibitors (SGLT2i) have shown cardioprotective effects via multiple mechanisms that may also contribute to decrease arrhythmias risk.MethodsWe searched in databases (PubMed, Embase, Cochrane Library, and clinicaltrials.gov) up to April 2023. RCTs comparing SGLT2i with placebo were included. The effects of SGLT2i on atrial fibrillation(AF), atrial flutter(AFL), composite AF/AFL, ventricular fibrillation(VF), ventricular tachycardia(VT), ventricular extrasystoles(VES), sudden cardiac death(SCD) and composite VF/VT/SCD were evaluated.Results33 placebo-controlled RCTs were included, comprising 88,098 patients (48,585 in SGLT2i vs. 39,513 in placebo). The mean age was 64.9 ± 9.4 years, 63.0% were male. The mean follow-up was 1.4 ± 1.1 years. The pooled-results showed that SGLT2i was associated with a significantly lower risk of AF [risk ratio(RR): 0.88, 95% confidence interval(CI) 0.78–1.00, P = 0.04] and composite AF/AFL (RR: 0.86, 95%CI 0.77–0.96, P = 0.01). This favorable effect appeared to be substantially pronounced in patients with HFrEF, male gender, dapagliflozin, and > 1 year follow-up. For SCD, only in heart failure patients, SGLT2i were found to be associated with a borderline lower risk of SCD (RR: 0.67, P = 0.05). No significant effects of SGLT2i on other ventricular arrhythmic outcomes were found.ConclusionsSGLT2i lowers the risks of AF and AF/AFL, and this favorable effect appeared to be particularly pronounced in patients with HFrEF, male gender, dapagliflozin, and longer follow-up (> 1 year). SGLT2i lowers the risk of SCD only in heart failure patients.Graphical

Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted. We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies. Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.

Thrombopoietin receptor agonists use and risk of thrombotic events in patients with immune thrombocytopenic purpura: A systematic review and meta‑analysis of randomized controlled trials.

Thrombopoietin receptor agonists (TPO-RAs) have a role in second-line immune thrombocytopenic purpura (ITP) treatment, binding to and activating thrombopoietin receptors on megakaryocyte membranes in the bone marrow. This promotes megakaryocyte maturation and increases platelet production. Despite a 2-6% incidence of thrombotic events during TPO-RA treatment, it remains uncertain whether TPO-RAs elevate thrombosis rates. A comprehensive search of electronic databases was conducted using the relevant search criteria. To assess the risk of bias, the included studies were assessed using the revised Cochrane Risk of Bias Assessment Tool 2.0, and a meta-analysis was performed using RevMan 5.4.1. A total of 1,698 patients with ITP were included from randomized controlled trials (RCTs). There were 26 thromboembolic events in the TPO-RAs group and 4 in the control group. However, there was no significant difference in the incidence of thrombotic events between the two groups [odds ratio (OR)=1.76, 95% confidence interval (CI): 0.78-4.00, P=0.18], even if the duration of treatment was >12 weeks (OR=2.46, 95% CI: 0.81-7.43, P=0.11). Subgroup analysis showed that none of the four drugs significantly increased the incidence of thrombotic events (romiplostim: OR=0.92, 95% CI: 0.14-6.13, P=0.93; eltrombopag: OR=2.32, 95% CI: 0.64-8.47, P=0.20; avatrombopag: OR=4.15, 95% CI: 0.20-85.23, P=0.36; and hetrombopag: OR=0.76, 95% CI: 0.03-18.76, P=0.87). There was also no significant difference in the results of the double-blinded placebo-controlled RCTs (OR=1.21, 95% CI: 0.41-3.58, P=0.73). Compared to patients with ITP who did not receive TPO-RA treatment, those receiving TPO-RA treatment did not exhibit a significantly increased risk of thrombotic events.

Lacticaseibacillus rhamnosus GG Versus Placebo for Eradication of Vancomycin-Resistant Enterococcus faecium in Intestinal Carriers: A Systematic Review and Meta-Analysis.

The aim of this review was to assess the efficacy and safety of Lacticaseibacillus rhamnosus GG (LGG) (previously known as Lactobacillus rhamnosus GG) for the eradication of vancomycin-resistant Enterococcus faecium (VREfm) in colonized carriers. We searched Cochrane Central, EMBASE, and the PubMed Library from inception to 21 August 2023, for randomized controlled trials (RCTs) investigating the effectiveness of LGG for the eradication of gastrointestinal carriage of VREfm. An initial screening was performed followed by a full-text evaluation of the papers. Out of 4076 articles in the original screening, six RCTs (167 participants) were included in the review. All were placebo-controlled RCTs. The meta-analysis was inconclusive with regard to the effect of LGG for clearing VREfm colonization. The overall quality of the evidence was low due to inconsistency and the small number of patients in the trials. We found insufficient evidence to support the use of LGG for the eradication of VREfm in colonized carriers. There is a need for larger RCTs with a standardized formulation and dosage of LGG in future trials.

Randomised controlled trials of antipsychotics for people with autism spectrum disorder: a systematic review and a meta-analysis.

Despite unclear evidence to support the long-term use of antipsychotics to treat challenging (problem) behaviours in people with autism in the absence of a psychiatric disorder, this practice is common. We conducted a systematic review and meta-analysis of all randomised controlled trials (RCTs) involving antipsychotics for people with autism of all ages, irrespective of the outcomes assessed. We searched seven databases and hand-searched ten relevant journals. Two authors independently screened titles, abstracts and full papers and extracted data using the Cochrane Handbook template. We conducted meta-analyses of outcomes and the rate of adverse events. We included 39 papers based on 21 primary RCTs that recruited 1482 people with autism. No RCT assessed any psychiatric disorder outcome, such as psychoses or bipolar disorder. A meta-analysis of ten placebo-controlled RCTs showed a significantly improved Aberrant Behaviour Checklist-Irritability score in the antipsychotic group with an effect size of -6.45 [95% confidence interval (CI) -8.13 to -4.77] (low certainty). Pooled Clinical Global Impression data on 11 placebo-controlled RCTs showed an overall effect size of 0.84 (95% CI 0.48 to 1.21) (moderate certainty). There was a significantly higher risk of overall adverse effects (p = 0.003) and also weight gain (p < 0.00001), sedation (p < 0.00001) and increased appetite (p = 0.001) in the antipsychotic group. There is some evidence for risperidone and preliminary evidence for aripiprazole to significantly improve scores on some outcome measures among children with autism but not adults or for any other antipsychotics. There is a definite increased risk of antipsychotic-related different adverse effects.

Anti-TNF Agents and New Biological Agents (Vedolizumab and Ustekinumab) in the Prevention and Treatment of Postoperative Recurrence After Surgery in Crohn's Disease.

Surgery for Crohn's disease (CD) is not curative, as postoperative recurrence (POR) after ileocolonic resection is the rule in the absence of prophylactic treatment. In the present article, we critically review available data on the role of anti-tumour necrosis factor (TNF) agents and new biologics (including vedolizumab and ustekinumab) in the prevention and treatment of POR after surgery in CD. Several studies (summarised in various meta-analyses) have confirmed the efficacy of anti-TNFs in the prevention of POR. We identified 37 studies, including 1863 CD patients, with mean endoscopic POR at 6-12 months of 29%. Only few randomised controlled trials (RCTs) have directly compared thiopurines and anti-TNFs, with controversial results, although the superiority of the latter is supported by several meta-analyses. Infliximab and adalimumab seem equally effective. The combination of anti-TNFs and immunosuppressives should be considered in patients previously exposed to anti-TNFs. Several studies have shown that anti-TNFs remain an effective option to prevent POR also in patients with anti-TNF failure before surgery. In fact, the use of the same anti-TNF before and after surgery might be effective for the prevention of POR. Prophylactic anti-TNF treatment, once started, should be continued long term. Anti-TNFs are also effective for the treatment of established POR. Retreatment with anti-TNFs for POR is a valid strategy even after their preoperative failure. In six studies (including 156 patients) evaluating vedolizumab, mean endoscopic POR at 6-12 months was 41%. The non-randomised comparison of anti-TNFs and vedolizumab has provided controversial results. One placebo-controlled RCT confirmed that vedolizumab is quite effective in preventing POR in CD patients with increased risk of recurrence. Seven studies (including 162 patients) evaluated ustekinumab, with a mean endoscopic POR at 6-12 months of 41%. The comparative efficacy of ustekinumab and anti-TNFs is still unclear. Ustekinumab and vedolizumab seem to be equally effective, although the experience is very limited. In conclusion, to date, anti-TNFs are the most effective agents in preventing and treating POR in CD. Anti-TNFs remain an effective option to prevent POR also in patients with anti-TNF failure before surgery. Vedolizumab seems to be quite effective in the prevention of POR in patients with increased risk of recurrence. Ustekinumab is probably also effective in the postoperative setting, although the comparative efficacy with anti-TNFs or vedolizumab is still unclear.

N-acetylcysteine for smoking cessation among dual users of tobacco and cannabis: Protocol and rationale for a randomized controlled trial

BackgroundTobacco and cannabis co-use is a growing public health problem. The synergistic effects of cannabis and nicotine on neurobiological systems that mediate reward and shared environmental cues reinforcing use may make tobacco smoking cessation more difficult. N-acetylcysteine (NAC), an FDA-approved medication and over-the-counter supplement, has shown promise in animal studies and randomized controlled trials (RCTs) in reducing tobacco and cannabis craving and use. NAC's potential efficacy in treating addiction may be attributable to its central nervous system effects in reducing excessive glutamatergic activity, oxidative stress, and inflammation. To date, no RCT has examined NAC for smoking cessation among dual users of tobacco and cannabis. MethodIn a double-blind, placebo-controlled RCT, we will examine NAC for smoking cessation among dual users of tobacco and cannabis. Sixty adult cigarette-cannabis co-users are randomized to receive NAC 3600 mg per day or placebo over 8 weeks. Participants in both groups receive 8 weekly cognitive behavioral therapy sessions addressing smoking cessation and cannabis reduction. Outcomes are assessed at Weeks 0, 4, 8, and 12. Primary aims are to determine NAC's efficacy in decreasing cigarette craving, nicotine dependence, and use; and cannabis craving and use. Exploratory aims include examination of changes in neurocognition with NAC and their potential mediational effects on cigarette and cannabis use outcomes. ConclusionResults will inform smoking cessation treatment among dual users of tobacco and cannabis.ClinicalTrials.gov Identifier: NCT04627922.

Sodium-glucose cotransporter-2 inhibitors and cardiovascular clinical outcomes in acute heart failure: A narrative review.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. This review describes the evidence from randomized controlled trials (RCTs) regarding the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular (CV) clinical outcomes when therapy is initiated during acute heart failure (HF). SGLT2 inhibitors have become a cornerstone of guideline-directed medical therapy (GDMT) for type 2 diabetes mellitus, chronic kidney disease, and HF. Because of their ability to promote natriuresis and diuresis as well as other potentially beneficial CV effects, use of SGLT2 inhibitors has been investigated when therapy is initiated during hospitalization for acute HF. We identified 5 placebo-controlled RCTs that reported CV clinical outcomes incorporating one or more components of all-cause mortality, CV mortality, CV hospitalization, HF worsening, and hospitalization for HF in patients treated with empagliflozin (n = 3 trials), dapagliflozin (n = 1 trial), and sotagliflozin (n = 1 trial). Nearly all CV outcomes in these trials showed benefit with SGLT2 inhibitor use during acute HF. Incidence of hypotension, hypokalemia, and acute renal failure was generally similar to that with placebo. These findings are limited by heterogeneous outcome definitions, variation in time to SGLT2 inhibitor initiation, and small sample sizes. SGLT2 inhibitors may have a role in inpatient management of acute HF, provided there is close monitoring for fluctuations in hemodynamic, fluid, and electrolyte status. Initiation of SGLT2 inhibitors at the time of acute HF may promote optimized GDMT, continued medication adherence, and reduced risk of CV outcomes.

A167 HISTOLOGICAL REMISSION PLACEBO RATES IN ULCERATIVE COLITIS TRIALS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background High histologic remission rates have been reported with placebos in randomized controlled trials (RCTs) evaluating ulcerative colitis (UC) therapies and have varied based on trial designs. We performed a systematic review and meta-analysis to quantify placebo histological remission rates and identify factors influencing those rates. Purpose This systematic review aims to improve future trials design and minimize placebo rates in UC trials. Method MEDLINE, EMBASE, and the Cochrane library were searched from inception of the databases until December 2021. We included placebo-controlled RCTs of adult patients with UC treated with aminosalicylates, corticosteroids, immunosuppressives, biologics, and small molecules. We pooled estimates using a random-effects model and performed subgroup analysis as well as meta-regression to evaluate the effect of different covariates on placebo rates. Result(s) Thirty-three studies (30 induction and 3 maintenance) were included. The overall placebo histological remission rate was 15.7% [95% CI 12.9-19%] across all 33 studies (Figure). High heterogeneity was observed among studies with I2 = 62.10%. In induction studies, the pooled estimate of histological remission was 15.8% [95% CI 12.7-19.5%], while in maintenance studies the pooled estimate was 14.5% [95% CI 8.4-24%]. Subgroup analysis revealed statistically significant differences in placebo rates when accounting for background medications, the intervention drug class, and disease severity [p= 0.041, 0.025, and 0.025, respectively]. There was no statistical difference between induction vs. maintenance studies or between different histological scales [p= 0.771, and 0.075, respectively]. Meta-regression showed similar results except that the therapy used was not statistically significant [p-value= 0.059]. Image Conclusion(s) Placebo histological remission rates range from 13-19% in UC RCTs, but studies are highly heterogeneous. Factors found to influence placebo rates include presence of background medications, the drug used and the disease severity in UC patients. These observations have important implications in informing future trial designs to minimize placebo rates and reduce heterogeneity. Disclosure of Interest M. Youssef: None Declared, K. Dong: None Declared, S. J. Lee: None Declared, N. Narula Speakers bureau of: received honoraria from Janssen, Abbvie, Takeda, Pfizer, Merck, Sandoz, Novartis, and Ferring

Clinician- versus caregiver-rated scales as outcome measures of repetitive-restricted behaviors in clinical trials of autism: A systematic review and meta-analysis

The agreement between treatment effects measured by clinician- and caregiver-ratings of repetitive-restricted behaviors (RRBs) is important for clinical practice and research but is still unclear.Therefore, we conducted a post-hoc meta-analysis of placebo-controlled randomized-controlled trials (RCTs) investigating pharmacological and dietary-supplement treatments for autism that reported both clinician- and caregiver-ratings of RRBs. Treatment effects between medications and placebo were quantified with standardized mean differences (SMDs). The agreement between clinician- and caregiver-rated SMDs was investigated with an intraclass correlation coefficient (ICC) and random-effects meta-analysis of their difference (Δg). A meta-regression investigated the association between clinician (dependent) and caregiver-rated SMDs (independent variable). Certainty in the evidence was evaluated using the GRADE approach.We identified 15 eligible placebo-controlled RCTs with 1567 participants, from which 13 included children/adolescents and 9 reported data for the pair of the clinician-rated Yale-Brown Obsessive Compulsive Scale (YBOCS) and the caregiver-rated Aberrant Behavior Checklist-Stereotypic Behavior (ABC-S). There was on average a good agreement between clinician- and caregiver-rated SMDs (ICC=0.84, 95% confidence intervals [0.55, 0.95]), no clear difference between them (Δg=0.08, 95%CI[-0.06, 0.21], 95% prediction intervals [-0.16, 0.31]), and the beta of the meta-regression was 0.62, 95%CI[0.27, 0.97]. The certainty of the evidence was low due to concerns in imprecision and inconsistency.Our analysis showed on average a good agreement between clinician- and caregiver-rated treatment effects in RRBs, yet discordance could be expected in future RCTs, given the wide prediction intervals. It is also not certain that these results could be generalizable to other rating scales and intervention modalities.Ethics committee approval: Not applicable as a meta-analysis of previously published studies..

Lifestyle and dietary interventions for Ménière's disease.

Ménière's disease is a condition that causes recurrent episodes of vertigo, associated with hearing loss and tinnitus. Lifestyle or dietary modifications (including reducing the amount of salt or caffeine in the diet) are sometimes suggested to be of benefit for this condition. The underlying cause of Ménière's disease is unknown, as is the way in which these interventions may work. The efficacy of these different interventions at preventing vertigo attacks, and their associated symptoms, is currently unclear. To evaluate the benefits and harms of lifestyle and dietary interventions versus placebo or no treatment in people with Ménière's disease. The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 September 2022. We included randomised controlled trials (RCTs) and quasi-RCTs in adults with Ménière's disease comparing any lifestyle or dietary intervention with either placebo or no treatment. We excluded studies with follow-up of less than three months, or with a cross-over design (unless data from the first phase of the study could be identified). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome - improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) change in hearing, 6) change in tinnitus and 7) other adverse effects. We considered outcomes reported at three time points: 3 to < 6 months, 6 to ≤ 12 months and > 12 months. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included two RCTs, one related to diet, and the other related to fluid intake and sleep. In a Swedish study, 51 participants were randomised to receive 'specially processed cereals' or standard cereals. The specially processed cereals are thought to stimulate the production of anti-secretory factor - a protein that reduces inflammation and fluid secretion. Participants received the cereals for three months. The only outcome reported by this study was disease-specific health-related quality of life. The second study was conducted in Japan. The participants (223) were randomised to receive abundant water intake (35 mL/kg/day), or to sleep in darkness (in an unlit room for six to seven hours per night), or to receive no intervention. The duration of follow-up was two years. The outcomes assessed were 'improvement in vertigo' and hearing. As these studies considered different interventions we were unable to carry out any meta-analysis, and for almost all outcomes the certainty of the evidence was very low. We are unable to draw meaningful conclusions from the numerical results. The evidence for lifestyle or dietary interventions for Ménière's disease is very uncertain. We did not identify any placebo-controlled RCTs for interventions that are frequently recommended for those with Ménière's disease, such as salt restriction or caffeine restriction. We identified only two RCTs that compared a lifestyle or dietary intervention to placebo or no treatment, and the evidence that is currently available from these studies is of low or very low certainty. This means that we have very low confidence that the effects reported are accurate estimates of the true effect of these interventions. Consensus on the appropriate outcomes to measure in studies of Ménière's disease is needed (i.e. a core outcome set) in order to guide future studies in this area and enable meta-analyses of the results. This must include appropriate consideration of the potential harms of treatment, as well as the benefits.

Meta-analysis: Placebo rates in microscopic colitis randomised trials and applications for future drug development using a historical control arm.

Effective medical therapies for patients with microscopic colitis (MC) who fail budesonide are lacking. However, conducting randomised controlled trials (RCTs) in MC has been challenging due to small sample sizes. Understanding placebo responses can help inform more efficient future trials. The aim of this study is to estimate clinical and histologic placebo response rates and to determine factors associated with placebo response in MC. EMBASE, MEDLINE, and CENTRAL were searched until 7 January 2022, to identify placebo-controlled RCTs in adult patients with MC. Clinical and histologic response in the placebo arms were pooled using random-effects models. Stratified analyses based on disease- and trial-level characteristics, leave-one-out meta-analysis, and cumulative meta-analysis were performed. Twelve RCTs enrolling a total of 391 patients (placebo n= 163) with MC were included. Pooled clinical and histologic placebo response rates were 24.4% (95% CI: 12.4%-38.4%), I2 = 60.8%, p < 0.01, and 19.9% (95% CI: 5.3%-39.0%), I2 = 66.4%, p= 0.01 (tests for heterogeneity), respectively. Clinical response to placebo was numerically higher in patients with lymphocytic compared to collagenous colitis (39.9% vs. 19.8%, p=0.08). Heterogeneity in clinical response to placebo was significantly reduced when the Miehlke 2014 RCT was excluded in the leave-one-out meta-analysis or when a more stringent secondary definition of response based on the Hjortswang criteria was applied. Approximately one-quarter of patients in MC trials respond to placebo, although with substantial heterogeneity, reflecting the need for standardised outcome definitions and study designs for MC. This analysis also serves to inform future MC trials that may consider incorporating an external, historical placebo control arm, rather than directly randomising patients to placebo.

Histological Remission Placebo Rates in Ulcerative Colitis Trials: A Systematic Review and Meta-analysis.

High histologic remission rates have been reported with placebos in randomized controlled trials (RCTs) evaluating ulcerative colitis (UC) therapies and have varied based on trial designs. We performed a systematic review and meta-analysis to quantify placebo histological remission rates and identify factors influencing those rates. MEDLINE, EMBASE, and the Cochrane library were searched from inception of the databases until December 2021. We included placebo-controlled RCTs of adult patients with UC treated with aminosalicylates, corticosteroids, immunosuppressives, biologics, and small molecules. We pooled estimates using a random-effects model and performed subgroup analysis and meta-regression to evaluate the effect of different covariates on placebo rates. Thirty-three studies (30 induction and 3 maintenance) were included. The overall placebo histological remission rate was 15.7% (95% confidence interval, 12.9%-19%) across all 33 studies. High heterogeneity was observed among studies with I2 = 62.10%. The pooled estimate of histological remission was 15.8% in induction studies and 14.5% in maintenance studies. Subgroup analysis revealed statistically significant differences in placebo rates when accounting for background medications, the intervention drug class, and disease severity (P = .041, .025, and .025, respectively). There was no statistical difference between induction vs maintenance studies or between different histological scales (P = .771, and .075, respectively). Placebo histological remission rates range from 13% to 19% in UC RCTs, but studies are highly heterogeneous. Factors found to influence placebo rates include presence of background medications, the drug used, and the disease severity. These observations inform future trial designs to minimize placebo rates and reduce heterogeneity.

The effect of pregabalin on postoperative pain after anterior cruciate ligament reconstruction: A systematic review of randomized clinical trials.

Despite the enormous success of anterior cruciate ligament (ACL) reconstruction, acute neuropathic pain can develop postoperatively and is both distressing and difficult to treat once established. Pregabalin, an anticonvulsant agent that selectively affects the nociceptive process, has been used as a pain relief agent. The purpose of this systematic review of randomized controlled trials (RCTs) was to evaluate the pain control effect of pregabalin versus placebo after ACL reconstruction. A search of the literature was performed from inception to June 2022, using PubMed, Scopus, Google Scholar, Web of Science, Cochrane and EBSCO. Studies considered for inclusion were RCTs that reported relevant outcomes (postoperative pain scores, cumulative opioid consumption, adverse events) following administration of pregabalin in patients undergoing ACL reconstruction. Five placebo-controlled RCTs involving 272 participants met the inclusion criteria. 75mg and 150mg oral pregabalin was used in included trials. Two studies used a single dose of pregabalin one hour before anesthesia induction. Two studies used pregabalin 1hour before anesthesia induction and 12hours after. One study used daily pregabalin 7days before and 7days after surgery. Out of five papers, three papers found significantly lower pain intensity and cumulative opioid consumption in pregabalin group compared with placebo group. However, a decrease in pain scores was found in all trials. Pregabalin administration was associated with dizziness and nausea. The use of pregabalin may be a valuable asset in pain management after ACL reconstruction. However, future studies with larger sample size and longer follow-up period are required.

PP02 Is Glycated Hemoglobin A Valid Surrogate Endpoint To Evaluate The Effectiveness Of Drugs In Diabetes Mellitus Studies?

IntroductionIn the field of drug development and effectiveness evaluation, the use of surrogate endpoints is acceptable if they reliably predict a positive effect on clinical outcomes such as mortality or morbidity. Hemoglobin A1c (HbA1c) is a widely used surrogate endpoint in phase 3 and 4 clinical trials evaluating drugs in patients with diabetes mellitus (DM). The objective of this study was to investigate whether HbA1c is a valid surrogate endpoint for evaluating the effectiveness of antihyperglycemic drugs in DM trials.MethodsWe conducted a systematic review of randomized placebo-controlled trials evaluating the effect of a treatment on levels of HbA1c and clinical outcomes in patients with DM. The association between the effects of treatment on HbA1c levels and clinical outcomes was then investigated using regression analysis at the trial level. The correlation coefficients (R) were interpreted using the cut-off points suggested by the German Institute for Quality and Efficiency in Health Care (IQWiG). HbA1c was considered a valid surrogate endpoint if it demonstrated a strong association with clinical outcomes (i.e., the lower limit of the 95% confidence interval [CI] of R≥ 0.85).ResultsNineteen phase 3 or 4 randomized controlled trials (RCTs) were identified. All studies included adults with type 2 DM. None of the associations evaluated was strong enough to validate HbA1c as a surrogate endpoint for any clinical outcome: mortality (R 0.34, 95% CI: -0.14, 0.69); myocardial infarction (R 0.20, 95% CI: -0.30, 0.61); heart failure (R 0.08, 95% CI: -0.40, 0.53); kidney injury (R -0.04, 95% CI: -0.52, 0.47); and stroke (R 0.81, 95% CI: 0.54, 0.93).ConclusionsThe evidence from multiple placebo-controlled RCTs of antihyperglycemic drugs in patients with type 2 DM suggests that a reduction in levels of HbA1c does not meet the IQWiG criteria for a valid surrogate endpoint. Consequently, the risk-benefit ratio of antihyperglycemic drugs in terms of patient relevant clinical outcomes, regardless of their hypoglycemic effect, should be the focus of therapeutic, regulatory, and reimbursement decisions.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.