Long-term effectiveness of a cognitive behavioural therapy (CBT) in the management of fatigue in patients with relapsing remitting multiple sclerosis (RRMS): a multicentre, randomised, open-label, controlled trial versus standard care.

BACKGROUND: Fatigue is a disabling symptom of multiple sclerosis (MS). The lack of effective therapeutics has promoted the development of cognitive behavioural therapy (CBT)-based fatigue management programmes. However, their efficacy does not sustain over time. We proposed to test the long-term effectiveness of a 6-week fatigue programme supplemented with four booster sessions ('FACETS+') in patients with relapsing remitting MS (RRMS) and fatigue. METHODS: This multicentre, randomised, controlled, open-label, parallel-group trial versus standard care enrolled patients with RRMS and fatigue. Participants were randomised to either FACETS+ plus standard care or standard care alone. The primary outcome measure was fatigue impact (Modified Fatigue Impact Scale (MFIS) at 12 months) based on intention-to-treat analyses. RESULTS: From May 2017 to September 2020, 162 patients were screened; 105 were randomly assigned to FACETS+ (n=57) or standard care (n=48) and 88 completed the primary outcome assessment for the MFIS. At month 12, participants showed improved MFIS compared with baseline in the intervention group (mean difference (MD)=14.0 points; (95% CI 6.45 to 21.5)) and the control group (MD=6.1 points; (95% CI -0.30 to 12.5)) with a significant between-group difference in favour of the intervention group (adjusted MD=7.89 points; (95% CI 1.26 to 14.52), standardised effect size=0.52, p=0.021). No trial-related serious adverse events were reported. CONCLUSIONS: A 6-week CBT-based programme with four booster sessions is superior to standard care alone to treat MS-related fatigue in the long term (12 months follow-up). The results support the use of the FACETS+ programme for the treatment of MS-related fatigue. TRIAL REGISTRATION NUMBER: NCT03758820.

Efficacy, safety and tolerability of rozanolixizumab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a trial and open-label extension study.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a peripheral nerve disorder characterised by weakness and sensory loss. We assessed the neonatal Fc receptor inhibitor rozanolixizumab for CIDP management. METHODS: CIDP01 (NCT03861481) was a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a study. Adults with definite or probable CIDP receiving subcutaneous or intravenous immunoglobulin maintenance therapy were randomised 1:1 to 12 once-weekly subcutaneous infusions of rozanolixizumab 10 mg/kg or placebo, stratified according to previous immunoglobulin administration route. Investigators administering treatment and assessing efficacy, and patients, were blinded. The primary outcome was a change from baseline (CFB) to day 85 in inflammatory Rasch-built Overall Disability Scale (iRODS) score. Eligible patients who completed CIDP01 entered the open-label extension CIDP04 (NCT04051944). RESULTS: In CIDP01, between 26 March 2019 and 31 March 2021, 34 patients were randomised to rozanolixizumab or placebo (17 (50%) each). No significant difference in CFB to day 85 in iRODS centile score was observed between rozanolixizumab (least squares mean 2.0 (SE 3.2)) and placebo (3.4 (2.6); difference -1.5 (90% CI -7.5 to 4.5)). Overall, 14 (82%) patients receiving rozanolixizumab and 13 (76%) receiving placebo experienced a treatment-emergent adverse event during the treatment period. Across CIDP01 and CIDP04, rozanolixizumab was well tolerated over up to 614 days; no clinically meaningful efficacy results were seen. No deaths occurred. CONCLUSIONS: Rozanolixizumab did not show efficacy in patients with CIDP in this study, although this could be due to a relatively high placebo stability rate. Rozanolixizumab was well tolerated over medium-to-long-term weekly use, with an acceptable safety profile.

Emulating randomised clinical trials in relapsing-remitting multiple sclerosis with non-randomised real-world evidence: an application using data from the MSBase Registry.

BACKGROUND: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon ß-1a (IFN) using observational data. METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression. RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51). CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.

Measurement properties of the Inclusion Body Myositis Functional Rating Scale.

OBJECTIVES: To evaluate the validity, reliability, responsiveness and meaningful change threshold of the Inclusion Body Myositis (IBM) Functional Rating Scale (FRS). METHODS: Data from a large 20-month multicentre, randomised, double-blind, placebo-controlled trial in IBM were used. Convergent validity was tested using Spearman correlation with other health outcomes. Discriminant (known groups) validity was assessed using standardised effect sizes (SES). Internal consistency was tested using Cronbach's alpha. Intrarater reliability in stable patients and equivalence of face-to-face and telephone administration were tested using intraclass correlation coefficients (ICCs) and Bland-Altman plots. Responsiveness was assessed using standardised response mean (SRM). A receiver operator characteristic (ROC) curve anchor-based approach was used to determine clinically meaningful IBMFRS change. RESULTS: Among the 150 patients, mean (SD) IBMFRS total score was 27.4 (4.6). Convergent validity was supported by medium to large correlations (rs modulus: 0.42-0.79) and discriminant validity by moderate to large group differences (SES=0.51-1.59). Internal consistency was adequate (overall Cronbach's alpha: 0.79). Test-retest reliability (ICCs=0.84-0.87) and reliability of telephone versus face-to-face administration (ICCs=0.93-0.95) were excellent, with Bland-Altman plots showing good agreement. Responsiveness in the worsened group defined by various external constructs was large at both 12 (SRM=-0.76 to -1.49) and 20 months (SRM=-1.12 to -1.57). In ROC curve analysis, a drop in at least two IBMFRS total score points was shown to represent a meaningful decline. CONCLUSIONS: When administered by trained raters, the IBMFRS is a reliable, valid and responsive tool that can be used to evaluate the impact of IBM and its treatment on physical function, with a 2-point reduction representing meaningful decline. TRIAL REGISTRATION NUMBER: NCT02753530.

Which men benefit from prostate cancer screening? Prostate cancer mortality by subgroup in the European Randomised Study of Screening for Prostate Cancer.

OBJECTIVE: To evaluate whether a subgroup of men can be identified that would benefit more from screening than others. MATERIALS AND METHODS: This retrospective cohort study was based on three European Randomised Study of Screening for Prostate Cancer (ERSPC) centres, Finland, the Netherlands and Sweden. We identified 126 827 men aged 55-69 years in the study who were followed for maximum of 16 years after randomisation. The primary outcome was prostate cancer (PCa) mortality. We analysed three age groups 55-59, 60-64 and 65-69 years and PCa cases within four European Association of Urology (EAU) risk groups: low, intermediate, high risk, and advanced disease. RESULTS: The hazard ratio (HR) for PCa mortality in the screening arm relative to the control arm for men aged 55-59 years was 0.96 (95% confidence interval [CI] 0.75-1.24) in Finland, 0.70 (95% CI 0.44-1.12) in the Netherlands and 0.42 (95% CI 0.24-0.73) in Sweden. The HR for men aged 60-64 years was 1.03 (95% CI 0.77-1.37) in Finland, 0.76 (95% CI 0.50-1.16) in the Netherlands and 0.97 (95% CI 0.64-1.48) in Sweden. The HR for men aged 65-69 years was 0.80 (95% CI 0.62-1.03) in Finland and 0.57 (95% CI 0.38-0.83) in the Netherlands, and this age group was absent in Sweden. In the EAU risk group analysis, PCa mortality rates were materially lower for men with advanced disease at diagnosis in all three countries: 0.67 (95% CI 0.56-0.82) in Finland, 0.28 (95% CI 0.18-0.44) in the Netherlands, and 0.48 (95% CI 0.30-0.78) in Sweden. CONCLUSION: We were unable to unequivocally identify the optimal age group for screening, as mortality reduction differed among centres and age groups. Instead, the screening effect appears to depend on screening duration, and the number and frequency of screening rounds. PCa mortality reduction by screening is largely attributable to stage shift.

A simple and effective method for simulating nested exchangeable correlated binary data for longitudinal cluster randomised trials.

BACKGROUND: Simulation is an important tool for assessing the performance of statistical methods for the analysis of data and for the planning of studies. While methods are available for the simulation of correlated binary random variables, all have significant practical limitations for simulating outcomes from longitudinal cluster randomised trial designs, such as the cluster randomised crossover and the stepped wedge trial designs. For these trial designs as the number of observations in each cluster increases these methods either become computationally infeasible or their range of allowable correlations rapidly shrinks to zero. METHODS: In this paper we present a simple method for simulating binary random variables with a specified vector of prevalences and correlation matrix. This method allows for the outcome prevalence to change due to treatment or over time, and for a 'nested exchangeable' correlation structure, in which observations in the same cluster are more highly correlated if they are measured in the same time period than in different time periods, and where different individuals are measured in each time period. This means that our method is also applicable to more general hierarchical clustered data contexts, such as students within classrooms within schools. The method is demonstrated by simulating 1000 datasets with parameters matching those derived from data from a cluster randomised crossover trial assessing two variants of stress ulcer prophylaxis. RESULTS: Our method is orders of magnitude faster than the most well known general simulation method while also allowing a much wider range of correlations than alternative methods. An implementation of our method is available in an R package NestBin. CONCLUSIONS: This simulation method is the first to allow for practical and efficient simulation of large datasets of binary outcomes with the commonly used nested exchangeable correlation structure. This will allow for much more effective testing of designs and inference methods for longitudinal cluster randomised trials with binary outcomes.

Vaginal misoprostol versus vaginal dinoprostone for cervical ripening and induction of labour: An individual participant data meta-analysis of randomised controlled trials.

BACKGROUND: Induction of labour (IOL) is common practice and different methods carry different effectiveness and safety profiles. OBJECTIVES: To compare the effectiveness, and maternal and perinatal safety outcomes of IOL with vaginal misoprostol versus vaginal dinoprostone using individual participant data from randomised clinical trials. SEARCH STRATEGY: The following databases were searched from inception to March 2023: CINAHL Plus, ClinicalTrials.gov, Cochrane Pregnancy and Childbirth Group Trial Register, Ovid Embase, Ovid Emcare, Ovid MEDLINE, Scopus and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: Randomised controlled trials (RCTs), with viable singleton gestation, no language restrictions, and all published and unpublished data. DATA COLLECTION AND ANALYSIS: An individual participant data meta-analysis was carried out. MAIN RESULTS: Ten of 52 eligible trials provided individual participant data, of which two were excluded after checking data integrity. The remaining eight trials compared low-dose vaginal misoprostol versus dinoprostone, including 4180 women undergoing IOL, which represents 32.8% of all participants in the published RCTs. Of these, 2077 were assigned to low-dose vaginal misoprostol and 2103 were assigned to vaginal dinoprostone. Compared with vaginal dinoprostone, low-dose vaginal misoprostol had a comparable rate of vaginal birth. Composite adverse perinatal outcomes did not differ between the groups. Compared with vaginal dinoprostone, composite adverse maternal outcomes were significantly lower with low-dose vaginal misoprostol (aOR 0.80, 95% CI 0.65-0.98, P = 0.03, I2 = 0%). CONCLUSIONS: Low-dose vaginal misoprostol and vaginal dinoprostone for IOL are comparable in terms of effectiveness and perinatal safety. However, low-dose vaginal misoprostol is likely to lead to a lower rate of composite adverse maternal outcomes than vaginal dinoprostone.

Monoclonal antibodies for treating early Alzheimer disease-a commentary on recent 'positive' trials.

Recent phase 3 randomised controlled trials of amyloid-targeting monoclonal antibodies in people with pre-clinical or early Alzheimer disease have reported positive results, raising hope of finally having disease-modifying drugs. Given their far-reaching implications for clinical practice, the methods and findings of these trials, and the disease causation theory underpinning the mechanism of drug action, need to be critically appraised. Key considerations are the representativeness of trial populations; balance of prognostic factors at baseline; psychometric properties and minimal clinically important differences of the primary efficacy outcome measures; level of study fidelity; consistency of subgroup analyses; replication of findings in similar trials; sponsor role and potential conflicts of interest; consistency of results with disease causation theory; cost and resource estimates; and alternative prevention and treatment strategies. In this commentary, we show shortcomings in each of these areas and conclude that monoclonal antibody treatment for early Alzheimer disease is lacking high-quality evidence of clinically meaningful impacts at an affordable cost.

Pharmacological non-hormonal treatment options for male infertility: a systematic review and network meta-analysis.

BACKGROUND: Male factor infertility affect up to 50% of couples unable to conceive spontaneously. Several non-hormonal pharmacological treatments have been proposed to boost spermatogenesis and increase chances of conception in men with infertility. Still, no clear evidence exists on the most effective treatment strategy. OBJECTIVE: We aimed to compare the effectiveness of non-hormonal pharmacological treatment options for men with infertility using a systematic review and network meta-analysis. METHODS: We searched MEDLINE, EMBASE, and CENTRAL until October 2023 for randomised/quasi-randomised trials that evaluated any non-hormonal pharmacological treatment options for men with idiopathic semen abnormalities or those with hypogonadism. We performed pairwise and network meta-analyses using a random effect model. We assessed risk of bias, heterogeneity, and network inconsistency. We calculated the mean rank and the surface under the cumulative ranking curve (SUCRA) for each intervention the maximum likelihood to achieve each of reported outcomes. We reported primarily on sperm concentration and other important semen and biochemical outcomes using standardised mean difference (SMD) and 95% confidence-intervals(CI). RESULTS: We included 14 randomised trials evaluating four treatments (Clomiphene citrate, Tamoxifen, Aromatase inhibitors, anti-oxidants) and their combinations in 1342 men. The overall quality of included trials was low. Sperm concentration improved with clomiphene compared to anti-oxidants (SMD 2.15, 95%CI 0.78-3.52), aromatase inhibitor (SMD 2.93, 95%CI 1.23-4.62), tamoxifen (SMD - 1.96, 95%CI -3.57; -0.36) but not compared to placebo (SMD - 1.53, 95%CI -3.52- 0.47). Clomiphene had the highest likelihood to achieve the maximum change in sperm concentration (SUCRA 97.4). All treatments showed similar effect for sperm motility, semen volume, and normal sperm morphology. FSH levels showed significant improvement with clomiphene vs.anti-oxidant (SMD 1.48, 95%CI 0.44-2.51) but not compared to placebo. The evidence networks for LH and testosterone suffered from significant inconsistency (p = 0.01) with similar trend of improvement with clomiphene compared to other treatments but not compared to placebo. CONCLUSION: There is insufficient evidence to support the routine use of Clomiphene, tamoxifen, and aromatase inhibitors to optimise semen parameters in men with infertility. Future randomised trials are needed to confirm the efficacy of clomiphene in improving fertility outcomes in men. PROSPERO: CRD42023430179.

Evidence of publication bias in multiple sclerosis clinical trials: a comparative analysis of published and unpublished studies registered in ClinicalTrials.gov.

BACKGROUND: Complete and timely publication of clinical trials ensures that patients and the medical community are fully informed when making treatment decisions. The aim of this study is to assess the publication of phase III and IV clinical trials on multiple sclerosis (MS) drugs that have been carried out between 2010 and 2019 and to identify the factors associated with their publication in peer-reviewed journals. METHODS: An advanced search in ClinicalTrials.gov was performed and consecutive searches in PubMed, EMBASE and Google Scholar were conducted looking for the associated publications of all completed trials. Study design characteristics, results and other relevant information were extracted. Data was analysed following a case-control design. Clinical trials with associated publications in peer-reviewed journals were the cases and unpublished trials were the controls. A multivariate logistic regression analysis was performed to identify factors associated with trial publication. RESULTS: One hundred and fifty clinical trials were included in the analysis. Ninety-six of them (64.0%) were published in peer-reviewed journals. In the multivariate analysis, factors associated with trial publication were a favourable primary outcome (OR 12.49, 95% CI 1.28 to 122.29) and reaching the originally estimated sample size (OR 41.97, 95% CI 1.96 to 900.48), while those associated with a lower odds of publication were having 20% or more patients lost to follow-up (OR 0.03, 95% CI 0.01 to 0.52) and evaluating drugs intended to improve treatment tolerability (OR 0.01, 95% CI 0.00 to 0.74). CONCLUSIONS: Phase III and IV clinical trials on MS drugs are prone to under-reporting and publication bias. Efforts must be made to promote a complete and accurate dissemination of data in MS clinical research.

Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder.

OBJECTIVE: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. METHODS: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). RESULTS: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). CONCLUSIONS: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. TRIAL REGISTRATION NUMBER: NCT02200770.

Effectiveness of an outpatient rehabilitation programme in patients with neuralgic amyotrophy and scapular dyskinesia: a randomised controlled trial.

BACKGROUND: Neuralgic amyotrophy (NA) is an acute inflammation of nerves within the brachial plexus territory leading to severe pain and multifocal paresis resulting in >60% of patients having residual complaints and functional limitations correlated with scapular dyskinesia. Our primary aim was to compare the effects of multidisciplinary rehabilitation (MR), focused on motor relearning to improve scapular dyskinesia and self-management strategies for reducing pain and fatigue, with usual care (UC) on shoulder, arm and hand functional capability in patients with NA. METHODS: In a non-blinded randomised controlled trial (RCT), patients with NA (aged≥18 years, scapular dyskinesia, >8 weeks after onset) were randomised to either an MR or an UC group. MR consisted of a diagnostic multidisciplinary consultation and eight sessions of physical and occupational therapy. Primary outcome was functional capability of the shoulder, arm and hand assessed with the Shoulder Rating Questionnaire-Dutch Language Version (SRQ-DLV). RESULTS: We included 47 patients with NA; due to drop-out, there were 22 participants in MR and 15 in UC for primary analysis. The mean group difference adjusted for sex, age and SRQ-DLV baseline score was 8.60 (95%CI: 0.26 to 16.94, p=0.044). The proportion attaining a minimal clinically relevant SRQ-DLV improvement (≥12) was larger for the MR group (59%) than the UC group (33%) with a number needed to treat of 4. CONCLUSION: This RCT shows that an MR programme focused on motor relearning to improve scapular dyskinesia, combined with self-management strategies for reducing pain and fatigue, shows more beneficial effects on shoulder, arm and hand functional capability than UC in patients with NA. TRIAL REGISTRATION NUMBER: NCT03441347.

Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: results from the CENTAUR trial.

BACKGROUND: An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS. We performed analyses of neuroinflammatory biomarkers associated with ALS in the literature, including YKL-40 (also known as chitinase-3-like protein 1), chitinase 1 (CHIT1) and C reactive protein (CRP), in plasma samples collected in CENTAUR. METHODS: Log10-transformed plasma biomarker measurements were analysed using a linear mixed-effects model. Correlation between paired biomarker concentrations and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores was assessed via Pearson correlation coefficients. RESULTS: By week 24, geometric least squares mean YKL-40 plasma concentration decreased by approximately 20% (p=0.008) and CRP by 30% (p=0.048) in the PB and TURSO versus placebo group. YKL-40 (r of -0.21; p<0.0001) and CRP (r of -0.19; p=0.0002) concentration correlated with ALSFRS-R total score. CHIT1 levels were not significantly different between groups. CONCLUSIONS: YKL-40 and CRP plasma levels were significantly reduced in participants with ALS receiving PB and TURSO in CENTAUR and correlated with disease progression. These findings suggest YKL-40 and CRP could be treatment-sensitive biomarkers in ALS, pending further confirmatory studies. TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/study/NCT03127514.

The impact of iterative removal of low-information cluster-period cells from a stepped wedge design.

BACKGROUND: Standard stepped wedge trials, where clusters switch from the control to the intervention condition in a staggered manner, can be costly and burdensome. Recent work has shown that the amount of information contributed by each cluster in each period differs, with some cluster-periods contributing a relatively small amount of information. We investigate the patterns of the information content of cluster-period cells upon iterative removal of low-information cells, assuming a model for continuous outcomes with constant cluster-period size, categorical time period effects, and exchangeable and discrete-time decay intracluster correlation structures. METHODS: We sequentially remove pairs of "centrosymmetric" cluster-period cells from an initially complete stepped wedge design which contribute the least amount of information to the estimation of the treatment effect. At each iteration, we update the information content of the remaining cells, determine the pair of cells with the lowest information content, and repeat this process until the treatment effect cannot be estimated. RESULTS: We demonstrate that as more cells are removed, more information is concentrated in the cells near the time of the treatment switch, and in "hot-spots" in the corners of the design. For the exchangeable correlation structure, removing the cells from these hot-spots leads to a marked reduction in study precision and power, however the impact of this is lessened for the discrete-time decay structure. CONCLUSIONS: Removing cluster-period cells distant from the time of the treatment switch may not lead to large reductions in precision or power, implying that certain incomplete designs may be almost as powerful as complete designs.

Minimisation for the design of parallel cluster-randomised trials: An evaluation of balance in cluster-level covariates and numbers of clusters allocated to each arm.

BACKGROUND: Cluster-randomised trials often use some form of restricted randomisation, such as stratified- or covariate-constrained randomisation. Minimisation has the potential to balance on more covariates than blocked stratification and can be implemented sequentially unlike covariate-constrained randomisation. Yet, unlike stratification, minimisation has no inbuilt guard to maintain close to a 1:1 allocation. A departure from a 1:1 allocation can be unappealing in a setting with a small number of allocation units such as cluster randomisation which typically include about 30 clusters. METHODS: Using simulation (10,000 per scenario), we evaluate the performance of a range of minimisation procedures on the likelihood of a 1:1 allocation of clusters (10-80 clusters) to treatment arms, along with its performance on covariate imbalance. The range of minimisation procedures includes varying: the proportion of clusters allocated to the least imbalanced arm (known as the stochastic element) - between 0.7 and 1, percentage of first clusters allocated completely at random (known as the bed-in period) - between 0% and 20% and adding 'number of clusters allocated to each arm' as a covariate in the minimisation algorithm. We additionally include a comparison of stratifying and then minimising within key strata (such as country within a multi country cluster trial) as a potential aid to increasing balance. RESULTS: Minimisation is unlikely to result in an exact 1:1 allocation unless the stochastic element is set higher than 0.9. For example, with 20 clusters, 2 binary covariates and setting the stochastic element to 0.7: only 41% of the possible randomisations over the 10,000 simulations achieved a 1:1 allocation. While typical sizes of imbalance were small (a difference of two clusters per arm), allocations as extreme as of 10:10 were observed. Adding the 'number of clusters' into the minimisation algorithm reduces this risk slightly, but covariate imbalance increases slightly. Stratifying and then minimising within key strata improve balance within strata but increase imbalance across all clusters, both on the number of clusters and covariate imbalance. CONCLUSION: In cluster trials, where there are typically about 30 allocation units, when using minimisation, unless the stochastic element is set very high, there is a high risk of not achieving a 1:1 allocation, and a small but nonetheless real risk of an extreme departure from a 1:1 allocation. Stratification with minimisation within key strata (such as country) improves the balance within strata although compromises overall balance.

Dual trigger improves the pregnancy rate in fresh in vitro fertilization (IVF) cycles compared with the human chorionic gonadotropin (hCG) trigger: a systematic review and meta-analysis of randomized trials.

PROPOSE: The purpose of this study was to assess whether the implementation of a "dual trigger" approach, utilizing gonadotropin-releasing hormone agonist (GnRHa) and human chorionic gonadotropin (hCG) in the GnRH antagonist protocol for in vitro fertilization (IVF), leads to improved pregnancy outcomes compared to the conventional hCG trigger alone. Previous meta-analyses have not provided sufficient evidence to support the superiority of the dual trigger over the hCG trigger in fresh or frozen embryo transfer cycles. Thus, a systematic review and meta-analysis of randomized trials were conducted to provide a comprehensive evaluation of the impact of the dual trigger on pregnancy outcomes in fresh or frozen embryo transfer cycles. METHOD: A systematic review and meta-analysis of randomised controlled trials (RCTs) were conducted. We searched the Medline and Embase databases for articles up to 2023 by using search terms: "dual trigger," "GnRHa," "hCG," "IVF." Eligible RCTs comparing the dual trigger with the hCG trigger were included. The primary outcome was the live birth rate (LBR) per cycle. The secondary outcomes were the number of oocytes retrieved, number of mature oocytes retrieved, implantation rate, biochemical pregnancy rate, CPR, miscarriage rate and ovarian hyperstimulation syndrome (OHSS) rate per started cycle We compared the oocyte maturation and pregnancy outcomes in the dual trigger and hCG trigger groups. In patients undergoing fresh embryo transfer (ET) and frozen-thawed ET, we also conducted a subgroup analysis to evaluate whether dual trigger improves the clinical pregnancy rate (CPR). RESULTS: We included 10 randomised studies, with 825 participants in the dual trigger group and 813 in the hCG trigger group. Compared with the hCG trigger, dual trigger was associated with a significant increase in the LBR per cycle (odds ratio (OR) = 1.61[1.16, 2.25]), number of oocytes retrieved (mean difference [MD] = 1.05 [0.43, 1.68]), number of mature oocytes retrieved (MD = 0.82 [0. 84, 1.16]), and CPR (OR = 1.48 [1.08, 2.01]). Subgroup analyses revealed that dual trigger was associated with a significantly increased CPR in patients who received fresh ET (OR = 1.68 [1.14, 2.48]). By contrast, the dual trigger was not associated with an increased CPR in the patient group with frozen-thawed ET (OR = 1.15 [0.64, 2.08]). CONCLUSION: The dual trigger was associated with a significantly higher number of retrieved oocytes, number of mature oocytes, CPR, and LBR in IVF than the hCG trigger. The beneficial effect for fresh ET cycles compared with frozen-thawed ET might be associated with increased endometrial receptivity. RELEVANCE: After dual trigger, delaying ET due to the concern of endometrial receptivity might not be needed.

A nurse-led intervention to reduce the incidence and duration of delirium among adults admitted to intensive care: A stepped-wedge cluster randomised trial.

BACKGROUND: Delirium is an acute change in behaviour, characterised by a fluctuating course, inattention, and disorganised thinking. For critically ill adults in the intensive care, the incidence of delirium has been reported to be at least 30% and is associated with both short-term and long-term complications, longer hospital stay, increased risk of mortality, and long-term cognitive problems. AIM: The objective of this study was to determine the effectiveness of a nurse-led delirium-prevention protocol in reducing the incidence and duration of delirium among adults admitted to intensive care. METHODS: A hybrid stepped-wedge cluster randomised controlled trial was conducted to assess the effectiveness of the implementation and dissemination of the nurse-led intervention to reduce the incidence and duration of delirium among adults admitted to the four adults intensive care units in the southwest of Sydney, Australia. RESULTS: Between May 2019 and February 2020, over a 10-month period, 2618 admissions, among 2566 patients, were included in the study. After an initial 3-month baseline period, each month there was a random crossover to the nurse-led intervention in one of the four intensive care units, and by the 7th month of the trial, all units were exposed to the intervention for at least 3 months. The incidence of acute delirium was observed to be 10.7% (95% confidence interval [CI] = 9.1-12.4%), compared to 14.1% (95% CI = 12.2-16.2%) during the preintervention (baseline) period (adjusted rate ratio [adjRR] = 0.78, 95% CI = 0.57-1.08, p = 0.134). The average delirium-free-days for these preintervention and postintervention periods were 4.1 days (95% CI = 3.9-4.3) and 4.4 days (95% CI = 4.2-4.5), respectively (adjusted difference = 0.24 days [95% CI = -0.12 to 0.60], p = 0.199). CONCLUSION: Following the introduction of a nurse-led, nonpharmacological intervention to reduce the burden of delirium, among adults admitted to intensive care, we observed no statistically significant decrease in the incidence of delirium or the duration of delirium.

Heterogeneity in pragmatic randomised trials: sources and management.

BACKGROUND: Pragmatic trials aim to generate evidence to directly inform patient, caregiver and health-system manager policies and decisions. Heterogeneity in patient characteristics contributes to heterogeneity in their response to the intervention. However, there are many other sources of heterogeneity in outcomes. Based on the expertise and judgements of the authors, we identify different sources of clinical and methodological heterogeneity, which translate into heterogeneity in patient responses-some we consider as desirable and some as undesirable. For each of them, we discuss and, using real-world trial examples, illustrate how heterogeneity should be managed over the whole course of the trial. MAIN TEXT: Heterogeneity in centres and patients should be welcomed rather than limited. Interventions can be flexible or tailored and control interventions are expected to reflect usual care, avoiding use of a placebo. Co-interventions should be allowed; adherence should not be enforced. All these elements introduce heterogeneity in interventions (experimental or control), which has to be welcomed because it mimics reality. Outcomes should be objective and possibly routinely collected; standardised assessment, blinding and adjudication should be avoided as much as possible because this is not how assessment would be done outside a trial setting. The statistical analysis strategy must be guided by the objective to inform decision-making, thus favouring the intention-to-treat principle. Pragmatic trials should consider including process analyses to inform an understanding of the trial results. Needed data to conduct these analyses should be collected unobtrusively. Finally, ethical principles must be respected, even though this may seem to conflict with goals of pragmatism; consent procedures could be incorporated in the flow of care.

Fat-rich versus carbohydrate-rich nutrition in ALS: a randomised controlled study.

OBJECTIVE: There is growing evidence that the course of amyotrophic lateral sclerosis (ALS) may be influenced beneficially by applying high-caloric food supplements (HCSs). However, it is unknown which composition of nutrients offers optimal tolerability and weight gain. METHODS: We conducted a randomised controlled study (Safety and Tolerability of Ultra-high-caloric Food Supplements in Amyotrophic Lateral Sclerosis (ALS); TOLCAL-ALS study) in 64 patients with possible, probable or definite ALS according to El Escorial criteria. Patients were randomised into four groups: a high-caloric fatty supplement (HCFS; 405 kcal/day, 100% fat), an ultra-high-caloric fatty supplement (UHCFS; 810 kcal/day, 100% fat), an ultra-high-caloric, carbohydrate-rich supplement (UHCCS; 900 kcal/day, 49% carbohydrates) and an open control (OC) group without any supplement. The primary endpoint was tolerability. Patients were followed up over 4 weeks. RESULTS: Gastrointestinal side effects were most frequent in the UHCFS group (75.0%), while loss of appetite was most frequent in the UHCCS group (35.3%). During intervention, patients gained +0.9 kg/month of body weight (IQR -0.9 to 1.5; p=0.03) in the HCFS group and +0.9 kg/month (IQR -0.8 to 2.0; p=0.05) in the UHCFS group. A non-significant trend for weight gain (+0.6 kg/month (IQR -0.3 to 1.9; p=0.08)) was observed in the UHCCS group. Patients in OC group continued to lose body weight (-0.5 kg/month, IQR -1.4 to 1.3; p=0.42). INTERPRETATION: The findings suggest that HCSs frequently cause mild to moderate tolerability issues in patients with ALS, most notably gastrointestinal symptoms in high-fat supplements, and loss of appetite in high-carbohydrate supplements. All three HCSs tested are suited to increase body weight.