Authors Of Trials Research Articles

Systematic review and meta-analysis of intravenous iron therapy for adults with non-anaemic iron deficiency: An abridged Cochrane review.

Iron is an essential nutrient for oxygen supply and aerobic metabolism. Iron deficiency impacts cellular respiration and mitochondrial energy metabolism, which can lead to reduced skeletal muscle function and muscle mass, causing sarcopenia. Intravenous iron offers the ability to rapidly correct iron deficiency, but the functional impact on patient mental and physical health is unclear. We assessed the effects of intravenous iron therapy on physical function and quality of life in the treatment of adults with non-anaemic iron deficiency. An update and reanalysis of a previously published Cochrane systematic review was performed to assess randomized controlled trials that compared any intravenous iron preparation with placebo in adults. The primary functional outcome measure was physical performance as defined by the trial authors. Secondary outcome measures included fatigue and quality-of-life scores, and adverse effects at the end of follow-up. Biochemical efficacy was assessed by change in serum ferritin and haemoglobin concentration levels. Twenty-one randomized controlled trials, comprising 3514 participants, were included. Intravenous iron compared with placebo resulted in significantly increased physical function measured by mean peak oxygen consumption (mean difference [MD] 1.77mL/kg/min, 95% confidence interval [CI] 0.57 to 2.97). An overall improvement in fatigue was seen (standardized MD 0.30, 95% CI -0.52 to -0.09) but no overall difference in quality of life (MD 0.15, 95% CI -0.01 to 0.31). Biochemically, intravenous iron resulted in improved serum ferritin (MD 245.52μg/L, 95% CI 152.1 to 338.9) and haemoglobin levels (MD 4.65g/L, 95% CI 2.53 to 6.78). There was a higher risk of developing mild adverse events in the intravenous iron group compared with the placebo group (risk ratio 1.77, 95% CI 1.10 to 2.83); however, no differences were seen in serious adverse events (risk difference 0, 95% CI -0.01 to 0.01). The quality of evidence was rated 'low' and 'very low' for all outcome variables, except for fatigue, mainly due to most studies being judged as having a high risk of bias. In non-anaemic iron-deficient adults, the use of intravenous iron compared with placebo improved physical function and reduced fatigue scores. However, we remain uncertain about theefficacy in this population due to low-quality evidence, and there is a need for further studies to address potential impact on overall quality of life.

Balloon catheters versus vaginal prostaglandins for labour induction (CPI Collaborative): an individual participant data meta-analysis of randomised controlled trials

Induction of labour is one of the most common obstetric interventions globally. Balloon catheters and vaginal prostaglandins are widely used to ripen the cervix in labour induction. We aimed to compare the effectiveness and safety profiles of these two induction methods. We did an individual participant data meta-analysis comparing balloon catheters and vaginal prostaglandins for cervical ripening before labour induction. We systematically identified published and unpublished randomised controlled trials that completed data collection between March 19, 2019, and May 1, 2021, by searching the Cochrane Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and PubMed. Further trials done before March 19, 2019, were identified through a recent Cochrane review. Data relating to the combined use of the two methods were not included, only data from women with a viable, singleton pregnancy were analysed, and no exclusion was made based on parity or membrane status. We contacted authors of individuals trials and participant-level data were harmonised and recoded according to predefined definitions of variables. Risk of bias was assessed with the ROB2 tool. The primary outcomes were caesarean delivery, indication for caesarean delivery, a composite adverse perinatal outcome, and a composite adverse maternal outcome. We followed the intention-to-treat principle for the main analysis. The primary meta-analysis used two-stage random-effects models and the sensitivity analysis used one-stage mixed models. All models were adjusted for maternal age and parity. This meta-analysis is registered with PROSPERO (CRD42020179924). Individual participant data were available from 12 studies with a total of 5460 participants. Balloon catheters, compared with vaginal prostaglandins, did not lead to a significantly different rate of caesarean delivery (12 trials, 5414 women; crude incidence 27·0%; adjusted OR [aOR] 1·09, 95% CI 0·95-1·24; I2=0%), caesarean delivery for failure to progress (11 trials, 4601 women; aOR 1·20, 95% CI 0·91-1·58; I2=39%), or caesarean delivery for fetal distress (10 trials, 4441 women; aOR 0·86, 95% CI 0·71-1·04; I2=0%). The composite adverse perinatal outcome was lower in women who were allocated to balloon catheters than in those allocated to vaginal prostaglandins (ten trials, 4452 neonates, crude incidence 13·6%; aOR 0·80, 95% CI 0·70-0·92; I2=0%). There was no significant difference in the composite adverse maternal outcome (ten trials, 4326 women, crude incidence 22·7%; aOR 1·02, 95% CI 0·89-1·18; I2=0%). In induction of labour, balloon catheters and vaginal prostaglandins have comparable caesarean delivery rates and maternal safety profiles, but balloon catheters lead to fewer adverse perinatal events. Australian National Health and Medical Research Council and Monash Health Emerging Researcher Fellowship.

Dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatment: protocol for a systematic review and individual participant data meta-analysis

IntroductionDietary and/or physical activity interventions are often recommended for women with overweight or obesity as the first step prior to fertility treatment. However, randomised controlled trials (RCTs) so far have...

The clear reporting of study limitations in the reports of orthodontic randomized controlled trials is not routinely undertaken: A systematic search and review

To ensure accurate interpretation of the generalizability of trial findings, the clear reporting of limitations is imperative. This review aimed to assess whether study limitations are reported in full-text articles of orthodontic randomized controlled trials (RCTs). Associations between the trial characteristics and the reporting of limitations were also explored. In this review, RCTs published between January 1, 2011 and December 31, 2021 were identified from 5 orthodontic journals with the highest impact factor. Trial characteristics were extracted from the individual reports. To ascertain if limitations were reported in reports of RCTs, a criterion was developed from previously published literature. Descriptive statistics and associations between the reporting of limitations and trial characteristics were explored. Three hundred and eighty-six trials were analyzed. In relation to the criterion, the clear reporting of trial limitations was deficient across several areas. Most RCTs were published in 2021 (12.7%), had authors based in Asia and other regions (42.2%), did not have a statistician involved (85.8%), and were materials and devices type trials (48.7%). An association was detected between the year of publication, impact factor, journal and journal submission instructions, and reporting of study limitations. More recent trials published in journals with higher impact factors were more likely to report limitations in the main manuscript. Journals with suggested or mandatory instructions were more likely to report limitations in the trials they publish than journals with no reference to reporting limitations in the manuscript in the journal submission instructions. Authors of trials should not view the reporting of limitations as a weakness of their trial but rather as an opportunity to provide further information to allow clinicians to fully interpret the generalizability of the results. Scientific journals should stipulate and facilitate the reporting of study limitations within manuscripts.

Absolute treatment effects for the primary outcome and all-cause mortality in the cardiovascular outcome trials in type 2 diabetes: a meta-analysis of individual patient data

Abstract Background and purpose Treatment effects from the large cardiovascular outcome trials (CVOTs) in diabetes are almost exclusively communicated as hazard ratios, although reporting guidelines recommend to report treatment effects also on an absolute scale, e.g. as numbers needed to treat (NNT). We aimed to analyze NNT in CVOTs of novel oral antidiabetic drugs comparing dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, or sodium-glucose cotransporter-2 (SGLT2) inhibitors to placebo. Methods and results We extracted individual time-to-event information for the primary outcome and all-cause mortality from 19 CVOTs that compared DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors to placebo. We estimated Weibull models for each trial and outcome and derived monthly NNTs. NNTs were summarized across all trials and within drug-classes by random effects meta-analysis methods. Treatment effects in the CVOTs appear smaller if they are reported as NNTs: Overall, 60 (95%-CI: 40–124) patients have to be treated for 29 months (the median follow-up time across all trials) to avoid a single event of the primary outcome, and 101 (95%-CI: 69–191) patients have to be treated for 39 months to avoid a single death. Conclusion We found that the respective treatment effects of novel oral antidiabetic drugs look less impressive when communicated on an absolute scale, as numbers needed to treat. For a valid overall picture of the benefit of these drugs, trial authors should thus also report treatment effects on an absolute scale. Funding Acknowledgement Type of funding sources: None.

S609 Gender Disparities in the Clinical Trial Enterprise: Lead Authorship in Gastroenterology Trials, 2013-2019

Introduction: Clinical trials are considered the gold standard for evaluating the safety and efficacy of new therapies and generating evidence-based guidelines. However, there is growing concern regarding gender inequality at the leadership level. Diversity in clinical trial leadership is associated with more diverse trial participants, which improves the generalizability of results. The objective of this study is to evaluate gender differences in lead authorship among gastroenterology clinical trials registered in the primary clinical trial database, ClinicalTrials.gov. Methods: We downloaded records of interventional clinical trials registered on ClinicalTrials.gov starting between January 1, 2013 and December 31, 2019. A study set consisting of only gastroenterology and hepatology trials was then created using disease condition terms (both Medical Subject Heading [MeSH] and non-MeSH) from the National Library of Medicine. Records were manually reviewed and verified as relating to either gastroenterology or hepatology. The ClinicalTrials.gov identifier was extracted for each entry and a linked search was performed on PubMed for associated publications. From this study set, the first randomized controlled trial (RCT) was evaluated for lead authorship gender and the publication journal’s impact factor. Results: 9,705 trials were manually reviewed, from which 4,182 were verified as trials relating to gastroenterology or hepatology. 1,148 trials (27.45%) had results posted as of January 1, 2022, and 462 (11.05%) had an associated publication indexed within PubMed. The gender was determined for 100% of lead authors of published RCTs. The lead author was male in 333 (72.08%) trials and female in 129 (27.92%) trials. The mean impact factor for male first-authored publications was 16.17 ± 1.06, while the mean for female first-authored publications was 18.73 ± 5.55. Conclusion: Women are under-represented as leaders of gastroenterology clinical trials, constituting fewer than 3 in 10 lead authors of gastroenterology trials in the examined study period. The rate of female first-authorship lags behind the broader rate of women entering the field. Recalibration efforts must address the structure and processes that lead to the gender gap in the clinical trial enterprise.

Scoping and targeted reviews to support development of SPIRIT and CONSORT extensions for randomised controlled trials with surrogate primary endpoints: protocol

IntroductionUsing a surrogate endpoint as a substitute for a primary patient-relevant outcome enables randomised controlled trials (RCTs) to be conducted more efficiently, that is, with shorter time, smaller sample size...

Repetitive peripheral magnetic stimulation for impairment and disability in people after stroke.

Repetitive peripheral magnetic stimulation (rPMS) is a non-invasive treatment method that can penetrate to deeper structures with painless stimulation to improve motor function in people with physical impairment due to brain or nerve disorders. rPMS for people after stroke has proved to be a feasible approach to improving activities of daily living and functional ability. However, the effectiveness and safety of this intervention for people after stroke remain uncertain. This is an update of the review published in 2019. To assess the effects of rPMS for improving activities of daily living and functional ability in people after stroke. We searched the Cochrane Stroke Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE; Embase; the Cumulative Index to Nursing and Allied Health Literature (CINAHL); PsycINFO; the Allied and Complementary Medicine Database (AMED); OTseeker: Occupational Therapy Systematic Evaluation of Evidence; the Physiotherapy Evidence Database (PEDro); Ichushi-Web; and six ongoing trial registries on 5 October 2021. We screened reference lists and contacted experts in the field. We placed no restrictions on the language or date of publication when searching the electronic databases. We included randomised controlled trials (RCTs) conducted to assess the therapeutic effect of rPMS for people after stroke. The following comparisons were eligible for inclusion: 1) active rPMS only compared with 'sham' rPMS (a very weak form of stimulation or a sound only); 2) active rPMS only compared with no intervention; 3) active rPMS plus rehabilitation compared with sham rPMS plus rehabilitation; and 4) active rPMS plus rehabilitation compared with rehabilitation only. Two review authors independently assessed studies for inclusion in the review. The same review authors assessed methods and risk of bias, undertook data extraction, and evaluated the certainty of the evidence using the GRADE approach. We contacted trial authors to request unpublished information if necessary. Any disagreements were resolved through discussion. We included four trials (three parallel-group RCTs and one cross-over trial) involving a total of 139 participants. This result was unchanged from the review published in 2019. Blinding of participants and physicians was well reported in three trials, with no information on whether personnel were blinded in one trial. We judged the overall risk of bias across trials as low. Only two trials (with 63 and 18 participants, respectively) provided sufficient information to be included in the meta-analysis. We found no clear effect of rPMS on activities of daily living at the end of treatment (mean difference (MD) -3.00, 95% confidence interval (CI) -16.35 to 10.35; P = 0.66; 1 trial; 63 participants; low-certainty evidence) and at the end of follow-up (MD -2.00, 95% CI -14.86 to 10.86; P = 0.76; 1 trial; 63 participants; low-certainty evidence) when comparing rPMS plus rehabilitation versus sham rPMS plus rehabilitation. We found no statistical difference in improvement of upper limb function at the end of treatment (MD 2.00, 95% CI -4.91 to 8.91; P = 0.57; 1 trial; 63 participants; low-certainty evidence) and at the end of follow-up (MD 4.00, 95% CI -2.92 to 10.92; P = 0.26; 1 trial; 63 participants; low-certainty evidence) when comparing rPMS plus rehabilitation versus sham rPMS plus rehabilitation. We observed a decrease in spasticity of the elbow at the end of follow-up (MD -0.41, 95% CI -0.89 to 0.07; 1 trial; 63 participants; low-certainty evidence) when comparing rPMS plus rehabilitation versus sham rPMS plus rehabilitation. In terms of muscle strength, rPMS treatment was not associated with improved muscle strength of the ankle dorsiflexors at the end of treatment (MD 3.00, 95% CI -2.44 to 8.44; P = 0.28; 1 trial; 18 participants; low-certainty evidence) when compared with sham rPMS. No studies provided information on lower limb function or adverse events, including death. Based on the GRADE approach, we judged the certainty of evidence related to the primary outcome as low, owing to the small sample size of the studies. There is insufficient evidence to permit the drawing of any conclusions about routine use of rPMS for people after stroke. Additional trials with large sample sizes are needed to provide robust evidence for rPMS after stroke.

Comparative Analysis of Sedative Efficacy of Dexmedetomidine and Midazolam in Pediatric Dental Practice: A Systematic Review and Meta-Analysis.

Children are particularly terrified of having dental treatment. They are physically resistant, frail, and unwilling to cooperate. This severe distress during the pre-operative phase could cause the dentist to have issues with behavior control. Additionally, it may make pediatric dental treatments less effective. In order to reduce anxiety and control behavior in children receiving dental care, sedation is a pharmacological management technique that supports the provision of effective and high-quality dental services. The aim is to compare and evaluate the efficacy of sedative agents like dexmedetomidine and midazolam in pediatric dental practice. A thorough review of the literature was conducted using electronic databases like “MEDLINE, PubMed, and CENTRAL (Cochrane Central Register of Controlled Trials), as well as the World Health Organization International Clinical Trials Registry Platform, www.clinicaltrials.gov, conference proceedings abstracts, a bibliography of pertinent references, and manual searches of journals, conferences, and books”. There were no restrictions on the language or the date of publication when searching the electronic databases.Randomized controlled trials were included which compared dexmedetomidine and midazolam in children up to 16 years of age subjected to dental treatment. Information on procedures, participants, interventions, outcome measures, and results were independently extracted by three review writers (TS, SL, and RO). Trial authors were contacted for papers that were confusing or lacking information. The risk of bias was evaluated for each study. We adhered to the Cochrane statistical recommendations. Three trials totaling 229 participants were included. All three studies were rated as having a low risk of bias, with none of them having a high or unclear risk. Meta-analysis was done for the available data for the primary outcomes like sedation level and recovery time. We searched for randomized controlled trials up to Jan 31, 2020. Participants are randomly assigned to an intervention or control group in randomized controlled trial research. While patients in the control group often get a placebo therapy or procedure, those in the interventional group receive the treatment being studied.We found three studies eligible to include in the review. One study evaluated 73 individuals who received general anesthesia for dental treatment. There were 72 and 84 individuals in the second and third investigations, respectively. All the participants of the three studies were divided randomly into two groups and were subjected to dexmedetomidine and midazolam as sedative agents. We gave the evidence an "extremely low certainty" rating. Because there are just three short trials with unusual parameters for comparison, the results are questionable. Overall, the results do not allow us to draw any firm conclusions. Three randomized controlled trials included in this systematic review reported data with varying conclusions; hence we recommend more randomized controlled trials to be conducted on this subject matter.

Access to unpublished protocols and statistical analysis plans of randomised trials

BackgroundAccess to protocols and statistical analysis plans (SAPs) increases the transparency of randomised trial by allowing readers to identify and interpret unplanned changes to study methods, however they are often not made publicly available. We sought to determine how often study investigators would share unavailable documents upon request.MethodsWe used trials from two previously identified cohorts (cohort 1: 101 trials published in high impact factor journals between January and April of 2018; cohort 2: 100 trials published in June 2018 in journals indexed in PubMed) to determine whether study investigators would share unavailable protocols/SAPs upon request. We emailed corresponding authors of trials with no publicly available protocol or SAP up to four times.ResultsOverall, 96 of 201 trials (48%) across the two cohorts had no publicly available protocol or SAP (11/101 high-impact cohort, 85/100 PubMed cohort). In total, 8/96 authors (8%) shared some trial documentation (protocol only [n = 5]; protocol and SAP [n = 1]; excerpt from protocol [n = 1]; research ethics application form [n = 1]). We received protocols for 6/96 trials (6%), and a SAP for 1/96 trial (1%). Seventy-three authors (76%) did not respond, 7 authors responded (7%) but declined to share a protocol or SAP, and eight email addresses were invalid (8%). A total of 329 emails were sent (an average of 41 emails for every trial which sent documentation). After emailing authors, the total number of trials with an available protocol increased by only 3%, from 52% in to 55%.ConclusionsMost study investigators did not share their unpublished protocols or SAPs upon direct request. Alternative strategies are needed to increase transparency of randomised trials and ensure access to protocols and SAPs.

Action observation for upper limb rehabilitation after stroke.

Action observation (AO) is a physical rehabilitation approach that facilitates the occurrence of neural plasticity through the activation of the mirror-neural system, promoting motor recovery in people with stroke. To assess whether AO enhances upper limb motor function in people with stroke. We searched the Cochrane Stroke Group Trials Register (last searched 18 May 2021), the Cochrane Central Register of Controlled Trials (18 May 2021), MEDLINE (1946 to 18 May 2021), Embase (1974 to 18 May 2021), and five additional databases. We also searched trial registries and reference lists. Randomized controlled trials (RCTs) of AO alone or associated with physical practice in adults after stroke. The primary outcome was upper limb (arm and hand) motor function. Secondary outcomes included dependence on activities of daily living (ADL), motor performance, cortical activation, quality of life, and adverse effects. Two review authors independently selected trials according to the predefined inclusion criteria, extracted data, assessed risk of bias using RoB 1, and applied the GRADE approach to assess the certainty of the evidence. The reviews authors contacted trial authors for clarification and missing information. We included 16 trials involving 574 individuals. Most trials provided AO followed by the practice of motor actions. Training varied between 1 day and 8 weeks of therapy, 10 to 90 minutes per session. The time of AO ranged from 1 minute to 10 minutes for each motor action, task or movement observed. The total number of motor actions ranged from 1 to 3. Control comparisons included sham observation, physical therapy, and functional activity practice. AO improved arm function (standardized mean difference (SMD) 0.39, 95% confidence interval (CI) 0.17 to 0.61; 11 trials, 373 participants; low-certainty evidence); and improved hand function (mean difference (MD) 2.76, 95% CI 1.04 to 4.49; 5 trials, 178 participants; low-certainty evidence). AO did not improve ADL performance (SMD 0.37, 95% CI -0.34 to 1.08; 7 trials, 302 participants; very low-certainty evidence), or quality of life (MD 5.52, 95% CI -30.74 to 41.78; 2 trials, 30 participants; very low-certainty evidence). We were unable to pool the other secondary outcomes (motor performance and cortical activation). Only two trials reported adverse events without significant adverse effects. The effects of AO are small for arm function compared to any control group; for hand function the effects are large, but not clinically significant. For both, the certainty of evidence is low. There is no evidence of benefit or detriment from AO on ADL and quality of life of people with stroke; however, the certainty of evidence is very low. As such, our confidence in the effect estimate is limited because it will likely change with future research.

Absolute treatment effects for the primary outcome and all-cause mortality in the cardiovascular outcome trials of new antidiabetic drugs: a meta-analysis of digitalized individual patient data

AimsTreatment effects from the large cardiovascular outcome trials (CVOTs) of new antidiabetic drugs are almost exclusively communicated as hazard ratios, although reporting guidelines recommend to report treatment effects also on an absolute scale, e.g. as numbers needed to treat (NNT). We aimed to analyse NNTs in CVOTs comparing dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, or sodium–glucose cotransporter-2 (SGLT2) inhibitors to placebo.MethodsWe digitalized individual time-to-event information for the primary outcome and all-cause mortality from 19 CVOTs that compared DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors to placebo. We estimated Weibull models for each trial and outcome and derived monthly NNTs. NNTs were summarized across all trials and within drug classes by random effects meta-analysis methods.ResultsTreatment effects in the CVOTs appear smaller if they are reported as NNTs: Overall, 100 (95%-CI: 60, 303) patients have to be treated for 29 months (the median follow-up time across all trials) to avoid a single event of the primary outcome, and 128 (95%-CI: 85, 265) patients have to be treated for 39 months to avoid a single death. NNT time courses are very similar for GLP-1 receptor agonists and SGLT2 inhibitors, whereas treatment effects with DPP-4 inhibitors are smaller.ConclusionsWe found that the respective treatment effects look less impressive when communicated on an absolute scale, as numbers needed to treat. For a valid overall picture of the benefit of new antidiabetic drugs, trial authors should also report treatment effects on an absolute scale.

Promoting positive parenting and mental wellbeing in Hong Kong Chinese parents: A pilot cluster randomised controlled trial.

Effective and brief positive parenting interventions could be adopted widely, but evidence is limited. We aimed to evaluate the effectiveness of a positive parenting programme in Hong Kong Chinese parents. We conducted a pilot cluster randomised controlled trial in 2017 in 144 Hong Kong Chinese parents (84.7% women, mean age 42.5 [SD 5.87] years) of school-age children (mean age 10.9 [2.8] years) in 4 family service centres (clusters). The intervention included two 2-hour interactive talks (4 hours in total). The contents covered skills of giving praise, showing appreciation and playing enjoyable family games. The control group was offered the intervention after all the data were collected. Praise, appreciation and enjoyment related behaviours were measured as primary outcomes at baseline, 1 month and 3 months. The secondary outcomes were subjective happiness, wellbeing, personal health and happiness, family health, family happiness and harmony, and family relationship. After the completion of all assessments, five focus group discussions with the parents and four individual in-depth interviews with community service providers were conducted to explore their experiences. Compared with the control group (n = 69), the intervention group (n = 75) showed greater positive changes in appreciation and enjoyment at 3 months with small effect sizes (d = 0.42 and 0.32, respectively), and greater improvements in the secondary outcomes at 3 months with small effect sizes (d: 0.29-0.48). In the focus groups, the parents reported more praise to their children, better temper control, more focus on their children's strengths and better family relationships. According to the service providers, most of the parents enjoyed the activities. The brief intervention in community settings with the engagement of community service providers has shown preliminary effectiveness in promoting positive parenting and mental wellbeing of Hong Kong Chinese parents. The authors confirm that all ongoing and related trials for this intervention are registered. The study reported in this manuscript is registered as clinical trial at clinicaltrials.gov: NCT03282071. https://clinicaltrials.gov/ct2/show/NCT03282071.

Inhaled nitric oxide for treating pain crises in people with sickle cell disease.

Inhaled nitric oxide for treating pain crises in people with sickle cell disease.

Getting it wrong most of the time? Comparing trialists’ choice of primary outcome with what patients and health professionals want

BackgroundRandomised trials support improved decision-making through the data they collect. One important piece of data is the primary outcome — so called because it is what the investigators decide is the most important. Secondary outcomes provide additional information to support decision-making. We were interested in knowing how important patients and healthcare professionals consider the outcomes (especially the primary outcome) measured in a selection of published trials.MethodsThe work had three stages: (1) We identified a body of late-stage trials in two clinical areas, breast cancer management and nephrology. (2) We identified the primary and secondary outcomes for these trials. (3) We randomly ordered these outcomes and presented them to patients and healthcare professionals (with experience of the clinical area), and we asked them to rank the importance of the outcomes. They were not told which outcomes trial authors considered primary and secondary.ResultsIn our sample of 44 trials with 46 primary outcomes, 29 patients, one patient representative and 12 healthcare professionals together ranked the primary outcome as the most important outcome 13/46 times or 28%. Breast cancer patients and healthcare professionals considered the primary outcome to be the most important outcome for 8/21 primary outcomes chosen by trialists. For nephrology, the equivalent figure was 5/25. The primary outcome appeared in a respondent’s top 5 ranked outcomes 151/178 (85%) times for breast cancer and 225/259 (87%) times for nephrology even if the primary was not considered the most important outcome.ConclusionsThe primary outcome in a trial is the most important piece of data collected. It is used to determine how many participants are required, and it is the main piece of information used to judge whether the intervention is effective or not. In our study, patients and healthcare professionals agreed with the choice of the primary outcome made by trial teams doing late-stage trials in breast cancer management and nephrology 28% of the time.

Pragmatic evaluation of methods for retrieving unpublished information on comparator interventions in a systematic review of smoking cessation trials

Objective Reporting of the content and delivery characteristics of comparator interventions in published articles is often incomplete. This study examines the feasibility and validity of two methods for collecting additional information on comparator interventions from trial authors. Methods & Measures In a systematic review of smoking cessation trials (IC-Smoke), all trial authors were asked to send unpublished comparator intervention materials and complete a specially-developed comparator intervention checklist. All published and additionally obtained information from authors were coded for behaviour change techniques (BCTs) and other characteristics (type of comparator, provider, provider training, delivery mode and treatment duration). To assess representativeness, we assessed the amount of additional information obtained from trial authors compared with the amount that was published. We examined known-group and convergent validity of comparator intervention data when using only published or also unpublished information. Results Additional information were obtained from 91/136 (67%) of trial authors. Representativeness, known-group and convergent validity improved substantially based on the data collected by means of the comparator intervention checklist, but not by requesting authors to send any existing comparator materials. Conclusions Requesting authors for unpublished comparator intervention data, using specially-developed checklists and unpublished materials, substantially improves the quality of data available for systematic reviews.

Antibiotics for uncomplicated diverticulitis.

Diverticulitis is a complication of the common condition, diverticulosis. Uncomplicated diverticulitis has traditionally been treated with antibiotics, as diverticulitis has been regarded as an infectious disease. Risk factors for diverticulitis, however, may suggest that the condition is inflammatory rather than infectious which makes the use of antibiotics questionable. The objectives of this systematic review were to determine if antibiotic treatment of uncomplicated acute diverticulitis affects the risk of complications (immediate or late) or the need for emergency surgery. For this update, a comprehensive systematic literature search was conducted in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov and WHO International Clinical Trial Registry Platform on February 2021. Randomised controlled trials (RCTs), including all types of patients with a radiologically confirmed diagnosis of left-sided uncomplicated acute diverticulitis. Comparator and interventions included antibiotics compared to no antibiotics, placebo, or to any other antibiotic treatment (different regimens, routes of administration, dosage or duration of treatment). Primary outcome measures were complications and emergency surgery. Secondary outcomes were recurrence, late complications, elective colonic resections, length of hospital stay, length to recovery of symptoms, adverse events and mortality. Two authors performed the searches, identification and assessment of RCTs and data extraction. Disagreements were resolved by discussion or involvement of the third author. Authors of trials were contacted to obtain additional data if needed or for preliminary results of ongoing trials. The Cochrane Collaboration's tool for assessing risk of bias was used to assess the methodological quality of the identified trials. The overall quality of evidence for outcomes was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Effect estimates were extracted as risk ratios (RRs) with 95% confidence intervals. Random-effects meta-analyses were performed with the Mantel-Haenzel method. The authors included five studies. Three studies compared no antibiotics to antibiotics; all three were original RCTs of which twoalso published long-term follow-up information. For the outcome of short-term complications there may be little or no difference between antibiotics and no antibiotics (RR 0.89; 95% CI 0.30 to 2.62; 3 studies, 1329 participants; low-certainty evidence). The rate of emergency surgery within 30 days may be lower with no antibiotics compared to antibiotics (RR 0.47; 95% CI 0.13, 1.71; 1329 participants; 3 studies; low-certainty evidence). However, there is considerable imprecision due to wide confidence intervals for this effect estimate causing uncertainty whichmeans that there may also be a benefit with antibiotics. One of the two remaining trialscompared single to double compound antibiotic therapy and, due to wide confidence intervals, the estimate was imprecise and indicated an uncertain clinical effect between these two antibiotic regimens (RR 0.70; 95% CI 0.11 to 4.58; 51 participants; 1 study; low-certainty evidence). The last trial compared short to long intravenous administration of antibiotics and did not report any events for our primary outcomes. Both trialsincluded few participants and one had overall high risk of bias. Since the first publication of this systematic review, an increasing amount of evidence supporting the treatment of uncomplicated acute diverticulitis without antibiotics has been published, but the total body of evidence is still limited. The evidence on antibiotic treatment for uncomplicated acute diverticulitis suggests that the effect of antibiotics is uncertain for complications, emergency surgery, recurrence, elective colonic resections, and long-term complications. The quality of the evidence is low. Only three RCTs on the need for antibiotics are currently available. More trialsare needed to obtain more precise effect estimates.

Abstract 5528: A highly potent anti-CD39 biparatopic antibody and bispecific for cancer therapy

Abstract Background: There is an increasing demand for effective combinatory agents to improve upon PD-1/PD-L1-based therapeutics. One combinatory target axis is the adenosine metabolism pathway that consists of three major players, including CD39, CD73 and A2AR. Inhibition of any of these targets have shown enhanced preclinical efficacy in combination with PD-1/PD-L1 inhibitors. CD39 is an ectonucleotidase which degrades extracellular ATP to adenosine monophosphate (AMP). This is considered a rate-limiting step for the further degradation to adenosine by CD73. Adenosine is an immunosuppressive metabolite that can suppress NK and T cells. Blockade of CD39-mediated degradation of ATP to AMP may therefore recover anti-tumor immunity through preventing the enrichment of adenosine in the tumor microenvironment. Method: Two anti-CD39 VHH molecules were generated, named Ye-37 and Ye-46, which bind to two different epitopes on CD39. Binding experiments were carried out by bio-layer interferometry. Cell binding experiments were tested on CD39-overexpression cell lines by flow cytometry. Cellular CD39 enzymatic inhibition experiments were tested using an MOLP-8 cell line and PBMC via a luminescence-based assay. Soluble CD39 enzymatic tests were carried out on recombinant CD39 protein using a similar method. T cell proliferation assays were performed and observed on CD4+ or CD8+ T cell populations. In vivo efficacy studies were tested in B-NDG B2M-KO mice that were injected subcutaneously with A375-CD39+ tumor cells and human PBMC. An anti-PD1 x CD39 bispecific antibody was then generated by fusing the anti-CD39 biparatopic antibody to the C-terminus of an anti-PD1 IgG and tested using similar methods. Results: Two candidates, Ye-37 and Ye-46, were selected for their functional activity that recognize non-overlapping epitopes on CD39. The combination of Ye-37 and Ye-46 shows high potency in cell-based and soluble CD39 assays in blocking CD39 activity. Two biparatopic molecules were generated by fusing the biparatopic unit to the N- or C-termini of Fc (46-37-Fc and Fc-37-46) and showed similar activity to the combination. In vivo, we showed single-agent control of tumor growth and potentiation of tumor-growth inhibition when combined with anti-CD73 antibodies. An anti-PD1 x CD39 bispecific was generated and showed potent inhibition of PD-1/PD-L1 interactions by cell-based assays. Potent anti-tumor efficacy was shown, which was as effective as the combination of anti-PD1 plus anti-CD39 antibodies. Conclusion: Potent anti-CD39 and anti-PD1 x CD39 therapeutic candidates have been generated with promising activity as a combinatory or single agent, respectively. As such, we plan to file for clinical trial authorization of these programs by 2022. Citation Format: Zhenqing Zhang, Yunli Jia, Xiaoniu Miao, Weifeng Huang, Chao Wang, Zhijun Yuan, Wenchao Jiang, Liandi Chen, Zhiyuan Li, Andy Tsun. A highly potent anti-CD39 biparatopic antibody and bispecific for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5528.

Protocol for balanced versus saline trialists: living systematic review and individual patient data meta-analysis of randomised controlled trials (BEST-Living study)

Objective: It remains unclear whether balanced solutions improve patient-centred outcomes in critically ill patients overall and whether the treatment effect is heterogeneous, with evidence that some populations of patients may be helped and others harmed. To provide the most up-to-date and comprehensive assessment of the totality of the evidence, we will perform an ongoing living systematic review with aggregated and individual patient data meta-analysis (IPDMA) comparing the use of balanced solutions with saline in critically ill adults. Design: Living systematic review using aggregated and individual patient data from randomised controlled trials. Data sources: We will conduct annual searches of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials. gov, the Australian New Zealand Clinical Trials Registry (ANZCTR), Japan's University Hospital Medical Information Network (UMIN) Center, and the Brazilian Registry of Clinical Trials (ReBEC). The first search was completed on 1 March 2022 and will be repeated annually. Authors of eligible trials will be invited to provide individual data for the IPDMA. The initial analysis will use all data received up to 30 June 2022. Review methods: We will include randomised controlled trials in adults treated in an intensive care unit that allocated individuals or clusters of patients to a balanced crystalloid solution or 0.9% saline for intravenous fluid therapy. Studies that used colloids as part of the intervention or that recruited only elective surgical patients will be excluded. The primary endpoint will be in-hospital mortality. The key secondary endpoint will be survival at longest follow-up for each trial. Data will be synthesised using both a random effect Bayesian meta-analysis and using hierarchical Bayesian models for individual patient data. Discussion: The use of balanced crystalloid solutions may reduce mortality and improve other outcomes in some critically ill patients. We will assess the totality of current and future evidence by performing an ongoing living systematic review with aggregated data and IPDMA. Protocol registration: CRD42022299282.

Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis.

Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis.