Effect of Direct Transportation to Thrombectomy-Capable Center vs Local Stroke Center on Neurological Outcomes in Patients With Suspected Large-Vessel Occlusion Stroke in Nonurban Areas: The RACECAT Randomized Clinical Trial.

Importance: In nonurban areas with limited access to thrombectomy-capable centers, optimal prehospital transport strategies in patients with suspected large-vessel occlusion stroke are unknown. Objective: To determine whether, in nonurban areas, direct transport to a thrombectomy-capable center is beneficial compared with transport to the closest local stroke center. Design, Setting, and Participants: Multicenter, population-based, cluster-randomized trial including 1401 patients with suspected acute large-vessel occlusion stroke attended by emergency medical services in areas where the closest local stroke center was not capable of performing thrombectomy in Catalonia, Spain, between March 2017 and June 2020. The date of final follow-up was September 2020. Interventions: Transportation to a thrombectomy-capable center (n = 688) or the closest local stroke center (n = 713). Main Outcomes and Measures: The primary outcome was disability at 90 days based on the modified Rankin Scale (mRS; scores range from 0 [no symptoms] to 6 [death]) in the target population of patients with ischemic stroke. There were 11 secondary outcomes, including rate of intravenous tissue plasminogen activator administration and thrombectomy in the target population and 90-day mortality in the safety population of all randomized patients. Results: Enrollment was halted for futility following a second interim analysis. The 1401 enrolled patients were included in the safety analysis, of whom 1369 (98%) consented to participate and were included in the as-randomized analysis (56% men; median age, 75 [IQR, 65-83] years; median National Institutes of Health Stroke Scale score, 17 [IQR, 11-21]); 949 (69%) comprised the target ischemic stroke population included in the primary analysis. For the primary outcome in the target population, median mRS score was 3 (IQR, 2-5) vs 3 (IQR, 2-5) (adjusted common odds ratio [OR], 1.03; 95% CI, 0.82-1.29). Of 11 reported secondary outcomes, 8 showed no significant difference. Compared with patients first transported to local stroke centers, patients directly transported to thrombectomy-capable centers had significantly lower odds of receiving intravenous tissue plasminogen activator (in the target population, 229/482 [47.5%] vs 282/467 [60.4%]; OR, 0.59; 95% CI, 0.45-0.76) and significantly higher odds of receiving thrombectomy (in the target population, 235/482 [48.8%] vs 184/467 [39.4%]; OR, 1.46; 95% CI, 1.13-1.89). Mortality at 90 days in the safety population was not significantly different between groups (188/688 [27.3%] vs 194/713 [27.2%]; adjusted hazard ratio, 0.97; 95% CI, 0.79-1.18). Conclusions and Relevance: In nonurban areas in Catalonia, Spain, there was no significant difference in 90-day neurological outcomes between transportation to a local stroke center vs a thrombectomy-capable referral center in patients with suspected large-vessel occlusion stroke. These findings require replication in other settings. Trial Registration: ClinicalTrials.gov Identifier: NCT02795962.

An iterative method to protect the type I error rate in bioequivalence studies under two-stage adaptive 2×2 crossover designs.

Bioequivalence studies are the pivotal clinical trials submitted to regulatory agencies to support the marketing applications of generic drug products. Average bioequivalence (ABE) is used to determine whether the mean values for the pharmacokinetic measures determined after administration of the test and reference products are comparable. Two-stage 2×2 crossover adaptive designs (TSDs) are becoming increasingly popular because they allow making assumptions on the clinically meaningful treatment effect and a reliable guess for the unknown within-subject variability. At an interim look, if ABE is not declared with an initial sample size, they allow to increase it depending on the estimated variability and to enroll additional subjects at a second stage, or to stop for futility in case of poor likelihood of bioequivalence. This is crucial because both parameters must clearly be prespecified in protocols, and the strategy agreed with regulatory agencies in advance with emphasis on controlling the overall type I error. We present an iterative method to adjust the significance levels at each stage which preserves the overall type I error for a wide set of scenarios which should include the true unknown variability value. Simulations showed adjusted significance levels higher than 0.0300 in most cases with type I error always below 5%, and with a power of at least 80%. TSDs work particularly well for coefficients of variation below 0.3 which are especially useful due to the balance between the power and the percentage of studies proceeding to stage 2. Our approach might support discussions with regulatory agencies.

A scoping review on the roles and tasks of peer reviewers in the manuscript review process in biomedical journals.

BACKGROUND: Although peer reviewers play a key role in the manuscript review process, their roles and tasks are poorly defined. Clarity around this issue is important as it may influence the quality of peer reviewer reports. This scoping review explored the roles and tasks of peer reviewers of biomedical journals. METHODS: Comprehensive literature searches were conducted in Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Educational Resources Information Center, EMBASE, MEDLINE, PsycINFO, Scopus and Web of Science from inception up to May 2017. There were no date and language restrictions. We also searched for grey literature. Studies with statements mentioning roles, tasks and competencies pertaining to the role of peer reviewers in biomedical journals were eligible for inclusion. Two reviewers independently performed study screening and selection. Relevant statements were extracted, collated and classified into themes. RESULTS: After screening 2763 citations and 600 full-text papers, 209 articles and 13 grey literature sources were included. A total of 1426 statements related to roles were extracted, resulting in 76 unique statements. These were grouped into 13 emergent themes: proficient experts in their field (3 items), dutiful/altruistic towards scientific community (7 items), familiar with journal (2 items), unbiased and ethical professionals (18 items), self-critical professionals (4 items), reliable professionals (7 items), skilled critics (15 items), respectful communicators (6 items), gatekeepers (2 items), educators (2 items), advocates for author/editor/reader (3 items) and advisors to editors (2 items). Roles that do not fall within the remit of peer reviewers were also identified (5 items). We also extracted 2026 statements related to peer reviewers' tasks, resulting in 73 unique statements. These were grouped under six themes: organisation and approach to reviewing (10 items), make general comments (10 items), assess and address content for each section of the manuscript (36 items), address ethical aspects (5 items), assess manuscript presentation (8 items) and provide recommendations (4 items). CONCLUSIONS: Peer reviewers are expected to perform a large number of roles and tasks for biomedical journals. These warrant further discussion and clarification in order not to overburden these key actors.

Tools used to assess the quality of peer review reports: a methodological systematic review.

BACKGROUND: A strong need exists for a validated tool that clearly defines peer review report quality in biomedical research, as it will allow evaluating interventions aimed at improving the peer review process in well-performed trials. We aim to identify and describe existing tools for assessing the quality of peer review reports in biomedical research. METHODS: We conducted a methodological systematic review by searching PubMed, EMBASE (via Ovid) and The Cochrane Methodology Register (via The Cochrane Library) as well as Google® for all reports in English describing a tool for assessing the quality of a peer review report in biomedical research. Data extraction was performed in duplicate using a standardized data extraction form. We extracted information on the structure, development and validation of each tool. We also identified quality components across tools using a systematic multi-step approach and we investigated quality domain similarities among tools by performing hierarchical, complete-linkage clustering analysis. RESULTS: We identified a total number of 24 tools: 23 scales and 1 checklist. Six tools consisted of a single item and 18 had several items ranging from 4 to 26. None of the tools reported a definition of 'quality'. Only 1 tool described the scale development and 10 provided measures of validity and reliability. Five tools were used as an outcome in a randomized controlled trial (RCT). Moreover, we classified the quality components of the 18 tools with more than one item into 9 main quality domains and 11 subdomains. The tools contained from two to seven quality domains. Some domains and subdomains were considered in most tools such as the detailed/thorough (11/18) nature of reviewer's comments. Others were rarely considered, such as whether or not the reviewer made comments on the statistical methods (1/18). CONCLUSION: Several tools are available to assess the quality of peer review reports; however, the development and validation process is questionable and the concepts evaluated by these tools vary widely. The results from this study and from further investigations will inform the development of a new tool for assessing the quality of peer review reports in biomedical research.

Adherence to reporting guidelines increases the number of citations: the argument for including a methodologist in the editorial process and peer-review.

BACKGROUND: From 2005 to 2010, we conducted 2 randomized studies on a journal (Medicina Clínica), where we took manuscripts received for publication and randomly assigned them to either the standard editorial process or to additional processes. Both studies were based on the use of methodological reviewers and reporting guidelines (RG). Those interventions slightly improved the items reported on the Manuscript Quality Assessment Instrument (MQAI), which assesses the quality of the research report. However, masked evaluators were able to guess the allocated group in 62% (56/90) of the papers, thus presenting a risk of detection bias. In this post-hoc study, we analyse whether those interventions that were originally designed for improving the completeness of manuscript reporting may have had an effect on the number of citations, which is the measured outcome that we used. METHODS: Masked to the intervention group, one of us used the Web of Science (WoS) to quantify the number of citations that the participating manuscripts received up December 2016. We calculated the mean citation ratio between intervention arms and then quantified the uncertainty of it by means of the Jackknife method, which avoids assumptions about the distribution shape. RESULTS: Our study included 191 articles (99 and 92, respectively) from the two previous studies, which all together received 1336 citations. In both studies, the groups subjected to additional processes showed higher averages, standard deviations and annual rates. The intervention effect was similar in both studies, with a combined estimate of a 43% (95% CI: 3 to 98%) increase in the number of citations. CONCLUSIONS: We interpret that those effects are driven mainly by introducing into the editorial process a senior methodologist to find missing RG items. Those results are promising, but not definitive due to the exploratory nature of the study and some important caveats such as: the limitations of using the number of citations as a measure of scientific impact; and the fact that our study is based on a single journal. We invite journals to perform their own studies to ascertain whether or not scientific repercussion is increased by adhering to reporting guidelines and further involving statisticians in the editorial process.

Thrombectomy within 8 hours after symptom onset in ischemic stroke.

BACKGROUND: We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry. METHODS: During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials. RESULTS: Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals. CONCLUSIONS: Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT ClinicalTrials.gov number, NCT01692379.).

Two-stage designs versus European scaled average designs in bioequivalence studies for highly variable drugs: Which to choose?

The usual approach to determine bioequivalence for highly variable drugs is scaled average bioequivalence, which is based on expanding the limits as a function of the within-subject variability in the reference formulation. This requires separately estimating this variability and thus using replicated or semireplicated crossover designs. On the other hand, regulations also allow using common 2 × 2 crossover designs based on two-stage adaptive approaches with sample size reestimation at an interim analysis. The choice between scaled or two-stage designs is crucial and must be fully described in the protocol. Using Monte Carlo simulations, we show that both methodologies achieve comparable statistical power, though the scaled method usually requires less sample size, but at the expense of each subject being exposed more times to the treatments. With an adequate initial sample size (not too low, eg, 24 subjects), two-stage methods are a flexible and efficient option to consider: They have enough power (eg, 80%) at the first stage for non-highly variable drugs, and, if otherwise, they provide the opportunity to step up to a second stage that includes additional subjects.

Association Between Time to Reperfusion and Outcome Is Primarily Driven by the Time From Imaging to Reperfusion.

BACKGROUND AND PURPOSE: A progressive decline in the odds of favorable outcome as time to reperfusion increases is well known. However, the impact of specific workflow intervals is not clear. METHODS: We studied the mechanical thrombectomy group (n=103) of the prospective, randomized REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) trial. We defined 3 workflow metrics: time from symptom onset to reperfusion (OTR), time from symptom onset to computed tomography, and time from computed tomography (CT) to reperfusion. Clinical characteristics, core laboratory-evaluated Alberta Stroke Program Early CT Scores (ASPECTS) and 90-day outcome data were analyzed. The effect of time on favorable outcome (modified Rankin scale, 0-2) was described via adjusted odds ratios (ORs) for every 30-minute delay. RESULTS: Median admission National Institutes of Health Stroke Scale was 17.0 (14.0-20.0), reperfusion rate was 66%, and rate of favorable outcome was 43.7%. Mean (SD) workflow times were as follows: OTR: 342 (107) minute, onset to CT: 204 (93) minute, and CT to reperfusion: 138 (56) minute. Longer OTR time was associated with a reduced likelihood of good outcome (OR for 30-minute delay, 0.74; 95% confidence interval [CI], 0.59-0.93). The onset to CT time did not show a significant association with clinical outcome (OR, 0.87; 95% CI, 0.67-1.12), whereas the CT to reperfusion interval showed a negative association with favorable outcome (OR, 0.72; 95% CI, 0.54-0.95). A similar subgroup analysis according to admission ASPECTS showed this relationship for OTR time in ASPECTS<8 patients (OR, 0.56; 95% CI, 0.35-0.9) but not in ASPECTS≥8 (OR, 0.99; 95% CI, 0.68-1.44). CONCLUSIONS: Time to reperfusion is negatively associated with favorable outcome, being CT to reperfusion, as opposed to onset to CT, the main determinant of this association. In addition, OTR was strongly associated to outcome in patients with low ASPECTS scores but not in patients with high ASPECTS scores. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.

Taking advantage of unexpected WebCONSORT results.

To estimate treatment effects, trials are initiated by randomising patients to the interventions under study and finish by comparing patient evolution. In order to improve the trial report, the CONSORT statement provides authors and peer reviewers with a guide of the essential items that would allow research replication. Additionally, WebCONSORT aims to facilitate author reporting by providing the items from the different CONSORT extensions that are relevant to the trial being reported. WebCONSORT has been estimated to improve the proportion of reported items by 0.04 (95% CI, -0.02 to 0.10), interpreted as "no important difference", in accordance with the scheduled desired scenario of a 0.15 effect size improvement. However, in a non-scheduled analysis, it was found that, despite clear instructions, around a third of manuscripts selected for trials by the editorial staff were not actually randomised trials. We argue that surprises benefit science, and that further research should be conducted in order to improve the performance of editorial staff.Please see related research: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0736-x.

Mechanical Thrombectomy in and Outside the REVASCAT Trial: Insights From a Concurrent Population-Based Stroke Registry.

BACKGROUND AND PURPOSE: Recent trials have shown the superiority of endovascular thrombectomy (EVT) over medical therapy alone in certain stroke patients with proximal arterial occlusion. Using data from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within 8-Hours of Symptom Onset (REVASCAT) and a parallel reperfusion treatment registry, we sought to assess the utilization of EVT in a defined patient population, comparing the outcomes of patients treated in and outside the REVASCAT trial. METHODS: SONIIA [Sistema Online d'Informació de l'Ictus Agut], a population-based, government-mandated, prospective registry of reperfusion therapies for stroke encompassing the entire population of Catalonia, was used as data source. The registry documents 5 key inclusion criteria of the REVASCAT trial: age, stroke severity, time to treatment, baseline functional status, and occlusion site. We compared procedural, safety, and functional outcomes in patients treated inside and outside the trial. RESULTS: From November 2012 to December 2014, out of 17596 ischemic stroke patients in Catalonia (population 7.5 million), 2576 patients received reperfusion therapies (17/100000 inhabitants-year), mainly intravenous thrombolysis only (2036). From the remaining 540 treated with EVT, 103 patients (out of 206 randomized) were treated within REVASCAT and 437 outside the trial. Of these, 399 did not fulfill some of the study criteria, and 38 were trial candidates (8 treated at REVASCAT centers and 30 at 2 non-REVASCAT centers). The majority of procedural, safety, and functional outcomes were similar in patients treated with EVT within and outside REVASCAT. CONCLUSIONS: REVASCAT enrolled nearly all eligible patients representing one third of all patients treated with EVT. Patients treated with EVT within and outside REVASCAT had similar outcomes, reinforcing the therapeutic value of EVT. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.

Phone and Video-Based Modalities of Central Blinded Adjudication of Modified Rankin Scores in an Endovascular Stroke Trial.

BACKGROUND AND PURPOSE: The standard outcome measure in stroke research is modified Rankin scale (mRS) evaluated by local blinded investigators. We aimed to assess feasibility and reliability of 2 central adjudication methods of mRS in the setting of a randomized endovascular stroke trial. METHODS: This is a secondary analysis derived from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset (REVASCAT) trial cohort. Primary outcome was distribution of mRS at 90 days. Local evaluation was done by certified investigators masked to treatment assignment using structured face-to-face interviews. In addition, central assessment was performed by 2 independent raters via structured phone interview (n=120) and via video recordings of the face-to-face interviews with local investigators (n=106). Interrater agreement was evaluated using kappa and discordance statistics. Sensitivity analyses for the primary end point using different adjudication approaches were performed. Correlation between mRS obtained with each modality and 24-hour follow-up infarct volumes was studied. RESULTS: Using local evaluation as the reference, higher agreement rates were noted with central video than with central phone evaluations (kw 0.92 [0.88-0.96] versus 0.77 [0.72-0.83]). Discrepancies in mRS scoring between local and central raters (phone- and video-based) were similar in both treatment allocation arms. Sensitivity analyses showed benefit of endovascular treatment irrespective of adjudication method, but higher odds ratios were observed with local evaluations. Final infarct volume was similarly correlated with mRS across all 3 evaluation modalities. CONCLUSIONS: Central adjudication of mRS is feasible, reducing interrater variability and avoiding potential problems related to lack of blinding. Our findings may have implications in the planning of future randomized acute stroke trials, especially in those including nonpharmacological interventions. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.

Exercise capacity and N-terminal pro-brain natriuretic peptide levels with biventricular vs. right ventricular pacing for atrioventricular block: results from the PREVENT-HF German Substudy.

AIMS: Previous studies showed unfavourable effects of right ventricular (RV) pacing. Ventricular pacing (VP), however, is required in many patients with atrioventricular (AV) block. The PREVENT-HF study explored left ventricular (LV) remodelling during RV vs. biventricular (BIV) pacing in AV block without advanced heart failure. The pre-specified PREVENT-HF German Substudy examined exercise capacity and N-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: Patients with expected VP ≥80% were randomized to RV or BIV pacing. Endpoints were peak oxygen uptake (pVO2), oxygen uptake at the anaerobic threshold (VO2AT), ventilatory efficiency (VE/VCO2), and logNT-proBNP. Considering crossover, intention to treat (ITT), and on-treatment (OT) analyses of covariance (ANCOVA) were performed. For exercise testing 44 (RV: 25, BIV: 19), and for NT-proBNP 53 patients (RV: 29, BIV: 24) were included. The ITT analysis revealed significant differences in pVO2 [ANCOVA effect 2.83 mL/kg/min, confidence interval (CI) 0.83-4.91, P = 0.007], VO2AT (ANCOVA effect 2.14 mL/min/k, CI 0.14-4.15, P = 0.03), and VE/VCO2 (ANCOVA effect -5.46, CI -10.79 to -0.13, P = 0.04) favouring BIV randomization. The significant advantage in pVO2 persisted in OT analysis, while VO2AT and VE/VCO2 showed trends favouring BIV pacing. LogNT-proBNP did not differ between groups. (ITT: ANCOVA effect 0.008, CI -0.40 to +0.41, P = 0.97; OT: ANCOVA effect -0.03, CI -0.44 to 0.30, P = 0.90). CONCLUSION: Our study suggests that BIV pacing produces better exercise capacity over 1 year compared with RV pacing in patients without advanced heart failure and AV block. In contrast, we observed no significant changes of NT-proBNP. Larger trials will allow appraising the clinical usefulness of BIV pacing in AV block. ClinicalTrials.gov Identifier: NCT00170326.

Heterogeneity of treatment response to beta-blockers in the treatment of portal hypertension: A systematic review.

BACKGROUND: It has been suggested that a relevant proportion of patients do not respond to nonselective beta-blockers (NSBB)s, which raises questions regarding the need for individualized therapy. The existence of potential heterogeneity in the treatment response can be assessed using the variability ratio (VR) of the outcome measurement (in this case, HVPG) between the treated and placebo groups. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the potential heterogeneity in the portal pressure response to NSBBs. METHODS: After a systematic search, we quantified the heterogeneity of treatment response with the VR between the treatment and control groups, with VR > 1 indicating potential heterogeneity. We used a similar approach to compare carvedilol with propranolol and statins with placebo. RESULTS: We identified 18 studies that included 965 patients. A comparison between beta-blockers and placebo showed a pooled VR of 0.99 (95% CI:0.87-1.14), which suggests a homogeneous HVPG response to NSBB at the individual patient level (ie, no evidence to support that some patients responded to beta-blockers and others did not). For the comparison between carvedilol and propranolol, pooled VR was 0.97 (95% CI 0.82-1.14), suggesting that carvedilol achieves a greater average response (rather than an increase in the proportion of responders). There was no evidence of a heterogeneous response to statins. CONCLUSION: Our analysis did not support the existence of a heterogeneous patient-by-patient response to NSBBs in cirrhosis. These findings challenge the concept of personalized therapy based on portal pressure response and indicate that routine portal pressure measurement may not be necessary to guide NSBB therapy.

Group-by-Treatment Interaction Effects in Comparative Bioavailability Studies.

Comparative bioavailability studies often involve multiple groups of subjects for a variety of reasons, such as clinical capacity limitations. This raises questions about the validity of pooling data from these groups in the statistical analysis and whether a group-by-treatment interaction should be evaluated. We investigated the presence or absence of group-by-treatment interactions through both simulation techniques and a meta-study of well-controlled trials. Our findings reveal that the test falsely detects an interaction when no true group-by-treatment interaction exists. Conversely, when a true group-by-treatment interaction does exist, it often goes undetected. In our meta-study, the detected group-by-treatment interactions were observed at approximately the level of the test and, thus, can be considered false positives. Testing for a group-by-treatment interaction is both misleading and uninformative. It often falsely identifies an interaction when none exists and fails to detect a real one. This occurs because the test is performed between subjects in crossover designs, and studies are powered to compare treatments within subjects. This work demonstrates a lack of utility for including a group-by-treatment interaction in the model when assessing single-site comparative bioavailability studies, and the clinical trial study structure is divided into groups.

Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial).

BACKGROUND: Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. METHODS: We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. RESULTS: 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events. INTERPRETATION: Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke. FUNDING: Ferrer Grupo.

APRIL: A double-blind, placebo-controlled, randomized, Phase Ib/IIa clinical study of ApTOLL for the treatment of acute ischemic stroke.

In the reperfusion era, a new paradigm of treating patients with endovascular treatment (EVT) and neuroprotective drugs is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). In this context, ApTOLL, a Toll-like receptor 4 (TLR4) antagonist with proven neuroprotective effect in preclinical models of stroke and a very good pharmacokinetic and safety profile in healthy volunteers, is a promising first-in-class aptamer with the potential to address this huge unmet need. This protocol establishes the clinical trial procedures to conduct a Phase Ib/IIa clinical study (APRIL) to assess ApTOLL tolerability, safety, pharmacokinetics, and biological effect in patients with AIS who are eligible for EVT. This will be a multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to evaluate the administration of ApTOLL together with EVT in patients with AIS. The study population will be composed of men and non-pregnant women with confirmed AIS with a <6h window from symptoms onset to ApTOLL/placebo administration. The trial is currently being conducted and is divided into two parts: Phase Ib and Phase IIa. In Phase Ib, 32 patients will be allocated to four dose ascending levels to select, based on safety criteria, the best two doses to be administered in the following Phase IIa in which 119 patients will be randomized to three arms of treatment (dose A, dose B, and placebo). Identification of the trial: EudraCT: 2020-002059-38 and ClinicalTrials.gov Identifier: NCT04734548 https://clinicaltrials.gov/ct2/show/NCT04734548?term=ApTOLL&cond=Stroke&draw=2&rank=1.

Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment: A Phase 1/2 Randomized Clinical Trial.

Importance: ApTOLL is a TLR4 antagonist with proven preclinical neuroprotective effect and a safe profile in healthy volunteers. Objective: To assess the safety and efficacy of ApTOLL in combination with endovascular treatment (EVT) for patients with ischemic stroke. Design, Setting, and Participants: This phase 1b/2a, double-blind, randomized, placebo-controlled study was conducted at 15 sites in Spain and France from 2020 to 2022. Participants included patients aged 18 to 90 years who had ischemic stroke due to large vessel occlusion and were seen within 6 hours after stroke onset; other criteria were an Alberta Stroke Program Early CT Score of 6 to 10, estimated infarct core volume on baseline computed tomography perfusion of 5 to 70 mL, and the intention to undergo EVT. During the study period, 4174 patients underwent EVT. Interventions: In phase 1b, 0.025, 0.05, 0.1, or 0.2 mg/kg of ApTOLL or placebo; in phase 2a, 0.05 or 0.2 mg/kg of ApTOLL or placebo; and in both phases, treatment with EVT and intravenous thrombolysis if indicated. Main Outcomes and Measures: The primary end point was the safety of ApTOLL based on death, symptomatic intracranial hemorrhage (sICH), malignant stroke, and recurrent stroke. Secondary efficacy end points included final infarct volume (via MRI at 72 hours), NIHSS score at 72 hours, and disability at 90 days (modified Rankin Scale [mRS] score). Results: In phase Ib, 32 patients were allocated evenly to the 4 dose groups. After phase 1b was completed with no safety concerns, 2 doses were selected for phase 2a; these 119 patients were randomized to receive ApTOLL, 0.05 mg/kg (n = 36); ApTOLL, 0.2 mg/kg (n = 36), or placebo (n = 47) in a 1:1:√2 ratio. The pooled population of 139 patients had a mean (SD) age of 70 (12) years, 81 patients (58%) were male, and 58 (42%) were female. The primary end point occurred in 16 of 55 patients (29%) receiving placebo (10 deaths [18.2%], 4 sICH [7.3%], 4 malignant strokes [7.3%], and 2 recurrent strokes [3.6%]); in 15 of 42 patients (36%) receiving ApTOLL, 0.05 mg/kg (11 deaths [26.2%], 3 sICH [7.2%], 2 malignant strokes [4.8%], and 2 recurrent strokes [4.8%]); and in 6 of 42 patients (14%) receiving ApTOLL, 0.2 mg/kg (2 deaths [4.8%], 2 sICH [4.8%], and 3 recurrent strokes [7.1%]). ApTOLL, 0.2 mg/kg, was associated with lower NIHSS score at 72 hours (mean difference log-transformed vs placebo, -45%; 95% CI, -67% to -10%), smaller final infarct volume (mean difference log-transformed vs placebo, -42%; 95% CI, -66% to 1%), and lower degrees of disability at 90 days (common odds ratio for a better outcome vs placebo, 2.44; 95% CI, 1.76 to 5.00). Conclusions and Relevance: In acute ischemic stroke, 0.2 mg/kg of ApTOLL administered within 6 hours of onset in combination with EVT was safe and associated with a potential meaningful clinical effect, reducing mortality and disability at 90 days compared with placebo. These preliminary findings await confirmation from larger pivotal trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04734548.

Boosting the chances to improve stroke treatment.

BACKGROUND AND PURPOSE: There is a lack of agreement regarding measuring the effects of stroke treatment in clinical trials, which often relies on the dichotomized value of 1 outcome scale. Alternative analyses consist mainly of 2 strategies: use all the information from an ordinal scale and combine information from several outcome scales in a single estimate. METHODS: We reanalyzed 3 outcome scales that assessed patient recovery (modified Rankin Scale, National Institutes of Health Stroke Scale, and Barthel Index). With data collected from the 1652 patients in the Citicoline pooling data analysis, we used 2 standard techniques of exploratory multivariate analysis to analyze the distances among ranks and to isolate the common and the unique information provided by each of the 3 scales. RESULTS: The different scale values correspond to gradually different patient status, confirming that information is lost when a scale is collapsed to just 2 values, whether recovered or not. The scales shared 90.7% (95% CI, 84.5-96.9) of their information, with no individual scale contributing unique information. CONCLUSIONS: Salient stroke outcome information is lost when an ordinal scale is collapsed into fewer categories. In contrast, the full scales provide a comprehensive patient outcome estimate. Furthermore, in the context of stroke clinical trials, those scales are highly correlated, providing the rationale to pool them into a single estimate. These insights may be used to optimize the analysis of stroke trials to increase study power to detect efficacious interventions.

Effect of an editorial intervention to improve the completeness of reporting of randomised trials: a randomised controlled trial.

OBJECTIVE: To evaluate the impact of an editorial intervention to improve completeness of reporting of reports of randomised trials. DESIGN: Randomised controlled trial (RCT). SETTING: BMJ Open's quality improvement programme. PARTICIPANTS: 24 manuscripts describing RCTs. INTERVENTIONS: We used an R Shiny application to randomise manuscripts (1:1 allocation ratio, blocks of 4) to the intervention (n=12) or control (n=12) group. The intervention was performed by a researcher with expertise in the content of the Consolidated Standards of Reporting Trials (CONSORT) and consisted of an evaluation of completeness of reporting of eight core CONSORT items using the submitted checklist to locate information, and the production of a report containing specific requests for authors based on the reporting issues found, provided alongside the peer review reports. The control group underwent the usual peer review. OUTCOMES: The primary outcome is the number of adequately reported items (0-8 scale) in the revised manuscript after the first round of peer review. The main analysis was intention-to-treat (n=24), and we imputed the scores of lost to follow-up manuscripts (rejected after peer review and not resubmitted). The secondary outcome is the proportion of manuscripts where each item was adequately reported. Two blinded reviewers assessed the outcomes independently and in duplicate and solved disagreements by consensus. We also recorded the amount of time to perform the intervention. RESULTS: Manuscripts in the intervention group (mean: 7.01; SD: 1.47) were more completely reported than those in the control group (mean: 5.68; SD: 1.43) (mean difference 1.43, 95% CI 0.31 to 2.58). We observed the main differences in items 6a (outcomes), 9 (allocation concealment mechanism), 11a (blinding) and 17a (outcomes and estimation). The mean time to perform the intervention was 87 (SD 42) min. CONCLUSIONS: We demonstrated the benefit of involving a reporting guideline expert in the editorial process. Improving the completeness of RCTs is essential to enhance their usability. TRIAL REGISTRATION NUMBER: NCT03751878.

Evaluation of a sequential global test of improved recovery following stroke as applied to the ICTUS trial of citicoline.

The International Citicoline Trial in acUte Stroke is a sequential phase III study of the use of the drug citicoline in the treatment of acute ischaemic stroke, which was initiated in 2006 in 56 treatment centres. The primary objective of the trial is to demonstrate improved recovery of patients randomized to citicoline relative to those randomized to placebo after 12 weeks of follow-up. The primary analysis will take the form of a global test combining the dichotomized results of assessments on three well-established scales: the Barthel Index, the modified Rankin scale and the National Institutes of Health Stroke Scale. This approach was previously used in the analysis of the influential National Institute of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator in stroke.The purpose of this paper is to describe how this trial was designed, and in particular how the simultaneous objectives of taking into account three assessment scales, performing a series of interim analyses and conducting treatment allocation and adjusting the analyses to account for prognostic factors, including more than 50 treatment centres, were addressed.