Improving efficiency in stroke trials: an exploration of methods to improve the use of the modified Rankin Scale in acute stroke trials

The modified Rankin Scale (mRS) is the preferred outcome measure in stroke trials. Typically, mRS assessment is based on a clinician’s rating of a patient interview and interobserver variability is common. Meta-analysis suggests an overall reliability of k=0.46 but this may be less (k=0.25) in multi-centre studies. Mandatory training in mRS assessment is employed in most trials to mitigate this but the problem persists. Variability in assigning outcomes may lead to endpoint misclassification increasing the challenge of accurately demonstrating a treatment effect. We aimed to assess the impact of endpoint misclassification on trial power and explore methods to improve the use of the mRS in acute stroke trials. First we used the mRS outcome distributions of previous phase III randomised controlled trials (RCT) in stroke (NXY059 study and tPA NINDS study) to perform statistical simulations. We generated power estimates and sample sizes from simulated mRS studies under various combinations of sample size, mRS reliability and adjudication panel size. Simulations suggest that the potential benefit of improving mRS reliability from k 0.25 to k 0.5, k 0.7 or k 0.9 may allow a reduction in sample size of n= 386, n= 490 or n= 488 in a typical n=2000 RCT. We then developed a method for providing group adjudication of mRS endpoints and examined the feasibility, reliability and validity of its use in a multicentre clinical trial. We conducted a “virtual” acute stroke trial across 14 UK sites. Local mRS interviews were scored as normal but also recorded to digital video camera. Video clips were uploaded via secure web portal for scoring by adjudication committee reviewers. We demonstrated excellent technical success rates with acceptability to both participants and investigators. 370 participants were included in our “virtual” acute stroke trial and 563 mRS video assessments were uploaded for central review. 96% (538/563) of study visits resulted in an adjudicated mRS score. At 30 and 90 days respectively, 57.5% (161/280) and 50.8% (131/258) of clips were misclassified. Agreement was measured using kappa statistics (k/kw) and intraclass correlation coefficient. Agreement between the adjudication committee was very good (30 days kw 0.85 [95%CI 0.81-0.86], 90 days kw 0.86 [95% CI 0.82-0.88]) with no significant or systematic bias in mRS scoring in comparison to the local mRS. We demonstrated criterion and construct validity of centrally adjudicated mRS scores through comparison with the locally assigned mRS score and other measures known to affect stroke outcome including baseline NIHSS (bNIHSS), Systolic Blood Pressure (SBP), blood glucose and home time. We studied our cohort of mRS video clips to identify any features predictive of variability in mRS scoring. Patient specific variables included participant age, pre stroke mRS, baseline stroke severity as graded by baseline NIHSS (bNIHSS) and presence of language disorder. Interview specific variables included length of interview, poor sound quality, location of the interview, use of a proxy or discussion of prior disability. At both 30 and 90 days only “interview length” was a significant predictor of agreement in mRS scoring. Using a sample of mRS video clips in English and Mandarin, we conducted a pilot study to assess the effect of translation of mRS interviews on interobserver reliability. The interobserver reliability of the translated mRS assessments was similar to native language clips (Native (n=69) kw 0.91 [95%CI 0.86-0.99], Translated (n=89) kw 0.90 [95% CI 0.83-0.96]). We then incorporated a translation step into the central adjudication model using our existing web portal. Inter observer reliability seen in the modified clips (kw 0.85 [95% CI 0.74-0.95]) was similar to that seen in the original video files (kw 0.88 [95% CI 0.78-0.99]). Finally we aimed to investigate the ability of raters to detect more subtle degrees of disability within mRS ranks through blinded assessment of pairs of clips with matching mRS grades. These pairs contained either two clips with full agreement in mRS grade at initial group review or one clip with full agreement and one clip where scores were skewed in the direction of “more” or “less” disability. Pairs were randomly assigned to multiple raters. We could not identify any reliable pattern in identification of the “less disabled” mRS clip. More sensitive grading of the mRS with “good” or “bad” forms of each grade is not reliable on the basis of this exploratory study. Perhaps alternative methods of converting the ordinal ranks of the mRS scale into a more continuous distribution should be investigated; such as the use of a mean mRS score following multiple mRS ratings. Prior estimates of mRS reliability in multicentre studies are poor [k=0.25]. The risks of endpoint misclassification affecting trial power are substantial. Simulations suggest that the effect of improving interobserver reliability and multiple mRS assessments may reduce study sample size by 25%, resulting in substantial ethical and financial benefits. Agreement between our adjudication committee was good [k=0.59(95% CI:0.53-0.63), kw=0.86(95% CI:0.82-0.88)]. Central review may bring many additional potential benefits: “expert” review, quality control and improved blinding in complex trial design. Central adjudication of mRS assessments is feasible, reliable and valid, including the use of translated mRS assessments. This model of outcome assessment has been incorporated into four ongoing large clinical trials: CLEAR-3, MISTIE-3, EUROHYP-1 and SITS-OPEN

Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia

Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38. The parallel screening of kinase inhibitors revealed that mouse and human neutrophil viability is dependent on cyclin-dependent kinase (CDK) activity but surprisingly only partially dependent on PI3 kinase and JAK/STAT signaling, revealing dominant pathways contributing to neutrophil viability. Mcl-1 haploinsufficiency sensitized neutrophils to CDK inhibition, demonstrating that Mcl-1 is a direct target for CDK inhibitors. This study reveals a therapeutic window for the kinase inhibitors BEZ235, BMS-3, AZD7762, and (R)-BI-2536 to induce apoptosis of leukemia cell lines whilst maintaining immunocompetence and hemostasis

Accurate prediction of clinical stroke scales and improved biomarkers of motor impairment from robotic measurements

Objective: One of the greatest challenges in clinical trial design is dealing with the subjectivity and variability introduced by human raters when measuring clinical end-points. We hypothesized that robotic measures that capture the kinematics of human movements collected longitudinally in patients after stroke would bear a significant relationship to the ordinal clinical scales and potentially lead to the development of more sensitive motor biomarkers that could improve the efficiency and cost of clinical trials. Materials and methods: We used clinical scales and a robotic assay to measure arm movement in 208 patients 7, 14, 21, 30 and 90 days after acute ischemic stroke at two separate clinical sites. The robots are low impedance and low friction interactive devices that precisely measure speed, position and force, so that even a hemiparetic patient can generate a complete measurement profile. These profiles were used to develop predictive models of the clinical assessments employing a combination of artificial ant colonies and neural network ensembles. Results: The resulting models replicated commonly used clinical scales to a cross-validated R2 of 0.73, 0.75, 0.63 and 0.60 for the Fugl-Meyer, Motor Power, NIH stroke and modified Rankin scales, respectively. Moreover, when suitably scaled and combined, the robotic measures demonstrated a significant increase in effect size from day 7 to 90 over historical data (1.47 versus 0.67). Discussion and conclusion: These results suggest that it is possible to derive surrogate biomarkers that can significantly reduce the sample size required to power future stroke clinical trials

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Robotic measurement of arm movements after stroke establishes biomarkers of motor recovery

Background and Purpose—Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers.<p></p> Methods—In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments.<p></p> Results—Among 208 patients, robotic measures predicted well the clinical measures (cross-validated R2 of modified Rankin scale=0.60; National Institutes of Health Stroke Scale=0.63; Fugl-Meyer=0.73; Motor Power=0.75). When suitably scaled and combined by an artificial neural network, the robotic measures demonstrated greater sensitivity in measuring the recovery of patients from day 7 to day 90 (increased standardized effect=1.47).<p></p> Conclusions—These results demonstrate that robotic measures of motor performance will more than adequately capture outcome, and the altered effect size will reduce the required sample size. Reducing sample size will likely improve study efficiency.<p></p&gt