Primary Outcome Measure For Trial Research Articles

Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia

IntroductionLower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known.MethodsPreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function.Results365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365).ConclusionsFindings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.

Differential Impact of Home Nurse Contact After Discharge by Financial Strain, Primary Care Access, and Medical Complexity.

The Hospital to Home Outcomes (H2O) trials examined the effectiveness of postdischarge nurse support on reuse after pediatric discharge. Unexpectedly, children randomly assigned to a nurse visit had higher rates of reuse than those in the control group. Participants in randomized control trials are heterogeneous. Thus, it is possible that the effect of the intervention differed across subgroups (ie, heterogeneity of treatment effect [HTE]). We sought to determine if different subgroups responded differently to the interventions. The H2O trial is a randomized controlled trial comparing standard hospital discharge processes with a nurse home visit within 96 hours of discharge. The second trial, H2O II, was similar, except the tested intervention was a postdischarge nurse phone call. For the purposes of the HTE analyses, we examined our primary trial outcome measure: a composite of unplanned 30-day acute health care reuse (unplanned readmission or emergency department or urgent care visit). We identified subgroups of interest before the trials related to (1) financial strain, (2) primary care access, (3) insurance, and (4) medical complexity. We used logistic regression modeling with an interaction term between subgroup and treatment group (intervention or control). For the phone call trial (H2O II), financial strain significantly modified the effect of the intervention such that the subgroup of children with high financial strain who received the intervention experienced more reuse than their control counterparts. In HTE analyses of 2 randomized controlled trials, only financial strain significantly modified the nurse phone call. A family's financial resources may affect the utility of postdischarge support.

To What Extent Do the NRS and CRQ Capture Change in Patients' Experience of Breathlessness in Advanced Disease? Findings From a Mixed-Methods Double-Blind Randomized Feasibility Trial

ContextChronic or refractory breathlessness is common and distressing. To evaluate new treatments, outcome measures that capture change in patients' experience are needed. ObjectivesTo explore the extent to which the numerical rating scale (NRS) worst and average, and the Chronic Respiratory Questionnaire capture change in patients' experience during a trial of mirtazapine for refractory breathlessness. MethodsConvergent mixed-methods design embedded within a randomized trial comprising 1) semi-structured qualitative interviews (considered to be the gold standard) and 2) outcome measure data collected pre- and post-intervention. Data were integrated, exploring examples where findings agreed and disagreed. Adults with advanced cancer, chronic obstructive pulmonary disease, interstitial lung disease, or chronic heart failure, with a modified Medical Research Council dyspnea scale grade 3 or 4 were recruited from three U.K. sites. ResultsData were collected for 22 participants. Eleven had a diagnosis of chronic obstructive pulmonary disease, eight interstitial lung disease, two chronic heart failure, and one cancer. Median age was 71 (56–84) years. Sixteen participants were men. Changes in the qualitative data were commonly captured in the NRS (worst and average) and the Chronic Respiratory Questionnaire. The NRS worst captured change most frequently. Improvement in the emotional domain was associated with physical changes, improved confidence, and control. ConclusionThis study found that the NRS using the question “How bad has your breathlessness felt at its worst over the past 24 hours?” captured change across multiple domains, and therefore may be an appropriate primary outcome measure in trials in this population. Future work should confirm the construct validity of this question.

TP1-7 Extended glasgow outcome scale – when would you rather die?

ObjectivesExtended Glasgow Outcome Scale is the primary outcome measure in trials involving neurotrauma patients. Conventional dichotomization characterises unfavourable outcomes as upper severe disability or worse, however RESCUE-ICP changed this to consider upper severe disability as a favourable outcome. As the recent consensus meeting in Cambridge proved, opinion of what constitutes acceptable recovery can vary widely between individuals.DesignTo survey patients with brain injury and compare them to the opinions of staff routinely involved in the care of such patients.SubjectsPatients with brain injuries, neurosurgery staff and ITU staff.MethodGOS-E sheets were given to neurotrauma patients and asked to circle the outcome they considered unfavourable and therefore would rather not survive. This was compared to the same question posed to neurosurgery staff members, and ITU staff members.Results67 responses collected (20 patients, 27 neurosurgery staff, 20 ITU staff). Mean GOS-E score deemed unfavourable and therefore not worth survival was 3.6, mode 3 (Patient mean 3.15, mode 3. Neurosurgery mean 3.63, mode 4. ITU mean 4.0, mode 5. p>0.05).ConclusionWhat constitutes unfavourable outcome varies between each group of people questioned. Patients who have experienced brain injuries were more likely to feel that upper severe disability was an acceptable outcome when compared to the staff that care for them. It is imperative we take this in to consideration when recommending treatment strategies in an acute setting.

Abstract TMP6: NIH Stroke Scale as the Primary Outcome Measure for Trials of Acute Treatment of Ischemic Stroke

Background: The 90-day modified Rankin Scale (mRS) is the most commonly used primary outcome measure in stroke treatment trials, but has drawbacks, including the potential loss of subjects due to prolonged follow-up. An alternative may be the NIH Stroke Scale (NIHSS) early after stroke, which is frequently used as a secondary outcome measure. The aim of this study was to evaluate whether the NIHSS assessed within one week after trial inclusion could serve as a primary outcome measure for trials of acute ischaemic stroke treatment. Methods: We used the Prentice criteria to evaluate NIHSS 1 day and 5-7 days after trial inclusion as primary outcome measures in two trials of endovascular treatment (EVT): the positive MR CLEAN and the neutral IMS III. The four Prentice criteria evaluate a surrogate endpoint against a true endpoint (Figure). We adjusted for age, baseline NIHSS, collateral score, and time of symptom onset to randomization. Results: The Prentice criteria were met for NIHSS at 1 day and 5-7 days in MR CLEAN (n=500). We found a significant treatment effect of EVT on the mRS and on the NIHSS at 1 day and 5-7 days. After adjustment for NIHSS at 1 day and 5-7 days, the effect of EVT on mRS decreased from common odds ratio 1·69 (95%CI: 1·22-2·33) to respectively 1·33 (95%CI: 0·95-1·85) and 1·21 (95%CI: 0·86-1·72). In IMS III (n=656) there was no treatment effect on NIHSS at 1 day (p=0.56) and 5-7 days (p=0.28), coinciding with the absence of a treatment effect on mRS. Conclusion: NIHSS is able to replace the mRS at 90 days as a measure of treatment effect. NIHSS within one week after trial inclusion may be used as a primary outcome measure in trials of acute ischemic stroke treatment, particularly in phase II(b) trials. This could minimize loss to follow-up, and reduce trial duration and costs.

Manipulation of Human Verticality Using High-Definition Transcranial Direct Current Stimulation.

Background: Using conventional tDCS over the temporo-parietal junction (TPJ) we previously reported that it is possible to manipulate subjective visual vertical (SVV) and postural control. We also demonstrated that high-definition tDCS (HD-tDCS) can achieve substantially greater cortical stimulation focality than conventional tDCS. However, it is critical to establish dose-response effects using well-defined protocols with relevance to clinically meaningful applications.Objective: To conduct three pilot studies investigating polarity and intensity-dependent effects of HD-tDCS over the right TPJ on behavioral and physiological outcome measures in healthy subjects. We additionally aimed to establish the feasibility, safety, and tolerability of this stimulation protocol.Methods: We designed three separate randomized, double-blind, crossover phase I clinical trials in different cohorts of healthy adults using the same stimulation protocol. The primary outcome measure for trial 1 was SVV; trial 2, weight-bearing asymmetry (WBA); and trial 3, electroencephalography power spectral density (EEG-PSD). The HD-tDCS montage comprised a single central, and 3 surround electrodes (HD-tDCS3x1) over the right TPJ. For each study, we tested 3x2 min HD-tDCS3x1 at 1, 2 and 3 mA; with anode center, cathode center, or sham stimulation, in random order across days.Results: We found significant SVV deviation relative to baseline, specific to the cathode center condition, with consistent direction and increasing with stimulation intensity. We further showed significant WBA with direction governed by stimulation polarity (cathode center, left asymmetry; anode center, right asymmetry). EEG-PSD in the gamma band was significantly increased at 3 mA under the cathode.Conclusions: The present series of studies provide converging evidence for focal neuromodulation that can modify physiology and have behavioral consequences with clinical potential.

Beta cell function in type 1 diabetes determined from clinical and fasting biochemical variables.

Beta cell function in type 1 diabetes is commonly assessed as the average plasma C-peptide concentration over 2h following a mixed-meal test (CPAVE). Monitoring of disease progression and response to disease-modifying therapy would benefit from a simpler, more convenient and less costly measure. Therefore, we determined whether CPAVE could be reliably estimated from routine clinical variables. Clinical and fasting biochemical data from eight randomised therapy trials involving participants with recently diagnosed type 1 diabetes were used to develop and validate linear models to estimate CPAVE and to test their accuracy in estimating loss of beta cell function and response to immune therapy. A model based on disease duration, BMI, insulin dose, HbA1c, fasting plasma C-peptide and fasting plasma glucose most accurately estimated loss of beta cell function (area under the receiver operating characteristic curve [AUROC] 0.89 [95% CI 0.87, 0.92]) and was superior to the commonly used insulin-dose-adjusted HbA1c (IDAA1c) measure (AUROC 0.72 [95% CI 0.68, 0.76]). Model-estimated CPAVE (CPEST) reliably identified treatment effects in randomised trials. CPEST, compared with CPAVE, required only a modest (up to 17%) increase in sample size for equivalent statistical power. CPEST, approximated from six variables at a single time point, accurately identifies loss of beta cell function in type 1 diabetes and is comparable to CPAVE for identifying treatment effects. CPEST could serve as a convenient and economical measure of beta cell function in the clinic and as a primary outcome measure in trials of disease-modifying therapy in type 1 diabetes.

Predictors of reliable symptom change: Secondary analysis of the Preschool Autism Communication Trial

Background and aims Despite recent gains in the amount and quality of early autism intervention research, identifying what works for whom remains an ongoing challenge. Exploiting data from the Preschool Autism Communication Trial (PACT), we undertook secondary analysis to explore prognostic indicators and predictors of response to one year of PACT therapy versus treatment as usual within this large and rigorously characterised cohort recruited across three UK trial sites. Methods In this secondary analysis of variability in child gains on the primary trial outcome measure – social-communication symptom severity – we used a pragmatic and data-driven approach to identify a subgroup of children who showed reliable improvement and a subgroup showing clear lack thereof. We then tested which among several baseline child and family factors – including measures routinely collected in research trials and clinical practice – varied as a function of child outcome status and treatment group. Results Greater baseline child non-verbal ability was a significant prognostic indicator of symptom reduction over time (i.e. irrespective of treatment group). By contrast, parent synchrony presented as marginal predictor, and trial recruitment site as a significant predictor, of differential outcome by treatment group. Specifically, lower parent synchrony showed some association with poorer outcomes for children from families assigned to treatment as usual (but with no such effect for those assigned to PACT). Similarly, children at one recruitment site were more likely to have poorer outcomes if assigned to treatment as usual, compared to children at the same site assigned to PACT. Conclusions The current data contribute to an evidence base indicting that early non-verbal ability is a robust indicator of generally better prognosis for young children with autism. Lower parent synchrony and a broadly more deprived socio-geographical context may inform the appropriate targeting of PACT. That is, given that the former factors predicted poorer outcome in children from families assigned to treatment as usual, the receipt of a relatively low-dose, parent-mediated and communication-focused therapy might be developmentally protective for young children with autism. Nevertheless, results from this study also highlight the paucity of meaningful predictors of outcome among routine clinical characterisation measures such as those investigated here. Implications Understanding the factors associated with differential treatment outcomes is critical if we are to individualise treatment decisions for children with autism. Inherently tied to this objective is a need to delineate those factors which specifically predict positive response (or lack of response) to one or other treatment option, versus those that indicate generally better (or poorer) prognosis, irrespective of treatment.

Acute Management of Hemostasis in Patients With Neurological Injury.

Neurological injuries can be divided into those with traumatic and nontraumatic causes. The largest groups are traumatic brain injury (TBI) and nontraumatic stroke. TBI patients may present with intracranial hemorrhages (contusions, or subdural or epidural hematomas). Strokes are ischemic or hemorrhagic. In all these disorders, thrombosis and hemostasis play a major role. Treatment aims to either cease bleeding and/or restore perfusion. We reviewed hemostatic and thrombolytic therapies in patients with neurological injuries by MEDLINE and EMBASE search using various key words for neurological disorders and hemostatic therapies restricted to English language and human adults. Review of articles fulfilling inclusion criteria and relevant references revealed that, in patients with ischemic stroke, intravenous thrombolytic therapy with recombinant tissue plasminogen activator within 4.5-5 hours after onset of symptoms improves clinical outcome. In contrast, there are no hemostatic therapies that are proven to improve clinical outcome of patients with hemorrhagic stroke or TBI. In patients with hemorrhagic stroke who use vitamin K antagonist or direct oral anticoagulants, there is evidence that specific reversal therapies improve hemostatic laboratory parameters but without an effect on clinical recovery. In patients with hemorrhagic stroke or TBI who use concomitant antiplatelet therapy, there is evidence for harm of platelet transfusion. In patients with aneurysmal subarachnoid hemorrhage, tranexamic acid was shown to reduce rebleeding rate without improving clinical outcome. The effects of tranexamic acid in patients with TBI are still under investigation. We conclude that, in patients with ischemic stroke, thrombolytic therapy improves outcome when given within 4.5-5 hours. In hemorrhagic stroke and TBI, most hemostatic therapies improved or corrected laboratory parameters but not clinical outcome. Currently, in several trials, the effects of tranexamic acid are being studied of which the results are eagerly awaited. Because improving clinical outcome should be the goal of new therapies, we encourage to use clinical outcome scales as the primary outcome measure in trials that investigate effects of hemostatic therapies in patients with neurological injury.

Maternal vitamin D supplementation during pregnancy and lactation to promote infant growth in Dhaka, Bangladesh (MDIG trial): study protocol for a randomized controlled trial

BackgroundVitamin D regulates bone mineral metabolism and skeletal development. Some observational studies have suggested that prenatal vitamin D deficiency increases the risk of adverse pregnancy and/or birth outcomes; however, there is scant evidence from controlled trials, leading the World Health Organization to advise against routine vitamin D supplementation in pregnancy. Importantly, little is known about the effect of maternal vitamin D status on infant linear growth in communities in South Asia where stunting is highly prevalent and maternal-infant vitamin D status is commonly suboptimal.Methods/DesignThe Maternal Vitamin D for Infant Growth study is a randomized, placebo-controlled, dose-ranging trial of maternal vitamin D supplementation during pregnancy and lactation in Dhaka, Bangladesh. The primary aims are to estimate (1) the effect of maternal prenatal oral vitamin D3 supplementation (4200 IU/wk, 16,800 IU/wk, or 28,000 IU/wk, administered as weekly doses) versus placebo on infant length at 1 year of age and (2) the effect of maternal postpartum oral vitamin D3 supplementation (28,000 IU/wk) versus placebo on length at 1 year of age among infants born to women who received vitamin D 28,000 IU/wk during pregnancy. Generally healthy pregnant women (n = 1300) in the second trimester (17–24 weeks of gestation) are randomized to one of five parallel arms: placebo 4200 IU/wk, 16,800 IU/wk, or 28,000 IU/wk in the prenatal period and placebo in the postpartum period or 28,000 IU/wk in the prenatal period and 28,000 IU/wk in the postpartum period. Household- and clinic-based follow-up of mother-infant pairs is conducted weekly by trained personnel until 26 weeks postpartum and every 3 months thereafter. The primary trial outcome measure is length for age z-score at 1 year of age. Anthropometric measurements, clinical information, and biological specimens collected at scheduled intervals will enable the assessment of a range of maternal, perinatal, and infant outcomes.DiscussionThe role of vitamin D in maternal and infant health remains unresolved. This trial is expected to contribute unique insights into the effects of improving maternal-infant vitamin D status in a low-income setting where stunting and adverse perinatal outcomes represent significant public health burdens.Trial registrationClinicalTrials.gov identifier: NCT01924013. Registered on 13 August 2013Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0825-8) contains supplementary material, which is available to authorized users.

Gender norms and economic empowerment intervention to reduce intimate partner violence against women in rural Côte d’Ivoire: a randomized controlled pilot study

BackgroundGender-based violence against women, including intimate partner violence (IPV), is a pervasive health and human rights concern. However, relatively little intervention research has been conducted on how to reduce IPV in settings impacted by conflict. The current study reports on the evaluation of the incremental impact of adding “gender dialogue groups” to an economic empowerment group savings program on levels of IPV. This study took place in north and northwestern rural Côte d’Ivoire.MethodsBetween 2010 and 2012, we conducted a two-armed, non-blinded randomized-controlled trial (RCT) comparing group savings only (control) to “gender dialogue groups” added to group savings (treatment). The gender dialogue group consisted of eight sessions that targeted women and their male partner. Eligible Ivorian women (18+ years, no prior experience with group savings) were invited to participate. 934 out of 981 (95.2%) partnered women completed baseline and endline data collection. The primary trial outcome measure was an overall measure of past-year physical and/or sexual IPV. Past year physical IPV, sexual IPV, and economic abuse were also separately assessed, as were attitudes towards justification of wife beating and a woman’s ability to refuse sex with her husband.ResultsIntent to treat analyses revealed that compared to groups savings alone, the addition of gender dialogue groups resulted in a slightly lower odds of reporting past year physical and/or sexual IPV (OR: 0.92; 95% CI: 0.58, 1.47; not statistically significant). Reductions in reporting of physical IPV and sexual IPV were also observed (not statistically significant). Women in the treatment group were significantly less likely to report economic abuse than control group counterparts (OR = 0.39; 95% CI: 0.25, 0.60, p < .0001). Acceptance of wife beating was significantly reduced among the treatment group (β = -0.97; 95% CI: -1.67, -0.28, p = 0.006), while attitudes towards refusal of sex did not significantly change Per protocol analysis suggests that compared to control women, treatment women attending more than 75% of intervention sessions with their male partner were less likely to report physical IPV (a OR: 0.45; 95% CI: 0.21, 0.94; p = .04) and report fewer justifications for wife beating (adjusted β = -1.14; 95% CI: -2.01, -0.28, p = 0.01) ; and both low and high adherent women reported significantly decreased economic abuse (a OR: 0.31; 95% CI: 0.18, 0.52, p < 0.0001; a OR: 0.47; 95% CI: 0.27, 0.81, p = 01, respectively). No significant reductions were observed for physical and/or sexual IPV, or sexual IPV alone.ConclusionsResults from this pilot RCT suggest the importance of addressing household gender inequities alongside economic programming, because this type of combined intervention has potential to reduce levels of IPV. Additional large-scale intervention research is needed to replicate these findings.Trial registrationRegistration Number: NCT01629472.

New horizons in the pathogenesis, diagnosis and management of sarcopenia

Sarcopenia is the age-related loss of skeletal muscle mass and function. It is now recognised as a major clinical problem for older people and research in the area is expanding exponentially. One of the most important recent developments has been convergence in the operational definition of sarcopenia combining measures of muscle mass and strength or physical performance. This has been accompanied by considerable progress in understanding of pathogenesis from animal models of sarcopenia. Well-described risk factors include age, gender and levels of physical activity and this knowledge is now being translated into effective management strategies including resistance exercise with recent interest in the additional role of nutritional intervention. Sarcopenia is currently a major focus for drug discovery and development although there remains debate about the best primary outcome measure for trials, and various promising avenues to date have proved unsatisfactory. The concept of ‘new tricks for old drugs’ is, however, promising, for example, there is some evidence that the angiotensin-converting enzyme inhibitors may improve physical performance. Future directions will include a deeper understanding of the molecular and cellular mechanisms of sarcopenia and the application of a lifecourse approach to understanding aetiology as well as to informing the optimal timing of interventions.

Sampling bias in an internet treatment trial for depression

Internet psychological interventions are efficacious and may reduce traditional access barriers. No studies have evaluated whether any sampling bias exists in these trials that may limit the translation of the results of these trials into real-world application. We identified 7999 potentially eligible trial participants from a community-based health cohort study and invited them to participate in a randomized controlled trial of an online cognitive behavioural therapy programme for people with depression. We compared those who consented to being assessed for trial inclusion with nonconsenters on demographic, clinical and behavioural indicators captured in the health study. Any potentially biasing factors were then assessed for their association with depression outcome among trial participants to evaluate the existence of sampling bias. Of the 35 health survey variables explored, only 4 were independently associated with higher likelihood of consenting—female sex (odds ratio (OR) 1.11, 95% confidence interval (CI) 1.05–1.19), speaking English at home (OR 1.48, 95% CI 1.15–1.90) higher education (OR 1.67, 95% CI 1.46–1.92) and a prior diagnosis of depression (OR 1.37, 95% CI 1.22–1.55). The multivariate model accounted for limited variance (C-statistic 0.6) in explaining participation. These four factors were not significantly associated with either the primary trial outcome measure or any differential impact by intervention arm. This demonstrates that, among eligible trial participants, few factors were associated with the consent to participate. There was no indication that such self-selection biased the trial results or would limit the generalizability and translation into a public or clinical setting.

Does the Extended Glasgow Outcome Scale Add Value to the Conventional Glasgow Outcome Scale?

The Glasgow Outcome Scale (GOS) is firmly established as the primary outcome measure for use in Phase III trials of interventions in traumatic brain injury (TBI). However, the GOS has been criticized for its lack of sensitivity to detect small but clinically relevant changes in outcome. The Glasgow Outcome Scale-Extended (GOSE) potentially addresses this criticism, and in this study we estimate the efficiency gain associated with using the GOSE in place of the GOS in ordinal analysis of 6-month outcome. The study uses both simulation and the reanalysis of existing data from two completed TBI studies, one an observational cohort study and the other a randomized controlled trial. As expected, the results show that using an ordinal technique to analyze the GOS gives a substantial gain in efficiency relative to the conventional analysis, which collapses the GOS onto a binary scale (favorable versus unfavorable outcome). We also found that using the GOSE gave a modest but consistent increase in efficiency relative to the GOS in both studies, corresponding to a reduction in the required sample size of the order of 3-5%. We recommend that the GOSE be used in place of the GOS as the primary outcome measure in trials of TBI, with an appropriate ordinal approach being taken to the statistical analysis.

Quality assurance for oral anticoagulation self management: a cluster randomized trial.

External quality assessment (EQA) should be an inherent component of patient self management (PSM) of oral anticoagulation. The aim of this study was to evaluate methods of EQA for patients within a cluster randomized trial. After development of methods, general practises were randomly allocated to a formal EQA scheme of patients performing the test independently at home or at their practise with supervision. The supervised group of practises was further sub divided to test two other EQA methods: (i) venous sample compared with patients' point of care (POC) device; and (ii) patients POC compared with reference POC. Primary trial outcome measure was reliability of results from the formal scheme taking into account adherence and test errors. Proportion of EQA scheme tests in range was 633/836 (75.7%). Proportion in range was significantly higher in group performing independently compared with supervised group, 80.1% vs. 71.5% respectively, P = 0.02. Sixty-six percent of tests were in range with venous compared with patients POC, and 88% in patients POC compared with reference POC. Patients are able to undertake a formal EQA scheme and perform more reliably at home independently. There are satisfactory alternatives if a formal scheme is not acceptable.

Clinical scoring methods for multiple sclerosis.

Multiple sclerosis (MS) clinical rating scales are used to classify the degree of neurological dysfunction and to plan treatment measures. In clinical trials, rating scales are used to monitor clinical course and response to experimental therapies. Selection of the appropriate clinical rating scale is determined by the nature of the research question (e.g., disability, impairment, handicap). The Expanded Disability Status Scale (EDSS, an impairment scale) has been the most widely used clinical rating method in natural history studies and clinical trials. The EDSS has the advantage of familiarity, yet is difficult to use consistently between evaluators. In the mid and higher ranges, the EDSS is relatively insensitive to clinical changes that do not impair gait. Evaluator unblinding may invalidate the clinical assessment of response to treatment. Additional work is needed to develop clinical and laboratory (imaging) measures of MS disease activity that will be objective, reliable, sensitive, responsive, and valid. Recent comparative studies have demonstrated that serial magnetic resonance imaging (MRI) studies are 7- to 10-fold more sensitive than clinical methods in detecting subclinical evidence of apparent MS disease activity. Widespread acceptance of MRI as a primary trial outcome measure awaits the results of studies designed to determine whether MRI findings accurately reflect irreversible pathological changes and predict future disability.