How a sequential design would have affected the GAIN international study of Gavestinel in stroke

While planning the GAIN International Study of gavestinel in acute stroke, a sequential triangular test was proposed but not implemented. Before the trial commenced it was agreed to evaluate the sequential design retrospectively to evaluate the differences in the resulting analyses, trial durations and sample sizes in order to assess the potential of sequential procedures for future stroke trials. This paper presents four sequential reconstructions of the GAIN study made under various scenarios. For the data as observed, the sequential design would have reduced the trial sample size by 234 patients and shortened its duration by 3 or 4 months. Had the study not achieved a recruitment rate that far exceeded expectation, the advantages of the sequential design would have been much greater. Sequential designs appear to be an attractive option for trials in stroke. Copyright 2004 S. Karger AG, Basel

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. Copyright (C) 2008 John Wiley & Sons, Ltd.

Using historical lesion volume data in the design of a new phase II clinical trial in acute stroke

Background and Purpose-Clinical research into the treatment of acute stroke is complicated, is costly, and has often been unsuccessful. Developments in imaging technology based on computed tomography and magnetic resonance imaging scans offer opportunities for screening experimental therapies during phase II testing so as to deliver only the most promising interventions to phase III. We discuss the design and the appropriate sample size for phase II studies in stroke based on lesion volume. Methods-Determination of the relation between analyses of lesion volumes and of neurologic outcomes is illustrated using data from placebo trial patients from the Virtual International Stroke Trials Archive. The size of an effect on lesion volume that would lead to a clinically relevant treatment effect in terms of a measure, such as modified Rankin score (mRS), is found. The sample size to detect that magnitude of effect on lesion volume is then calculated. Simulation is used to evaluate different criteria for proceeding from phase II to phase III. Results-The odds ratios for mRS correspond roughly to the square root of odds ratios for lesion volume, implying that for equivalent power specifications, sample sizes based on lesion volumes should be about one fourth of those based on mRS. Relaxation of power requirements, appropriate for phase II, lead to further sample size reductions. For example, a phase III trial comparing a novel treatment with placebo with a total sample size of 1518 patients might be motivated from a phase II trial of 126 patients comparing the same 2 treatment arms. Discussion-Definitive phase III trials in stroke should aim to demonstrate significant effects of treatment on clinical outcomes. However, more direct outcomes such as lesion volume can be useful in phase II for determining whether such phase III trials should be undertaken in the first place. (Stroke. 2009;40:1347-1352.)

Acute stroke predisposes to oral gram-negative bacilli - a cause of aspiration pneumonia?

Objectives: To assess any change in the oral flora in the mouths of stroke patients during the acute and rehabilitation phases and to determine whether this is related to episodes of aspiration pneumonia and clinical outcome. Materials and Methods: This observational study was carried out in hospital wards in a University teaching hospital. The subjects were patients immediately post-stroke and during the rehabilitation period, acute admissions and a group of healthy volunteers. An assessment of dentition and swallow in the presence or absence of oral aerobic gram-negative bacilli (AGNB) was correlated. Results: Of the acute stroke patients 52% had an unsafe swallow. AGNB carriage was documented in 34% of the acute stroke group. Of the 11 patients who died 55% had AGNB, 73% had an unsafe swallow and 36% had a combination of both. Conclusion: AGNB is a common finding in acute stroke patients. It is not a consequence of age or acute hospitalisation and is associated with an unsafe swallow and a higher mortality. Copyright (C) 2003 S. Karger AG, Basel.

Disruption of sitting balance after stroke: influence of spoken output

Objectives: To identify the extent of dual task interference between cognitive and motor tasks, (cognitive motor interference (CMI)) in sitting balance during recovery from stroke; to compare CMI in sitting balance between stroke and non-stroke groups; and to record any changes to CMI during sitting that correlate with functional recovery. Method: 36 patients from stroke rehabilitation settings in three NHS trusts. Healthy control group: 21 older volunteers. Measures of seated postural sway were taken in unsupported sitting positions, alone, or concurrently with either a repetitive utterance task or an oral word category generation task. Outcome measures were variability of sway area, path length of sway, and the number of valid words generated. Results: Stroke patients were generally less stable than controls during unsupported sitting tasks. They showed greater sway during repetitive speech compared with quiet sitting, but did not show increased instability to posture between repetitive speech and word category generation. When compared with controls, stroke patients experienced greater dual task interferences during repetitive utterance but not during word generation. Sway during repetitive speech was negatively correlated with concurrent function on the Barthel ADL index. Conclusions: The stroke patients showed postural instability and poor word generation skills. The results of this study show that the effort of verbal utterances alone was sufficient to disturb postural control early after stroke, and the extent of this instability correlated with concomitant Barthel ADL function.

Changing patterns of cognitive-motor interference (CMI) over time during recovery from stroke

Objective: To explore the extent and nature of change in cognitive-motor interference (CMI) among rehabilitating stroke patients who showed dual-task gait decrement at initial assessment. Design: Experimental, with in-subjects, repeated measures design. Setting: Rehabilitation centre for adults with acquired, nonprogressive brain injury. Subjects: Ten patients with unilateral stroke, available for reassessment 1-9 months following their participation in a study of CMI after brain injury. Measures: Median stride duration; mean word generation. Methods: Two x one-minute walking trials, two x one-minute word generation trials, two x one-minute trials of simultaneous walking and word generation; 10-metre walking time; Barthel ADL Scale score. Results: Seven out of ten patients showed reduction over time in dual-task gait decrement. Three out of ten showed reduction in cognitive decrement. Only one showed concomitant reduction in gait and word generation decrement. Conclusion: Extent of CMI during relearning to walk after a stroke reduced over time in the majority of patients. Effects were more evident in improved stride duration than improved cognitive performance. Measures of multiple task performance should be included in assessment for functional recovery.

Analysis of the Fugl-Meyer outcome measures assessing the effectiveness of robot-mediated stroke therapy

Robot-mediated therapies offer a new approach to neurorehabilitation. This paper analyses the Fugl-Meyer data from the Gentle/S project and finds that the two intervention phases (sling suspension and robot mediated therapy) have approximately equal value to the further recovery of chronic stroke subjects (on average 27 months post stroke). Both sling suspension and robot mediated interventions show a recovery over baseline and further work is needed to establish the common factors in treatment, and to establish intervention protocols for each that will give individual subjects a maximum level of recovery.

Reach and grasp therapy: effects of the Gentle/G System assessing sub-acute stroke whole-arm rehabilitation

This paper reports preliminary results of a reach and grasp study of robot mediated neurorehabilitation. These results are presented on a case-by-case basis and give a good indication of a positive effect of robot mediated therapy. The study investigated both reach and grasp assistance and although it is not possible to attribute the response to the benefits of providing assistance of both modalities the study is a good indicator that this strategy should be pursued. The paper also reports on the benefits of motivational queues such as exercise scores and on subject attitudes to the robot mediated therapy.

Structural design of an escort type rehabilitation robot for post-stroke therapies of upper-limb

This paper describes a structural design technique for rehabilitation robot intended for upper-limb post-stroke therapy. First, a novel approach to a rehabilitation robot is proposed and the features of the robot are explained. Second, the direct kinematics and the inverse kinematics of the proposed robot structure are derived. Finally, a mechanical design procedure is explained that achieves a compromise between the required motion range and assuring the workspace safety. The suitability of a portable escort type structure for upper limb rehabilitation of both acute and chronic stroke is discussed

Multivariate analysis of the Fugl-Meyer outcome measures assessing the effectiveness of GENTLE/S robot-mediated stroke therapy

Background: Robot-mediated therapies offer entirely new approaches to neurorehabilitation. In this paper we present the results obtained from trialling the GENTLE/S neurorehabilitation system assessed using the upper limb section of the Fugl-Meyer ( FM) outcome measure. Methods: We demonstrate the design of our clinical trial and its results analysed using a novel statistical approach based on a multivariate analytical model. This paper provides the rational for using multivariate models in robot-mediated clinical trials and draws conclusions from the clinical data gathered during the GENTLE/S study. Results: The FM outcome measures recorded during the baseline ( 8 sessions), robot-mediated therapy ( 9 sessions) and sling-suspension ( 9 sessions) was analysed using a multiple regression model. The results indicate positive but modest recovery trends favouring both interventions used in GENTLE/S clinical trial. The modest recovery shown occurred at a time late after stroke when changes are not clinically anticipated. Conclusion: This study has applied a new method for analysing clinical data obtained from rehabilitation robotics studies. While the data obtained during the clinical trial is of multivariate nature, having multipoint and progressive nature, the multiple regression model used showed great potential for drawing conclusions from this study. An important conclusion to draw from this paper is that this study has shown that the intervention and control phase both caused changes over a period of 9 sessions in comparison to the baseline. This might indicate that use of new challenging and motivational therapies can influence the outcome of therapies at a point when clinical changes are not expected. Further work is required to investigate the effects arising from early intervention, longer exposure and intensity of the therapies. Finally, more function-oriented robot-mediated therapies or sling-suspension therapies are needed to clarify the effects resulting from each intervention for stroke recovery.

The effect of the GENTLE/s robot-mediated therapy system on arm function after stroke

Objective: To evaluate the effect of robot-mediated therapy on arm dysfunction post stroke. Design: A series of single-case studies using a randomized multiple baseline design with ABC or ACB order. Subjects (n = 20) had a baseline length of 8, 9 or 10 data points. They continued measurement during the B - robot-mediated therapy and C - sling suspension phases. Setting: Physiotherapy department, teaching hospital. Subjects: Twenty subjects with varying degrees of motor and sensory deficit completed the study. Subjects attended three times a week, with each phase lasting three weeks. Interventions: In the robot-mediated therapy phase they practised three functional exercises with haptic and visual feedback from the system. In the sling suspension phase they practised three single-plane exercises. Each treatment phase was three weeks long. Main measures: The range of active shoulder flexion, the Fugl-Meyer motor assessment and the Motor Assessment Scale were measured at each visit. Results: Each subject had a varied response to the measurement and intervention phases. The rate of recovery was greater during the robot-mediated therapy phase than in the baseline phase for the majority of subjects. The rate of recovery during the robot-mediated therapy phase was also greater than that during the sling suspension phase for most subjects. Conclusion: The positive treatment effect for both groups suggests that robot-mediated therapy can have a treatment effect greater than the same duration of non-functional exercises. Further studies investigating the optimal duration of treatment in the form of a randomized controlled trial are warranted.