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Trial registered on ANZCTR


Registration number
ACTRN12613001136796
Ethics application status
Approved
Date submitted
3/07/2013
Date registered
11/10/2013
Date last updated
12/10/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effective sensory rehabilitation after stroke: Targeting viable brain networks.
Scientific title
Do stroke survivors with impaired body sensations who undertake sensory rehabilitation demonstrate different patterns of functional connectivity in the brain associated with improvements in sensory function depending on lesions of cortical or subcortical somatosensory areas and approach to training?
Secondary ID [1] 282560 0
Nil
Universal Trial Number (UTN)
Trial acronym
CoNNECT - Connecting New Networks for Everyday Contact through Touch
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Somatosensory processing deficit after stroke 289263 0
Condition category
Condition code
Stroke 289591 289591 0 0
Ischaemic
Stroke 289845 289845 0 0
Haemorrhagic
Physical Medicine / Rehabilitation 289895 289895 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stroke survivors will be assessed at least 3 months post stroke for clinical and imaging outcomes, then randomized into one of 3 treatment packages of 2X6-week intervention/no intervention phases.
Arm 1: The first package involves 6 weeks of no training followed by 6 weeks of transfer enhanced training of body sensation.
Arm 2: The second package involves 6 weeks of stimulus specific training of touch sensation followed by 6 weeks of transfer enhanced training of body sensation.
Arm 3: The third package involves 6 weeks of transfer enhanced training of body sensation, followed by 6 weeks of no training.

Each training phase involves 15 training sessions at a rate of approximately 3 times per week and duration of 60 minutes per session. Training sessions are one on one with an experienced research therapist. Each participant has an individual training log, where the research therapist stores forms to record each session in order to monitor their progress.

Stimulus specific training involves graded and repeated learning-based discrimination training of specific sensory stimuli, ie. texture grids.
Transfer enhanced training involves learning-based discrimination training of a variety of sensory attributes, across a matrix of sensory tasks including common textures, limb positions and everyday objects. A variety of stimuli and learning conditions, tuition of training principles and feedback on the act of transfer to novel stimuli are used to facilitate transfer.
Intervention code [1] 287244 0
Rehabilitation
Comparator / control treatment
Comparisons will be made between stroke groups in the intervention and non-intervention phases. A control group of age and gender matched healthy volunteers will provide a comparison of typical sensory networks and processing before and after a 6 week interval.
Control group
Active

Outcomes
Primary outcome [1] 289680 0
Tactile Discrimination Test (TDT) - participants are required to discriminate differences in finely graded plastic ridged surfaces using a three-alternative forced choice design. Excellent test-retest reliability (r=0.92).

Carey LM, Oke LE, Matyas TA. Impaired touch discrimination after stroke: a quantitative test. Neurorehabil Neural Repair. 1997;11:219-32.
Timepoint [1] 289680 0
Pre- and post- 6 week stimulus specific sensory intervention/no intervention phases and at 3 months follow up
Primary outcome [2] 289681 0
The Standardized Somatosensory Deficit score (SSD) - a composite index of functional somatosensory discrimination capacity.

The composite index of sensory function is derived from standardized scores of texture discrimination (Fabric Matching Test), limb position sense (Wrist Position Sense Test) and tactile object recognition (functional Tactile Object Recognition Test). Each component measure has age-adjusted normative standards, high reliability (r = 0.85 to 0.92) and good discriminative test properties.

Carey LM, Macdonnell R, Matyas D. SENSe: Study of the Effectiveness of Neurorehabilitation on Sensation. A randomized controlled trial. Neurorehabil Neural Repair. 2011;25:304-313.
Timepoint [2] 289681 0
Pre- and post- 6 week transfer enhanced training intervention/no intervention phases and at 3 months follow up
Primary outcome [3] 289682 0
Strength of functional connections in somatosensory neural networks - neurimaging outcome
Timepoint [3] 289682 0
Pre- and post- 6 week intervention/no intervention phases
Secondary outcome [1] 303303 0
Upper limb function (9-hole peg test, Action Research Arm Test, Motor Activity Log-Short Version)
Timepoint [1] 303303 0
Pre- and post- 6 week intervention/no intervention phases and at 3 month follow up.
Secondary outcome [2] 303304 0
Functional independence (Modified Rankin Scale, Stroke Impact Scale)
Timepoint [2] 303304 0
Pre- and post- 6 week intervention/no intervention phases and at 6 month follow up.

Eligibility
Key inclusion criteria
Stroke patients:

1) first episode of cortical or sub-cortical stroke;
2) Somatosensory impairment clinically apparent or queried;
3) Medically stable;
4) able to give informed consent and comprehend simple instructions;
5) right hand dominant

Healthy participants:

1) medically stable;
2) able to give informed consent and comprehend simple instructions;
3) right hand dominant
Minimum age
18 Years
Maximum age
90 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Stroke patients:

1) Brainstem stroke;
2) Previous neurological dysfunction or medical history that impairs hand function or precludes MRI;
3) Peripheral neuropathy in the upper limbs;
4) Evidence of neglect on standard neuropsychological tests;
5) Not suitable for MRI.

Healthy participants:

1) any history of neurological, psychiatric or somatosensory impairment;
2) previous neurological dysfunction or medical history that impairs hand function or precludes MRI.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients with a somatosensory impairment will be assessed at least 3 months post-stroke for clinical and imaging outcomes and randomized into one of 3 treatment packages of 2 x 6-week intervention/no intervention phases.

They will be matched for lesion location (cortical vs subcortical), and severity of somatosensory impairment at baseline. The assessing therapist and data analyst will be blinded to group allocation and other identifying information.

Allocation to intervention is concealed with independent assignment managed centrally by a researcher who does not have any contact with stroke survivors and only remote contact with treating therapists to inform them of allocation via sealed opaque envelopes or electronic mail just prior to commencement of intervention.

Randomisation is computer generated with minimisation strategies to control for lesion location (cortical/subocrtical) and severity of somatosensory impairment at baseline (mild/moderate/severe).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation is computer generated with minimisation strategies to control for lesion location (cortical/subocrtical) and severity of somatosensory impairment at baseline (mild/moderate/severe).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
POWER ANALYSIS OF SAMPLE SIZE (based on pilot data)

-Functional connectivity (FC): Our pilot studies revealed large differences in primary and secondary somatosensory cortex (SI & SII) FC (mean differences in T scores) over no intervention (n=9) and intervention (n=6) periods, with a Cohen's d of 1.5. Assuming a within-group SD for change scores of 1, the effect size index for this interaction contrast (Cohen's f), is 0.866. This effect would be readily detected with a total sample size of 48, with a power exceeding 0.99. Even with an effect size half of that estimated (f=0.433) a sample of 44 is required, for a power of 0.8 and an alpha of 0.05. Thus the study is well powered (n=72), for this comparison. The second hypothesis will involve exploratory analysis of functional connectivity maps involving 6 seeds. Inclusion of 24 in each of the treatment package groups will permit comparison between (Stimulus Specific Training) SST and (Transfer Enhanced Training) TET subgroups (n=48) as well as an interaction effect with lesion location.

- Structural connectivity: The anticipated effect size for the proportion of the overall variance predicted by the model,
i.e. R-squared, is based on a published model of fibre tract integrity in motor recovery that found an R-squared of 0.7, suggesting a power in excess of 0.95 with a total of 11 patients. We will employ two indexes of structural connectivity to predict change in the behavioural score. When n=48, alpha= 0.05, and power is 0.80, R-squared values of 0.177 (i.e. R=0.42) or more could be detected when fitting two-predictor variables.

-Healthy controls (n=72) will permit characterization of functional and structural connectivity maps for interpretation and direct comparison with stroke groups.

DATA ANALYSES

Testing H1: Impact of lesion location on interhemispheric functional connectivity following sensory rehabilitation:
Strength of interhemispheric FC between SI-SI and thalamic (Th) seed pairs will be compared pre-post intervention in subgroups with cortical or subcortical sensory lesions. The design, 2 lesion levels (cortical, subcortical) x 2 treatment conditions (training, no training) x 2 interhemispheric pathways (SI, thalamic) x 2 test occasions (pre, post), simplifies to four difference scores contrasting the pre-post change in SI-SI with the pre-post change in Th-Th for each of the four groups (2 lesion levels x 2 treatment conditions). Planned interaction comparisons will permit statistical investigation of two competing predictions: (i) that therapy facilitates the spared functional interhemispheric connections, i.e. results in increases in SI-SI, but not Th-Th after subcortical lesions, versus increases in Th-Th, but not SI-SI, after cortical lesions, or (ii) that therapy restores interhemispheric connections, when the reverse would be observed, i.e. increases in Th-Th after subcortical lesions and in SI-SI after cortical. We will also test independently for differences between no treatment and each treatment type (SST, TET) to verify the hypothesis for each. The extent of clinical improvement (change in tactile and sensory capacity score) will be analyzed for its correlation with interhemispheric FC of SI and thalamus.

Testing H2: Differential impact of rehabilitation approach on functional connectivity (FC) maps:
Change in FC maps over the initial intervention period (SST or TET) will be calculated as "difference maps", i.e. within-subject index of change. These maps, seeded in SI, SII and Th bilaterally, will permit exploratory investigation of connectivity from these regions of interest to distributed regions and networks. Differences in connectivity maps following SST and TET will be investigated using a 2 (SST/TET treatment group) x 2 (cortical/subcortical) ANOVA with longitudinal FC maps as the dependent variable. Between group differences will be tested using random effects analysis in SPM8 (www.fil.ion.ucl.ac.uk/spm). Based on this analysis we will also determine whether the hypothesized change associated with treatment (SST vs TET) is qualified by the lesion location (eg. increase in FC to distributed regions following TET will be from spared Th seeds for cortical lesions while subcortical lesions will show increased FC from SI and SII seeds). FC maps will be thresholded at Z > 3.1 and differences reported at a cluster corrected false discovery rate of P < 0.05. Within-individual change in those receiving SST followed by TET will also be analysed.

Testing H3: Structural connectivity of interhemispheric SI-SI and ipsilesional SI-Th connections and ability to benefit from rehabilitation:
Response to rehabilitation will be the change in tactile and sensory capacity scores pre-post intervention. Independent variables will be probability of fibre tracts between (i) SI-SI and (ii) ipsilesional Th-SI. Focus will be on connectivity of fibre tracts from seed regions not directly lesioned. Using the entire sample (n=72), multiple regression analysis will quantify the predictability of response to therapy based on the two indexes of spared connectivity.

Exploratory analyses: While our hypotheses are focused on strength of connectivity in inter-hemispheric SI and thalamo-cortical regions, we will also identify connectivity of other networks, such as visual and attention, in a whole brain, hypothesis generating exploratory analyses.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 1130 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 1131 0
Austin Health - Heidelberg Repatriation Hospital - Heidelberg West
Recruitment hospital [3] 1133 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [4] 1134 0
The Northern Hospital - Epping
Recruitment hospital [5] 1135 0
Royal Talbot Rehabilitation Centre - Kew

Funding & Sponsors
Funding source category [1] 287461 0
Government body
Name [1] 287461 0
NHMRC
Address [1] 287461 0
National Health and Medical Research Council, GPO Box 1421, Canberra ACT 2601
Country [1] 287461 0
Australia
Primary sponsor type
Other Collaborative groups
Name
National Stroke Research Institute
Address
The Florey Institute of Neuroscience and Mental Health
Melbourne Brain Centre - Austin Campus
245 Burgundy Street
Heidelberg Vic 3084
Country
Australia
Secondary sponsor category [1] 286205 0
None
Name [1] 286205 0
Address [1] 286205 0
Country [1] 286205 0
Other collaborator category [1] 277453 0
Hospital
Name [1] 277453 0
Austin Health
Address [1] 277453 0
145 Studley Rd Heidelberg VIC 3084
Country [1] 277453 0
Australia
Other collaborator category [2] 277455 0
Hospital
Name [2] 277455 0
Melbourne Health
Address [2] 277455 0
Royal Melbourne Hospital
Grattan St, Parkville, VIC 3052
Country [2] 277455 0
Australia
Other collaborator category [3] 277456 0
Hospital
Name [3] 277456 0
Northern Health
Address [3] 277456 0
175 Cooper Street
Epping, VIC 3076
Country [3] 277456 0
Australia
Other collaborator category [4] 277457 0
Hospital
Name [4] 277457 0
Hunter New England Areas Health Services
Address [4] 277457 0
John Hunter Hospital
Lookout Road, New Lambton Heights, NSW 2305
Country [4] 277457 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289436 0
Austin Human Research Ethics Committee
Ethics committee address [1] 289436 0
Austin Hospital
145 Studley Road
Heidelberg, Victoria, 3084
Ethics committee country [1] 289436 0
Australia
Date submitted for ethics approval [1] 289436 0
Approval date [1] 289436 0
14/03/2013
Ethics approval number [1] 289436 0
H2013 / 04915

Summary
Brief summary
One in two people experience loss in their ability to feel everyday objects through touch or know where their limbs are in space after a stroke. The loss impairs their ability to explore the environment, execute everyday tasks such as grasping and manipulating objects, and participate in previous activities. Patients vary in their ability to benefit from rehabilitation. Yet we do not have effective means of identifying individuals who may benefit nor how to select the most optimal therapy.
This study will compare brain networks involved in recovery of touch sensation under two new training conditions, and in individuals with interruption to different parts of the network. Brain imaging will identify the functional and anatomical connections between regions involved in recovery. Knowledge of how brain networks adapt under these two training conditions is fundamental to guide individually tailored rehabilitation and to advance our understanding of core learning-based rehabilitation approaches. Our findings will guide therapists in choosing the best therapy for the right individual, based on knowledge of brain networks that have capacity to adapt.
Trial website
Trial related presentations / publications
Carey, LM. (2012) Touch and body sensations. In Carey, L (editor) Stroke Rehabilitation: Insights from Neuroscience and Imaging. Oxford University Press. pp. 157-172.

Carey, L.M. (2012) Neuroscience to Neurorehabilitation: Connecting new networks for everyday contact through touch. 7th World Congress of Neurorehabilitation. Melbourne, Australia. 16-19 May

Carey, L.M. (2011) Sensory Rehabilitation Post-Stroke: Connecting New Networks for Everyday Contact through Touch. Feb 17. Washington University, St Louis. Neurorehabilitation Grand Round
Public notes

Contacts
Principal investigator
Name 39646 0
Prof Leeanne Carey
Address 39646 0
Head, Neurorehabilitation and Recovery, Stroke Division
The Florey Institute of Neuroscience and Mental Health
Melbourne Brain Centre - Austin Campus
245 Burgundy Street
Heidelberg Vic 3084
Country 39646 0
Australia
Phone 39646 0
+61 3 9035 7088
Fax 39646 0
+61 3 9035 7303
Email 39646 0
leeanne.carey@florey.edu.au
Contact person for public queries
Name 39647 0
Prof Leeanne Carey
Address 39647 0
Head, Neurorehabilitation and Recovery, Stroke Division
The Florey Institute of Neuroscience and Mental Health
Melbourne Brain Centre - Austin Campus
245 Burgundy Street
Heidelberg Vic 3084
Country 39647 0
Australia
Phone 39647 0
+61 3 9035 7088
Fax 39647 0
+61 3 9035 7303
Email 39647 0
leeanne.carey@florey.edu.au
Contact person for scientific queries
Name 39648 0
Prof Leeanne Carey
Address 39648 0
Head, Neurorehabilitation and Recovery, Stroke Division
The Florey Institute of Neuroscience and Mental Health
Melbourne Brain Centre - Austin Campus
245 Burgundy Street
Heidelberg Vic 3084
Country 39648 0
Australia
Phone 39648 0
+61 3 9035 7088
Fax 39648 0
+61 3 9035 7303
Email 39648 0
leeanne.carey@florey.edu.au

No information has been provided regarding IPD availability
Summary results
No Results