SISTERS: Spasticity In Stroke Study - Randomized Study

Study Overview
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Brief Summary
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To demonstrate that Intrathecal Baclofen (ITB) Therapy, compared to Best Medical Treatment (BMT), has superior efficacy in the treatment of severe spasticity in adult post-stroke patients with generalized spastic hypertonia who have not reached their therapy goal with other treatment interventions assessed by a decrease in the average Ashworth Scale (AS) score in the lower extremities.

Detailed Description
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This is a randomized, controlled open-label parallel group study to demonstrate the efficacy benefit of ITB Therapy over BMT in post-stroke patients with severe spasticity who have not reached their therapy goal with other treatment interventions. In order to evaluate the efficacy benefit of ITB Therapy over BMT in post-stroke patients, a two-arm parallel group design will be applied. Patients will be equally randomized to one of two treatment arms: ITB Therapy arm; or BMT arm The study consists of a run-in phase of 21 days for the BMT treatment arm and 2-25 days for the ITB Therapy treatment arm, followed by a 6 month active trial. The BMT treatment arm will receive a combination of oral antispastic medication and physiotherapy. Patients must be prescribed at least one or a combination of the following oral antispastic medications: oral baclofen, tizanidine, diazepam (or other benzodiazepines) or dantrolene. Following the run-in phase, patients will enter the 6 month active trial. The ITB Therapy treatment arm will receive a combination of ITB Therapy and physiotherapy. During the run-in phase, a test with intrathecal baclofen will be performed to evaluate the response of the patient. Patients fulfilling the test success criterium will be implanted with a Medtronic SynchroMed®II infusion system. Following implant, patients will enter into the 6 month active trial, which includes a 6 week titration phase, during which time oral antispastic medications must be gradually reduced with complete discontinuation by the end of the titration period. During the 6 month active trial, patients will be assessed at 3 and 6 months. All primary and secondary endpoint assessments will be performed by a blinded assessor. The total study duration is expected to be 60 months, including a 39 month enrollment period. The total duration per patient is approximately 7 months (approximately 1 month run-in period followed by 6 months active treatment).

Official Title
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A Randomized, Controlled, Open-label, Parallel-group, Multi-center Study to Compare the Effect of Intrathecal Baclofen Therapy Versus Best Medical Treatment on Severe Spasticity in Post-stroke Patients After 6 Months Active Treatment

Conditions
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Severe Spasticity

Intervention / Treatment
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* Drug: intrathecal baclofen


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: To be eligible for inclusion into this study, patients must fulfill all of the following criteria prior to study enrollment: patient (or legal guardian) has been informed of the study procedures and has given written informed consent patient experienced last stroke > 6 months prior to enrollment patient presents spasticity in at least 2 extremities patient presents an Ashworth score ≥ 3 in a minimum of two of the affected muscle groups in the lower extremities patient is eligible to receive ITB Therapy following the Adult Spasticity Algorithm. A patient does not reach his/her therapy goal with other treatment interventions stable blood pressure: no change in hypertensive medication in last month (NOTE: ventriculoperitoneal shunts and valves can be present) if female, she must either be post-menopausal or surgically sterilized; or use a hormonal contraceptive, intrauterine device, diaphragm with spermicide, or condom with spermicide, for the duration of the study patient/family is willing to comply with study protocol including attending the study visits Exclusion criteria: To be eligible for inclusion in this study the patients must not meet any of the following criteria: patient/family is considered by the physician to be unable or unwilling to participate in long-term ITB Therapy management patient has known hypersensitivity to baclofen active systemic infection (NOTE: pressure sores are not a contraindication unless they are present near the implant sites) presence of a cardiac pacemaker, ICD, implantable neurostimulator or drug delivery device uncontrolled refractory epilepsy use of oral vitamin K antagonists, e.g. warfarin/coumadin; unless the patient can switch to another accepted anticoagulant (e.g. heparin, aggrenox, fragmin, plavix, ticlid) for the period of ITB test and implant patient is pregnant or breastfeeding patient received a Botulinum toxin injection less than 4 months ago

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ITB therapy<br>Intrathecal Baclofen therapy (Intrathecal baclofen + implantable pump) | Drug: intrathecal baclofen<br>* ITB test, implant, 6 months follow-up<br>|
| No Intervention: Best Medical Treatment (BMT)<br>Use one or a combination oral antispastic medication. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average Ashworth Scale (AS) in Affected Lower Extremities From Baseline to Month 6 | AS is a manual test, measuring the resistance to passive movement about a joint with varying degrees of velocity. Scores range from 1-5, with 5 choices. A score of 1 indicates no resistance, and 5 indicates rigidity. The following muscle groups in the lower extremities were assessed: hip flexors, hip adductors, knee extensors, knee flexors, plantar flexors and ankle-dorsal flexors. Average AS was calculated as the average of AS scores of the 6 muscles of the affected lower extremity. Change in average AS in affected lower extremities from baseline to month 6 between ITB and BMT arm was assessed. Change= AS at month 6 - AS at baseline. | Baseline and month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average Ashworth Scale (AS) in Affected Upper Extremities From Baseline to Month 6 | AS is a manual test, measuring the resistance to passive movement about a joint with varying degrees of velocity. Scores range from 1-5, with 5 choices. A score of 1 indicates no resistance, and 5 indicates rigidity. The following muscle groups in the upper extremities were assessed: wrist flexors, elbow flexors, elbow extensors, shoulder abductors and shoulder adductors. Average AS was calculated as the average of AS scores of the 5 muscles of the affected lower extremities. Change in average AS in affected upper extremities from baseline to month 6 between ITB and BMT arm was assessed. Change= AS at month 6 - AS at baseline. | Baseline and month 6 | 
| Change in Functional Independence Measure (FIM) Score From Baseline to Month 6 | FIM contains 18 items composed of 13 motor tasks and 5 cognitive tasks. Tasks are rated on a 7-point ordinal scale that ranges from total assistance (or complete dependence) to complete independence. Ratings should reflect actual observed performance, not capability. Total score ranges from 18 (lowest) to 126 (highest) level of independence. Change in FIM total score from baseline to month 6 between ITB and BMT arm was assessed. Change=FIM score at month 6 - FIM score at baseline. | Baseline and month 6 | 
| Change in Average 10 Meter Time Walking Test (10MTWT) From Baseline to Month 6 | Change in average 10MTWT from baseline to month 6 beetween ITB and BMT arm. Change=10MTWT at month 6 - 10MTWT at baseline | Baseline and month 6 | 
| Number of Participants Who Were Able to Transfer From the Wheelchair to Bed Without Human Assistance | Patient was asked to transfer from the wheelchair to bed without human assistance. High level functional patient (HLP) could transfer. Low level functional patient (LLP) was not able to transfer. Comparison of the number and percentage of HLP and LLP between ITB and BMT arms was evaluated. | baseline, month 3, month 6 | 
| Change in Numeric Pain Rating Scale (NPRS) From Baseline to Month 6 | NPRS is designed to assess the level of pain a patient is feeling at a point in time. The following questions has been presented to patients: What is your actual spasticity-related or spasm-related pain? What was your least spasticity-related or spasm-related pain during the last week? What was your worst spasticity-related or spasm-related pain during the last week? The patient indicated how much pain he is feeling on a scale from 0 to 10. A score of 0 (zero) is no pain while a score of 10 (ten) is worst possible pain. Change in NPRS related to actual, least or worst pain from baseline to month 6 between ITB and BMT arm was assessed. Change=NPRS at month 6 - NPRS at baseline. | Baseline and month 6 | 
| Number of Participants Who Achieved Their Primary Therapeutic Goal Assessed With the Goal Attainment Scale (GAS) | GAS is designed to measure the achievement of treatment goals using the following 6 levels of achievement: worse than start (-3), much less than expected (-2), somewhat less than expected (-1), as expected (0), somewhat more than expected (+1), much more than expected (+2). The primary therapy goal and the criteria for the levels of achievement was defined by the medical team together with the patient and his/her family/legal representative/caregiver at the first day of the study. The number and percentage of patients who achieved the therapeutic goal at Month 6 was compared between the ITB and BMT arm. | month 6 | 
| Change in Euro QoL Group-5 Dimensional, 3 Level Version (EQ-5D-3L) From Baseline to Month 6 | The EQ-5D-3L is a generic measure of health status consisting in the EQ-5D-3L descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system is characterized on five dimensions: mobility, self-care, ability to undertake usual activities, pain and anxiety/depression. Patients were asked to indicate their level of health on each dimension using one of three levels: no health problems, moderate health problems, and severe health problems. Responses from the questionnaire were converted to a single health index utility score; this ranges from -0.595 to 1. EQ VAS records the patient's self-rated health on a vertical visual analogue scale from 0 to 100 where the endpoints are labelled 'Best imaginable health state' (100) and 'Worst imaginable health state' (0). Change in EQ-5D-3L utility score and VAS score from baseline to month 6 between ITB and BMT arm were assessed. Change=EQ-5D-3L utility or VAS score at month 6 - EQ-5D-3L utility or VAS score. | Baseline and month 6 | 
| Change in SF-12 (12-item Short Form) From Baseline to Month 6 | The SF-12 is generic assessment of health-related quality of life, which evaluates 8 health dimensions (physical functioning, role physical, bodily pain, vitality, social functioning, role emotional, mental health, and general health). Subscale scores for each dimension were aggregated into summary scores for physical (PCS) and mental health (MCS) components (ranging from 0 to 100, with higher scores indicating better health). Changes in the PCS and MCS from baseline to Month 6 were both compared between the BMT and ITB arms. Change=SF-12 score at month 6 - SF-12 score at baseline. | Baseline and month 6 | 
| Change in Stroke Specific Quality of Life (SS-QoL ) From Baseline to Month 6 | SS-QoL questionnaire is a self-assessed quality of life questionnaire specifically designed for post-stroke patients. It evaluates 49 items across 12-domains: personality, energy, language, mobility, vision, upper extremity function, thinking, mood, work/productivity, self-care, and family and social roles. Each item is rated on a 5-point Likert Scale, measuring either positive or negative response to a statement. Summary score is composed of an unweighted average of the 12 domain scores, with higher scores indicating better QoL. Total score ranges from 1 to 5. Change in SS-QoL summary score from baseline to month 6 between ITB and BMT arm was assessed. Change=SS-QoL score at month 6 - SS-QoL score at baseline. | Baseline and month 6 | 
| Therapy Satisfaction | Patients were presented with two statements (I am satisfied with the reduction in spasticity provided by my treatment, and I would recommend this therapy to a friend). They agreed, disagreed or were neutral with the statements. | month 6 | 
| Healthcare Resource Utilization | Number of patients with healthcare professional contacts outside of study visits in the ITB and BMT between baseline and months 6 | baseline, ITB test (only ITB arm), second assessment (only BMT arm), week 6 (only ITB arm), month 3, month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe spasticity in post-stroke patients