A Phase III, Multicentre, Prospective, Open Label Extension Study to Assess the Long Term Safety and Efficacy of Repeated Treatment of Dysport® Intramuscular Injections Used for the Treatment of Upper Limb Spasticity in Adult Subjects With Spastic Hemiparesis Due to Stroke or Traumatic Brain Injury
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Ipsen
- Enrollment
- 258
- Locations
- 34
- Primary Endpoint
- Mean Change From Baseline to End of Study/Early Withdrawal in Total Bilirubin and Creatinine
Study Overview
Brief Summary
The purpose of this research study is to assess the long term safety of Dysport® in hemiparetic subjects with upper limb spasticity due to stroke or traumatic brain injury over repeated treatment cycles.
Detailed Description
This was a phase III, multicentre, prospective, open label, repeat treatment cycles, extension to the double study Y-52-52120-145 (Study 145) . The study included both rollover subjects from Study 145 and de novo subjects. The primary study objective was to assess the long term safety of Dysport® in hemiparetic subjects with upper limb spasticity due to stroke or traumatic brain injury over repeated treatment cycles. The secondary study objective was to assess the long term efficacy of repeated treatment with Dysport®.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Completion of the double blind study, Y-52-52120-145
Exclusion Criteria
- •Major limitation in the passive range of motion in upper limb
Arms & Interventions
Total Dysport®
A total of 254 subjects in the open label study received between 1 and 5 intramuscular (i.m) injections of Dysport® according to their individual needs, for a period of up to 12 months. All subjects were administered an appropriate dosage of Dysport® (1000 Units [U] or 500 U) on Day 1 of treatment Cycle 1. At each study visit from Week 12 onwards, subjects were assessed to determine whether a subsequent treatment cycle was required and treatment cycles were administered at intervals of a minimum of 12 weeks apart depending on the subject's safety and efficacy response. From Cycle 2 onwards, a total dose of 1500 U could be administered in subjects requiring treatment with Dysport® in their shoulder and other upper limb muscles. Subjects who showed improvement in their upper limb during the first two treatment cycles were able to receive concomitant injections of Dysport® 500 U into at least one calf muscle, from Cycle 3 onwards as long as the total dose did not exceed 1500 U.
Intervention: Botulinum toxin type A (Biological)
Outcomes
Primary Outcomes
Mean Change From Baseline to End of Study/Early Withdrawal in Total Bilirubin and Creatinine
Time Frame: Up to Week 52
Blood samples for clinical chemistry analysis of total bilirubin and creatinine were taken at baseline, at post treatment follow up visit Week 4, and at end of study/early withdrawal. Outcome measure is reported for number of subjects with data available for analysis.
Mean Change From Baseline to End of Study/Early Withdrawal in 12 Lead ECG - HR
Time Frame: Up to Week 52
HR was measured by 12-lead ECG tracing, performed at baseline, at post treatment follow up visit Week 4, and at the end of study or early withdrawal visit. The 12-lead ECG recordings were performed at a paper speed of 25 mm/s, recorded with the subject in a supine position after 5 minutes rest.
Mean Change From Baseline to End of Study/Early Withdrawal in Haemoglobin and Mean Corpuscular Haemoglobin Concentration (MCHC)
Time Frame: Up to Week 52
Blood samples for haemoglobin and MCHC were taken at baseline, at post treatment follow up visit Week 4, and at the end of study/early withdrawal. Outcome measure is reported for number of subjects with data available for analysis.
Mean Change From Baseline to End of Study/Early Withdrawal in Blood Urea Nitrogen (BUN) and Fasting Blood Glucose
Time Frame: Up to Week 52
Blood samples for analysis of BUN and fasting blood glucose levels were taken at baseline, at post treatment follow up visit Week 4, and at end of study/early withdrawal.
Mean Change From Baseline to End of Study/Early Withdrawal in Heart Rate (HR)
Time Frame: Up to Week 52
HR was recorded at screening, baseline and at each post baseline visit. Vital signs were measured with the subject in a sitting position after resting for 3 minutes. Outcome measure is reported for number of subjects with data available for analysis.
Mean Change From Baseline to End of Study/Early Withdrawal in Red Blood Cell (RBC) Count
Time Frame: Up to Week 52
Blood samples for RBC count were taken at baseline, at post treatment follow up visit Week 4, and at end of study/early withdrawal. Outcome measure is reported for number of subjects with data available for analysis.
Mean Change From Baseline to End of Study/Early Withdrawal in Haematocrit
Time Frame: Up to Week 52
Blood samples for haematocrit were taken at baseline, at post treatment follow up visit Week 4, and at end of study/early withdrawal. Outcome measure is reported for number of subjects with data available for analysis.
Mean Change From Baseline to End of Study/Early Withdrawal in Mean Corpuscular Volume (MCV)
Time Frame: Up to Week 52
Blood samples for MCV were taken at baseline, at post treatment follow up visit Week 4, and at end of study/early withdrawal. Outcome measure is reported for number of subjects with data available for analysis.
Assessment of the Long-term Safety of Dysport® Through the Collection of Treatment Emergent Adverse Events (TEAEs)
Time Frame: Up to Week 52
A TEAE was reported as emergent if it arose (i.e. started or worsened in severity) in the treatment phase after the subject received study medication. Adverse events of special interest (AESIs) were identified as those assessed as being due to remote spread of effect of Dysport®, or any adverse event (AE) that was assessed as a hypersensitivity reaction. TEAEs, AESIs, severe TEAEs, serious adverse events (SAEs), treatment related TEAEs, TEAEs leading to withdrawal and fatal SAEs are summarised by treatment cycle.
Mean Change From Baseline to End of Study/Early Withdrawal in Diastolic and Systolic Blood Pressure (BP)
Time Frame: Up to Week 52
Systolic and diastolic BP were recorded at screening, baseline and at each post baseline visit. Vital signs were measured with the subject in a sitting position after resting for 3 minutes. Outcome measure is reported for number of subjects with data available for analysis.
Mean Change From Baseline to End of Study/Early Withdrawal in White Blood Cell (WBC) Count, Neutrophils, Lymphocytes and Platelets
Time Frame: Up to Week 52
Blood samples for WBC count with differentials (neutrophils, lymphocytes) and platelet count were taken at baseline, at post treatment follow up visit Week 4, and at end of study or early withdrawal.
Mean Change From Baseline to End of Study/Early Withdrawal in Alkaline Phosphatase (ALP), Gamma Glutamyl Transferase (GGT), Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvic Transaminase (SGPT)
Time Frame: Up to Week 52
Blood samples for analysis of the following clinical chemistry parameters: ALP, GGT, SGOT and SGPT were taken at baseline, at post treatment follow up visit Week 4, and at end of study/early withdrawal. Outcome measure is reported for number of subjects with data available for analysis.
Mean Change From Baseline to End of Study/Early Withdrawal in 12-Lead Electrocardiogram (ECG)
Time Frame: Up to Week 52
12-lead ECG tracing was performed at baseline, post treatment at Week 4 and at the end of study/early withdrawal visit. The 12-lead ECG recordings were performed at a paper speed of 25 mm/s, recorded with the subject in a supine position after 5 minutes rest. The ECG parameters reported were QRS duration, PR duration, QT duration, QTcB (QT interval corrected for HR according to Bazett), and QTcF (QT interval corrected for HR according to Fridericia) at baseline and the change to end of study/early withdrawal visit (EOS).
Mean Change From Baseline to End of Study/Early Withdrawal in Mean Corpuscular Haemoglobin (MCH)
Time Frame: Up to Week 52
Blood samples for MCH were taken at baseline, at post treatment follow up visit Week 4, and at end of study/early withdrawal. Outcome measure is reported for number of subjects with data available for analysis.
Number of Subjects With Botulinum Toxin A Binding and Neutralising Putative Antibodies
Time Frame: Up to Week 52
Blood samples were collected at baseline, Week 4 of each cycle, and at the end of study/early withdrawal to test for the presence of Botulinum Toxin A Binding antibodies. Samples positive for the presence of binding antibodies were then analysed for the presence of neutralising putative antibodies. The number of subjects who were either positive (+ve) or negative (-ve) at baseline and then positive post baseline for binding or neutralising antibodies were reported.
Secondary Outcomes
- Percentage of Subjects With at Least 1 or 2 Grade Reduction in MAS for Extrinsic Finger Flexors at Week 4(At Week 4)
- Mean Change From Baseline MAS in the Wrist Flexors at Week 4(At Week 4)
- Mean Change From Baseline Modified Ashworth Scale (MAS) in the Overall Primary Targeted Muscle Group (PTMG) for Upper Limb at Week 4(At Week 4)
- Percentage of Subjects With at Least 1 or 2 Grade Reduction in MAS for Overall PTMG(At Week 4)
- Percentage of Subjects With at Least 1 or 2 Grade Reduction in MAS for Wrist Flexors at Week 4(At Week 4)
- Mean Change From Baseline MAS in the Shoulder Extensors at Week 4(At Week 4)
- Percentage of Subjects With at Least 1 Grade Reduction in DAS for PTT at Week 4(At Week 4)
- Mean Change From Baseline to Week 4 for Angle of Arrest (XV1), Angle of Catch (XV3) and Angle of Spasticity (X) in Extrinsic Finger Flexors as PTMG(At Week 4)
- Mean Change From Baseline MAS in the Extrinsic Finger Flexors at Week 4(At Week 4)
- Physician's Global Assessment (PGA) of Treatment Response at Week 4(At Week 4)
- Percentage of Subjects With at Least One Grade Reduction in DAS for Individual Domains at Week 4(At Week 4)
- Mean Change From Baseline to Week 4 for Spasticity Grade (Y) in Elbow Flexors as PTMG(At Week 4)
- Mean Change From Baseline at Week 4 in Ease of Applying a Splint(At Week 4)
- Mean Change From Baseline MAS in the Elbow Flexors at Week 4(At Week 4)
- Mean Change From Baseline to Week 4 for Spasticity Grade (Y) in Extrinsic Finger Flexors as PTMG(At Week 4)
- Mean Change From Baseline to Week 4 for Angle of Arrest (XV1), Angle of Catch (XV3) and Angle of Spasticity (X) in Shoulder Extensors(At Week 4)
- Percentage of Subjects With at Least 1 or 2 Grade Reduction in MAS for Elbow Flexors at Week 4(At Week 4)
- Mean Change From Baseline in Disability Assessment Scale (DAS) Score for the Principal Target of Treatment (PTT) at Week 4(At Week 4)
- Mean Change From Baseline in Active Range of Motion (AROM) at Week 4 in the 3 Possible PTMGs(At Week 4)
- Mean Change From Baseline in Modified Frenchay Scale (MFS) at Week 4(At Week 4)
- Mean Change From Baseline in Short Form (36) Health Survey (SF-36) Quality of Life (QoL) at End of Study/Early Withdrawal Visit(Up to Week 52)
- Mean Change From Baseline to Week 4 for Angle of Arrest (XV1), Angle of Catch (XV3) and Angle of Spasticity (X) in Elbow Flexors as PTMG(At Week 4)
- Mean Change From Baseline to Week 4 for Spasticity Grade (Y) in Shoulder Extensors(At Week 4)
- Mean Change From Baseline to Week 4 for Angle of Arrest (XV1), Angle of Catch (XV3) and Angle of Spasticity (X) in Wrist Flexors as PTMG(At Week 4)
- Mean Change From Baseline to Week 4 for Spasticity Grade (Y) in Wrist Flexors as PTMG(At Week 4)
- Mean Change From Baseline in European 5 Dimensions, 5 Level (EQ-5D-5L) QoL at End of Study/Early Withdrawal Visit(Up to Week 52)