Multiple System Atrophy
Conditions
Brief summary
Fifty patients with early stage Multiple System Atrophy (MSA) will be recruited and randomised to receive Exenatide injections, or to act as controls in this open label trial. For half of the patients, Exenatide will be given as a once weekly subcutaneous injection in addition to participant's regular medication. All patients will continue to receive standard of care treatment for MSA. Detailed assessments will be made of all patients at baseline and periodically for a total of 48 weeks. The primary endpoint will be the difference in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (Parts I and II) at 48 weeks comparing Exenatide treated to best medically treated patients (controls). Secondary measures will include adverse event reports, self-completed questionnaires, and blood test results. Aside from these assessments, all patients will continue any regular MSA medications throughout the trial with adjustments made only according to clinical need. Standard of care treatment for patients on non IMP arm will be dependant on the patients individual symptoms - there is no broad standard treatment for every patient.
Detailed description
Fifty patients with early stage MSA will be recruited and randomised to receive Exenatide injections, or to act as controls in this open label trial. Once a potential participant has been identified they will receive a patient information leaflet, and will be given a minimum of 24 hours to read this before being recruited on to the trial. Patients will need to be eligible for the trial by meeting the inclusion criteria. During pre-treatment there will be a screening visit and a baseline visit. Pre-treatment assessments will include: demographics, medical history, family history, any previous genetic tests recorded, previous drug compliance issues recorded, physical examination, neurological examination, 12-lead ECG, routine bloods (FBC, U&E, LFT, glucose, amylase, HbA1c, PT and APTT), height, weight, vital signs, serum or urine pregnancy tests (for women of childbearing potential), MoCA, BDI-II and Concomitant medications. Patients will then wear a sensor attached to their lower back for a week. They will then return for their baseline visit. At the baseline visit assessments will include: physical exam, neurological exam, lumbar puncture for CSF collection, serum collection, fasting blood tests, vital signs, UMSARS, COMPASS Select, COMPASS Change scale, timed motor tests, The Unified Dystonia Rating Scale, MoCA, BDI-II, Concomitant medication review and adverse event review. Participants will then be randomised to both control arm or trial drug arm and receive the according treatment. The baseline visit will also include a training session for self-administration of IMP. Patients randomised to receive the trial drug will receive 2mg Exenatide once a week for 48 weeks via subcutaneous injection. Follow up visits will be every 12 weeks and patients will be given a sufficient supply to last them till their next follow up appointment (can be stored in fridge at home). They will also be given a dosing diary to record the time and day of injection administration. Patients will continue to attend their normal neurology appointments as well as trial specific appointments. Patients will have a telephone call with the research nurse at week 4. Thereafter detailed assessments including Physical and Neurological exam, ECG's, Movement tests Including the Unified Multiple System Atrophy Rating Scale (videotaped), concomitant medications review, adverse event review, and blood sampling at baseline and every 12 weeks for a total of 48 weeks. Each patient will also have a Lumbar Puncture at baseline and at their final visit. The primary endpoint will be the difference in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (Parts I and II) at 48 weeks comparing Exenatide to best medically treated patients. Secondary measures will include adverse event reports, self-completed questionnaires, and blood test results. Aside from these assessments, all patients will continue any regular MSA medications throughout the trial with adjustments made only according to clinical need.
Interventions
DRUGExenatide Pen Injector [Bydureon]
Exenatide is a treatment licensed for use in Type 2 diabetes.
Sponsors
University College, London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Participants aged 30-80 years old with a diagnosis of Possible or Probable MSA of the parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (Gilman et al. 2008). * Participants who are less than five years from the time of documented MSA diagnosis or from the time of documented parkinsonian / ataxic neurological condition that later turns out to be MSA. * Participants who are able to walk at least 10 metres with or without assistance. Participants with an anticipated survival of at least three years in the opinion of the investigator. * Participants that are willing to adhere to the study drug regimen. * Participants that are willing and able to perform all protocol-specified assessments and comply with the study visit schedule. * Females of childbearing potential and male participants with partners of childbearing potential must agree to use an effective method of contraception from the time consent is signed until 10 weeks after treatment discontinuation. Females of childbearing potential have a negative pregnancy test within 7 days prior to being randomised. * Willing and able to provide written informed consent. * Subjects who are not able to write may give verbal consent in the presence of at least one witness, and the witness should sign the informed consent form.
Exclusion criteria
* Females who are pregnant, planning pregnancy or breastfeeding. * Women of child-bearing potential who do not practice an acceptable method of birth control. Subjects who meet any of the following criteria which tend to suggest advance disease: 1. Speech impairment as assessed by a score of ≥ 3 on UMSARS question 1 2. Swallowing impairment as assessed by a score of ≥ 3 on UMSARS question 2 3. Impairment in ambulation as assessed by a score of ≥ 3 on UMSARS question 7 4. Falling more frequently than once per week as assessed by a score of ≥ 3 on UMSARS question 8. Participants with a clinically significant or unstable medical or surgical condition, which in the opinion of the investigator might preclude safe completion of the study. * Participants with active malignant neoplasms or history of malignant neoplasm in the last 5 years. Participants with movement disorders other than MSA. * Concurrent dementia defined by a score lower than 21 on the MoCA. * Concurrent severe depression defined by a score of ≥30 on the Beck Depression Inventory-II. * History of deep brain stimulation surgery. * Participants who have taken any investigational products within 90 days prior to baseline. * Participants with a BMI \< 18.5. * Participants with diabetes, end stage renal disease or severely impaired renal function. * History of clinically significant cardiac disease, pancreatitis and/or alcoholism. * Participants with severe gastrointestinal disease including gastroparesis. * Ongoing treatment with sulphonylurea. * Known allergies to the IMP and excipients of IMP.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in UMSARS Score (Parts I+II) From Baseline | Baseline and 48 weeks | The primary endpoint is the total Unified Multiple System Atrophy Rating Scale (UMSARS) score (Parts I and II), exploring the change from baseline overtime (evaluated at 48-weeks). Part I is a 12-item historical interview (max score 48) and Part II is a 14-item clinical examination (max score 56). Part I and II are added together to give a total score, which can range from 0 to 104. Higher scores indicate worse disease severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Multiple System Atrophy Quality of Life (MSA-QoL) Scale | 48 weeks | The Multiple System Atrophy Quality of Life (MSA-QoL) scale measured health-related quality of life across three subscales (motor, nonmotor, and emotional/social functioning). Each item (40 in total) has five increasing levels of impairment (0 to 4), with 0 representing no impairment and 4 representing extreme impairment. Scores for the three subscales were generated by summing items and transformed to a range of 0 to 100 (100 × \[(observed score minus min possible score)/(max possible score minus min possible score)\]). |
| Number of Falls | 48 weeks | Number of falls reported by the participant at 48-weeks. |
| Milestones on UMSARS Part 1 (Speech, Swallow and Falling) | 48 weeks | The UMSARS Part 1 is 12-item sub-scale which comprises a historic review of disease-related impairments. A single score using a 0 (no impairment) to 4 (severe impairment) was generated for each item (max score 48 points). We examined the proportion of participants reaching a score of ≥ 3 on UMSARS item 1 (speech), item 2 (swallowing) and item 8 (falling) by 48 weeks. |
| Loss of Independent Ambulation | 48 weeks | Proportion of participants with loss of independent ambulation, defined by a score of 4 on the UMSARS-I Item 7 (walking) at 48 weeks. |
| Montreal Cognitive Assessment (MoCA) | 48 weeks | The MoCA is a brief cognitive scale (scored out of 0-30 points). A score of 26 or more reflects normal cognitive abilities, whereas lower scores indicate cognitive impairment. The difference between groups (total score out of 30) was explored at 48 weeks. |
| UMSARS Part IV | Score at 48 Weeks | The UMSARS Part 4 measures global disability (1 item) scored from 1 (completely independent) to 5 (totally dependent and helpless. Bedridden). |
| Beck Depression Inventory II (BDI-II) | 48 weeks | The BDI-II is a self-report questionnaire designed to measure the severity of depression symptomatology (scored out of 0-63 points). A score of 13 or less indicated minimal, 14-19 indicated mild, 20-28 indicated moderate and 29-63 indicated severe depression. The difference between groups was explored at 48 weeks. |
| Clinical Global Impression (CGI) Scale | 48 weeks | The CGI evaluates the change from the initiation of treatment on a seven-point scale (1 = =very much improved to 7 = very much worse since the initiation of treatment). A single score at 48 weeks was recorded. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Participants randomised to receive exenatide. | 25 |
| Standard of Care Participants randomised to receive standard care only. | 25 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Standard of Care | Total | Exenatide |
|---|---|---|---|
| Age, Continuous | 62.4 Age in years STANDARD_DEVIATION 7.3 | 63.3 Age in years STANDARD_DEVIATION 7.9 | 63.3 Age in years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 50 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| MSA Sub-type MSA-C | 11 Participants | 22 Participants | 11 Participants |
| MSA Sub-type MSA-P | 14 Participants | 28 Participants | 14 Participants |
| Sex: Female, Male Female | 13 Participants | 26 Participants | 13 Participants |
| Sex: Female, Male Male | 12 Participants | 24 Participants | 12 Participants |
| UMSARS (Part 1+2) | 42.6 Points STANDARD_DEVIATION 8.2 | 44.9 Points STANDARD_DEVIATION 9.8 | 46.0 Points STANDARD_DEVIATION 11.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 25 | 2 / 25 |
| other Total, other adverse events | 6 / 25 | 1 / 25 |
| serious Total, serious adverse events | 10 / 25 | 10 / 25 |
Outcome results
Primary
Change in UMSARS Score (Parts I+II) From Baseline
The primary endpoint is the total Unified Multiple System Atrophy Rating Scale (UMSARS) score (Parts I and II), exploring the change from baseline overtime (evaluated at 48-weeks). Part I is a 12-item historical interview (max score 48) and Part II is a 14-item clinical examination (max score 56). Part I and II are added together to give a total score, which can range from 0 to 104. Higher scores indicate worse disease severity.
Time frame: Baseline and 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Exenatide | Change in UMSARS Score (Parts I+II) From Baseline | 6.1 score on a scale |
| Standard of Care | Change in UMSARS Score (Parts I+II) From Baseline | 13.3 score on a scale |
Secondary
Beck Depression Inventory II (BDI-II)
The BDI-II is a self-report questionnaire designed to measure the severity of depression symptomatology (scored out of 0-63 points). A score of 13 or less indicated minimal, 14-19 indicated mild, 20-28 indicated moderate and 29-63 indicated severe depression. The difference between groups was explored at 48 weeks.
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Beck Depression Inventory II (BDI-II) | 14.3 Score on a scale | Standard Deviation 8.8 |
| Standard of Care | Beck Depression Inventory II (BDI-II) | 15.2 Score on a scale | Standard Deviation 8 |
Secondary
Clinical Global Impression (CGI) Scale
The CGI evaluates the change from the initiation of treatment on a seven-point scale (1 = =very much improved to 7 = very much worse since the initiation of treatment). A single score at 48 weeks was recorded.
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Clinical Global Impression (CGI) Scale | 3.1 score on a scale | Standard Deviation 1 |
| Standard of Care | Clinical Global Impression (CGI) Scale | 2.4 score on a scale | Standard Deviation 0.8 |
Secondary
Loss of Independent Ambulation
Proportion of participants with loss of independent ambulation, defined by a score of 4 on the UMSARS-I Item 7 (walking) at 48 weeks.
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exenatide | Loss of Independent Ambulation | 2 Participants |
| Standard of Care | Loss of Independent Ambulation | 2 Participants |
Secondary
Milestones on UMSARS Part 1 (Speech, Swallow and Falling)
The UMSARS Part 1 is 12-item sub-scale which comprises a historic review of disease-related impairments. A single score using a 0 (no impairment) to 4 (severe impairment) was generated for each item (max score 48 points). We examined the proportion of participants reaching a score of ≥ 3 on UMSARS item 1 (speech), item 2 (swallowing) and item 8 (falling) by 48 weeks.
Time frame: 48 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Exenatide | Milestones on UMSARS Part 1 (Speech, Swallow and Falling) | UMSARS Part 1 Item 1 (Speech) | 3 Participants |
| Exenatide | Milestones on UMSARS Part 1 (Speech, Swallow and Falling) | UMSARS Part 1 Item 2 (Swallowing) | 2 Participants |
| Exenatide | Milestones on UMSARS Part 1 (Speech, Swallow and Falling) | UMSARS Part 1 Item 8 (Falling) | 3 Participants |
| Standard of Care | Milestones on UMSARS Part 1 (Speech, Swallow and Falling) | UMSARS Part 1 Item 1 (Speech) | 7 Participants |
| Standard of Care | Milestones on UMSARS Part 1 (Speech, Swallow and Falling) | UMSARS Part 1 Item 2 (Swallowing) | 8 Participants |
| Standard of Care | Milestones on UMSARS Part 1 (Speech, Swallow and Falling) | UMSARS Part 1 Item 8 (Falling) | 6 Participants |
Secondary
Montreal Cognitive Assessment (MoCA)
The MoCA is a brief cognitive scale (scored out of 0-30 points). A score of 26 or more reflects normal cognitive abilities, whereas lower scores indicate cognitive impairment. The difference between groups (total score out of 30) was explored at 48 weeks.
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Montreal Cognitive Assessment (MoCA) | 26.0 score on a scale | Standard Deviation 2.7 |
| Standard of Care | Montreal Cognitive Assessment (MoCA) | 27.2 score on a scale | Standard Deviation 2.5 |
Secondary
Multiple System Atrophy Quality of Life (MSA-QoL) Scale
The Multiple System Atrophy Quality of Life (MSA-QoL) scale measured health-related quality of life across three subscales (motor, nonmotor, and emotional/social functioning). Each item (40 in total) has five increasing levels of impairment (0 to 4), with 0 representing no impairment and 4 representing extreme impairment. Scores for the three subscales were generated by summing items and transformed to a range of 0 to 100 (100 × \[(observed score minus min possible score)/(max possible score minus min possible score)\]).
Time frame: 48 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide | Multiple System Atrophy Quality of Life (MSA-QoL) Scale | MSA QoL (Motor Domain) | 53.1 score on a scale | Standard Deviation 19.8 |
| Exenatide | Multiple System Atrophy Quality of Life (MSA-QoL) Scale | MSA QoL (Non-motor Domain) | 37.4 score on a scale | Standard Deviation 17.8 |
| Exenatide | Multiple System Atrophy Quality of Life (MSA-QoL) Scale | MSA QoL (Emotional/Social Functioning Domain) | 33.3 score on a scale | Standard Deviation 22.8 |
| Standard of Care | Multiple System Atrophy Quality of Life (MSA-QoL) Scale | MSA QoL (Motor Domain) | 53.7 score on a scale | Standard Deviation 23.7 |
| Standard of Care | Multiple System Atrophy Quality of Life (MSA-QoL) Scale | MSA QoL (Non-motor Domain) | 39.3 score on a scale | Standard Deviation 15.4 |
| Standard of Care | Multiple System Atrophy Quality of Life (MSA-QoL) Scale | MSA QoL (Emotional/Social Functioning Domain) | 43.1 score on a scale | Standard Deviation 23.9 |
Secondary
Number of Falls
Number of falls reported by the participant at 48-weeks.
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Number of Falls | 1.7 Number of falls | Standard Deviation 2.9 |
| Standard of Care | Number of Falls | 3.0 Number of falls | Standard Deviation 6.8 |
Secondary
UMSARS Part IV
The UMSARS Part 4 measures global disability (1 item) scored from 1 (completely independent) to 5 (totally dependent and helpless. Bedridden).
Time frame: Score at 48 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | UMSARS Part IV | 2.8 Score on a scale | Standard Deviation 1.1 |
| Standard of Care | UMSARS Part IV | 3.0 Score on a scale | Standard Deviation 0.9 |