Clinical trial NCT04431713
Conditions: Multiple System Atrophy
Sponsor: University College, London
Start date: 2020-09-16; Completion date: 2024-03-22
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Exenatide Pen Injector [Bydureon]
Intervention descriptions: intervention 1: Exenatide is a treatment licensed for use in Type 2 diabetes.

Protocol documents:
Prot_000.pdf: 
Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
Page 1 of 58 
Protocol Version 6.0 Dated 13 June 2024 
 
 
Clinical Trial of Investigational Medicinal Product 
 
 
 
 
 
 
Full title of trial 
 
A Phase IIa, open label, single-site, 48 week 
randomised controlled trial evaluating the safety 
and efficacy of Exenatide once-weekly in the 
treatment of patients with Multiple System 
Atrophy.  
Short title 
 
Exenatide once-weekly as a treatment for Multiple 
System Atrophy. 
Version and date of protocol 
 
Version 6.0, 13 June 2024 
  
Sponsor: 
University College London (UCL) 
Sponsor protocol number 
125591 
Funder (s): 
John Black Charitable Foundation, Van Andel 
Institute, Defeat MSA.] 
EudraCT no  
 
2020-000122-26 
ISRCTN / Clinicaltrials.gov no:  
  
 
 
ACTIVE IMP(s): 
Exenatide 
Phase of trial 
Phase IIa 
Sites(s) 
Single site  
 
Chief investigator: 
Professor Thomas Foltynie  
Box 146, 
National Hospital for Neurology & Neurosurgery, 
Queen Square, London WC1E 3BG 
 
Sponsor Representative: 
Joint Research Office, UCL, 4th Floor, West 
250 Euston Road, London, NW1 2PG 
  
Postal address: 
Joint Research Office, UCL 
Gower Street,  
London WC1E 6BT 
 
 


Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
Page 2 of 58 
Protocol Version 6.0 Dated 13 June 2024 
 
Protocol Version History 
Version 
Number 
Date 
Protocol Update 
Finalised By 
(insert name of 
person):  
Reasons for Update 
2.0 
25/09/2020 
Prof Tom 
Foltynie 
Addition of flexibility for remote 
visits 
3.0 
01/03/2021 
Prof Tom 
Foltynie 
Addition of BCise IMP 
4.0 
13 Sep 2021 
Prof Tom 
Foltynie 
Insertion of 96 week follow-up visit, 
update to exclusion criterion 12 
5.0  
3 August 
2022 
Prof Tom 
Foltynie 
Added in option of home visits if a 
participant is unable or unwilling to 
attend site for any of the follow up 
assessments (weeks 12,24,36,48 and 
96) 
6.0 
13 June 2024 
Alison Evans and 
Prof Tom 
Foltynie 
Section 4 (Objectives) and Section 
11.4 (Statistical analysis plan) - 
removed biomarker analysis as an 
exploratory outcome.  Samples will be 
analysed under separate REC 
approved studies 


Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
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Protocol Version 6.0 Dated 13 June 2024 
Signatures 
The Chief Investigator and the JRO have discussed this protocol. The investigator agrees to perform the 
investigations and to abide by this protocol  
The investigator agrees to conduct the trial in compliance with the approved protocol, EU GCP and UK 
Regulations for CTIMPs (SI 2004/1031; as amended), the UK Data Protection Act (2018), the Trust 
Information Governance Policy (or other local equivalent), the current UK Policy Framework for Health 
and Social Care Research, 
 
 
Chief investigator 
Professor Thomas Foltynie 
Signature
Date
Sponsor  
Rajinder Sidhu 
UCL
Signature
Date
 
 


Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
Page 4 of 58 
Protocol Version 6.0 Dated 13 June 2024 
Contents 
 
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Protocol Version 6.0 Dated 13 June 2024 
List of abbreviations 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CI 
Chief Investigator 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
 
DI 
Designated Individual 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
European Commission 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVigilance 
European database for Pharmacovigilance 
GAfREC 
Governance Arrangements for NHS Research Ethics 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
GMO 
Genetically Modified Organisms 
HRA  
Health Research Authority  
HTA 
Human Tissue Authority 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised   
MA 
Marketing Authorisation 


Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
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Protocol Version 6.0 Dated 13 June 2024 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MS 
Member State 
MSA 
Multiple System Atrophy 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PL 
Product License 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person (for release of trial drug) 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
RSI 
Reference Safety Information 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SDV 
Source Document Verification 
SOP 
Standard Operating Procedure  
SPC 
Summary of Product Characteristics  
SSA 
Site Specific Assessment 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UMSARS 
Unified Multiple System Atrophy Rating Scale 


Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
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Protocol Version 6.0 Dated 13 June 2024 
1 
Trial personnel 
See protocol cover page for Chief Investigator and Sponsor contact details. 
 
Statistician 
Dr Gareth Ambler  
Joint Research Office (Research Support Centre), 1st Floor 
Maple House B, 149 Tottenham Court Road, London, W1T 7DN 
Email: g.ambler@ucl.ac.uk  
Tel: 020 3447 2178 
Trial Management 
Leonard Wolfson Experimental Neuroscience Centre 
 
National Hospital for Neurology & Neurosurgery 
 
Queen Square 
 
London 
 
WC1N 3BG 
 
Central labs  
National Hospital for Neurology & Neurosurgery 
 
Queen Square 
 
London 
 
WC1N 3BG 
 
Head of Department 
Prof A Schapira 
 
National Hospital for Neurology & Neurosurgery 
 
Queen Square 
 
London 
 
WC1N 3BG 
 
 


Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
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Protocol Version 6.0 Dated 13 June 2024 
2 
Summary 
 
Objectives: 
Primary Objective 
To collect pilot data from which to estimate the effectiveness of 
Exenatide in modifying disease progression of patients with 
Multiple System Atrophy. The primary endpoint will be the 
(UMSARS) score (Parts I and II) at 48 weeks comparing exenatide 
to best medically treated patients.  
Secondary Outcomes 
 
The proportion of patients with loss of independent 
ambulation by the end of the study, defined by a score of 
4 or more in UMSARS-I item 7 (walking),  
 
The difference at week 48 in the MSA-QoL scale, 
 
The difference at week 48 in UMSARS parts III and IV, 
 
The difference in anti-parkinsonian or anti-orthostatic 
hypotension drugs, 
 
The number of falls,  
 
The proportion of patients reaching a score of 3 or more 
on UMSARS-I items 1 (speech), 2 (swallowing), and 8 
(falling),  
 
The difference at week 48 in clinical global impression 
(CGI); difference at week 48 in MoCA scores. 
Exploratory Outcomes 
 
The d
Rating Scale (UMSARS) score (Parts I and II) at 96 weeks 
comparing exenatide to best medically treated patients, 
 
The difference at 96 weeks in the MSA-QoL scale
comparing exenatide to best medically treated patients, 
 
The difference at 96 weeks in UMSARS parts III and IV
comparing exenatide to best medically treated patients, 
 
The difference in anti-parkinsonian or anti-orthostatic 
hypotension drugs at 96 weeks comparing exenatide to 
best medically treated patients, 
 
The difference in the number of falls at 96 weeks 
comparing exenatide to best medically treated patients,  
 
The difference in the proportion of patients reaching a 
score of 3 or more on UMSARS-I items 1 (speech), 2 
(swallowing), and 8 (falling) at 96 weeks comparing 
exenatide to best medically treated patients,  


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Protocol Version 6.0 Dated 13 June 2024 
 
The difference at 96 weeks in clinical global impression 
(CGI) and MoCA scores comparing exenatide to best 
medically treated patients. 
 
Type of trial: 
Phase IIa, open label, randomised, parallel group, single site trial in 
Multiple System Atrophy. 
Trial design and methods: 
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. Exenatide will be given as a once weekly 
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 96 weeks. The 
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. 
 
 
Estimated total trial 
duration: 
96 weeks per patient 
48 months total trial duration.  
Planned trial sites: 
Single-site- National Hospital for Neurology & Neurosurgery.  
Total number of 
participants planned: 
50 participants.  
Main inclusion/exclusion 
criteria: 
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.  


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Page 12 of 58 
Protocol Version 6.0 Dated 13 June 2024 
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 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 
UMSARS question 1 
2. 
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 
 
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.  


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Page 13 of 58 
Protocol Version 6.0 Dated 13 June 2024 
Concurrent severe depression defined by a score of 
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 with creatinine clearance <30ml/min.  
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.  
 
 
 
Statistical methodology 
and analysis: 
Multiple System Atrophy Rating Scale (UMSARS) score (Parts I and 
II) at 48 weeks comparing Exenatide to best medically treated 
patients. The main statistical analysis of the primary endpoint will 
be based on the intent-to-treat population (ITT). The analysis will 
use ANCOVA to allow adjustment for baseline severity and MSA 
subtype. 
 
 
 
 
 
 


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Page 14 of 58 
Protocol Version 6.0 Dated 13 June 2024 
3 
Background and Rationale 
Multiple System Atrophy (MSA) is a rare, progressive neurodegenerative disorder clinically 
characterized by autonomic dysfunction, parkinsonism and cerebellar impairment. Like 
the pathological correlate is the formation of glial cytoplasmic inclusions, composed of 
accumulated alpha-synuclein. Despite sharing many clinical similarities with PD, unlike PD, there 
are no effective symptomatic therapies available and no approaches for slowing disease 
progression, meaning the average survival time from diagnosis is around 6-9 years (Fanciulli and 
Wenning 2015). There is thus a great unmet need for neuroprotective or disease modifying 
therapies.  
Accumulating data suggest that Exenatide, a glucagon-like peptide-1 (GLP-1) agonist used in the 
treatment of Type 2 diabetes (T2DM) may offer a novel approach to treating MSA (Bassil et al. 
2017). Numerous epidemiological studies have indicated T2DM is a risk factor for developing 
-
40% increased risk of developing PD, while patients with PD and T2DM have a more aggressive 
disease course, and require increasing amounts of medication (De Pablo-Fernandez et al. 2017; 
 
Studies have suggested that these age-related diseases share dysfunctional insulin signaling 
linking diabetes and neurodegeneration. Via insulin receptors found throughout the brain, 
insulin is responsible for modulating many cellular processes including inflammation, protein 
aggregation, oxidative stress, autophagy and apoptosis, via the actions of two main downstream 
pathways Akt and MAPK (Talbot et al. 2012; Athauda and Foltynie 2016). Importantly, these 
dysregulation of processes are thought to be involved in the pathogenesis of MSA.  
Peripheral insulin and insulin-like growth factor levels are increased in the serum of MSA 
patients and this has been shown to correlate with disease progression, suggesting a link 
between insulin signalling and MSA (Bassil et al. 2017; Bassil et al. 2017). More recently, a study 
by Bassil et al. has shown evidence of insulin resistance in the brains of patients with MSA. A 
measure of insulin resistance is the amount of the downstream messenger insulin receptor 
substrate-1 (IRS-1) phosphorylated at serine residues 312 (IRS-1pS312) or 616 (IRS-1pS616) and 
the authors demonstrated increased expression of these markers of insulin resistance that 
occurred in the context of neuronal cell loss compared to controls. Therefore, if insulin 
resistance occurs in the brain in MSA, modulating insulin/IGF-1 signalling might provide an 
effective approach to disease modification.  
Exenatide has been a treatment licensed for use in Type 2 diabetes since 2005 and activates the 
GLP-1 receptor. The GLP-1 receptor is expressed throughout the brain and activates similar 
pathways to those of insulin (Cork et al. 2015).  Previous studies have shown that activation of 
this receptor by E
nd multiple sclerosis through positive effects on cell survival, apoptosis, 
and protein aggregation (Athauda and Foltynie 2016; Greig et al. 2014). 
Indeed, a recent study using Exenatide in a transgenic mouse model of MSA showed that 
Exenatide treatment had positive effects on insulin resistance and monomeric alpha-synuclein 


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Page 15 of 58 
Protocol Version 6.0 Dated 13 June 2024 
levels in the striatum, as well as improving survival of nigral dopamine neurons (Bassil et al. 
2017).  
Based on these encouraging data, 2 clinical trials of Exenatide in patients with moderate stage 
PD have been conducted. 
-of-
-label phase 2 clinical trial evaluating the safety and efficacy of 
Exenatide in PD which showed a significant improvement in motor scores and cognitive 
efficiency at 12 months in patients with PD treated with Exenatide compared to a control group, 
which persisted following drug withdrawal (Aviles-Olmos et al. 2013, 2014). Despite the open-
label design, this study demonstrated that a drug in clinical use for another medical condition 
could be successfully tested for its disease-modifying effects in patients with PD using standard 
clinical measures, without the need to include a placebo-controlled arm, in a relatively 
inexpensive way. The aim of the open label trial was to provide proof of concept of possible 
efficacy to reassure investment into more formal double blind placebo controlled efficacy trials.  
Following on from this, a fully randomised, placebo-controlled trial of Exenatide in patients with 
moderate stage PD was conducted, which replicated the results of the previous open label trial 
and showed Exenatide reduced motor severity of PD compared to placebo. Exenatide was well-
tolerated in this patient group and it was shown for the first time that peripherally administered 
Exenatide crossed the blood brain barrier and is detectable in the cerebrospinal fluid at a ratio 
of around 3% of that detected in serum (Athauda et al. 2017). Post hoc analysis also indicated 
possible beneficial effects on depression which can be a major contributor to morbidity in both 
PD and MSA (Athauda et al. 2018). Using patient serum, we isolated and analysed neuronal 
derived exosomes to assess target engagement and demonstrated that Exenatide appears to 
normalise brain insulin signalling with subsequent activation of downstream effectors Akt and 
mTOR (Athauda et al. 2019). 
These encouraging results have set the ground for translation into early clinical trials of 
Exenatide in further neurodegenerative diseases. 
Clinical trials in MSA can be conducted with smaller group sizes, due to the marked faster disease 
progression of MSA compared with that of PD (Fernagut et al. 2014). In addition, previous 
studies have demonstrated a consistent rate of progression in the Unified Multiple System 
Atrophy Rating Scale (UMSARS) Part II (Motor examination) (Wenning et al. 2004, 2013; Low et 
al. 2015; Dodel et al. 2010; Poewe, Hauser, and Lang 2015; Low et al. 2014) 
There are no effective treatments that can slow down or modify the course of disease 
progression. MSA has a prevalence of 4.4 in 100,000 individuals and affects males and females 
equally. Currently, treatment strategies focus on symptomatic control of parkinsonism, 
autonomic dysfunction and mood problems. However, despite this, the prognosis remains poor 
with average survival of eight years. There is thus an urgent unmet need for novel treatments 
that may slow or halt disease progression in MSA.  Patients with MSA require care from a range 
of services, and as the disease progresses these care needs increase, thus a disease modifying 
treatment would have a massive impact on caregivers and social services. 
Based on prevalence figures of MSA, the estimated annual healthcare costs associated with MSA 
are estim
3.0 billion across 27 countries in the European Union. Unpaid care 
accounts for 68 76%. If an intervention were to reduce the rate of disease progression even by 


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Page 16 of 58 
Protocol Version 6.0 Dated 13 June 2024 
30%, the costs to services would be 9-10% lower and 7-12% lower in unpaid care costs. 
Preliminary data obtained by this study would provide an urgent impetus for further funding for 
a larger scale study to assess the effects of Exenatide and other GLP-1 agonists in a wider 
population of MSA patients. 
 
3.1 
Assessment and management of risk  
The table below summarises the risks, frequencies and mitigations of the IMP(s) 
Name of IMP(s) / 
NIMP  
 
Potential risk 
 
Risk 
Frequency 
 
Risk Management 
Exenatide 
Weight loss 
Common 
Underweight people will not be recruited.  
Patients losing weight too rapidly (>10% body 
weight per month)  will temporarily stop the 
IMP. 
 
Exenatide 
Nausea/ Vomiting 
Very 
common 
In most cases, nausea is mild and self limiting.
In more severe cases, patients will be 
prescribed 
a 
temporary 
course 
of 
Domperidone. 
Exenatide 
Diarrhoea 
Very 
common 
In most cases, diarrhoea is mild and self 
limiting. 
Symptomatic and supportive treatment will 
be given as necessary. 
Exenatide 
Decreased Appetite 
Common 
In most cases, loss of appetite is transient and 
self limiting. Weight will be measured and 
exenatide will be transiently stopped if 
weight loss exceeds 10% of body weight per 
month.  
Exenatide 
Headache 
Common 
In most cases, headache is transient and self 
limiting. Participants will be assessed and 
given standard of care treatment for 
persistent headaches. 
Exenatide 
Dizziness 
Common 
In most cases, dizziness, is transient and self 
limiting. 
Participants will be assessed and given 
standard of care treatment for persistent 
dizziness. 


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Protocol Version 6.0 Dated 13 June 2024 
Exenatide 
Dyspepsia/ 
Abdominal pain 
Common 
In most cases, abdominal pain is transient and 
self limiting. Any suspicion of pancreatitis will 
lead 
to 
temporary 
discontinuation 
of 
exenatide 
until 
pancreatitis 
has 
been 
excluded.  Participants will be assessed and 
given standard of care treatment for 
persistent abdominal pain. 
Exenatide 
Abdominal 
Distension/ 
Flatulence 
Common 
In 
most 
cases, 
abdominal 
distension/ 
flatulence is transient and self limiting. 
Participants will be assessed and given 
standard of care treatment for persistent 
abdominal distension/flatulence. 
Exenatide 
Constipation 
Common 
In most cases, constipation is is transient and 
self limiting.  
Participants will be assessed and given 
standard of care treatment for persistent 
constipation. 
Exenatide 
Anaphylactic 
reaction 
Rare 
Patients will self administer their first 
Exenatide injection in the trial centre under 
supervision by the trial team. 
 
 
The table below summarise the risks and mitigations of all test above standard care that are 
being performed in a table: 
Intervention  
 
Potential risk 
 
Risk Management 
 
Blood tests 
Bruising at phlebotomy 
site 
Compression will be applied 
to minimise bruising. 
Lumbar 
puncture 
Post lumbar puncture 
headache. 
Atraumatic needles will be 
used which have been 
shown to minimise the risk 
of post lumbar puncture 
headache. 
 
In accordance with the MRC/DH/MHRA Joint Project Risk-adapted Approaches to the 
Management of Clinical Trials of Investigational Medicinal Products, this trial is categorised as:  
Type B = Somewhat higher than the risk of standard medical care: 
This trial is involving a medicinal product licensed in the EU Member State and is being used 
for a new indication. 


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4 
Objectives 
Primary: 
(UMSARS) score (Parts I and II) at 48 weeks comparing exenatide to best medically treated 
patients.  
 
Secondary: 
 
The proportion of patients with loss of independent ambulation by the end of the study, defined 
by a score of 4 in UMSARS-I item 7 (walking),  
 
The difference at week 48 in the MSA-QoL scale, 
 
The difference at week 48 in UMSARS parts III and IV, 
 
The difference in anti-parkinsonian or anti-orthostatic hypotension drugs, 
 
The number of falls, 
 
The proportion of patients reaching a score of 3 or more on UMSARS-I items 1 (speech), 2 
(swallowing), and 8 (falling), 
 
The difference at week 48 in clinical global impression (CGI) 
 
The difference at week 48 in MoCA scores. 
 
Safety of exenatide in MSA based on Adverse event reporting 
 
Exploratory 
 
The d
II) at 96 weeks comparing exenatide to best medically treated patients, 
 
The difference at 96 weeks in the MSA-QoL scale comparing exenatide to best medically treated 
patients, 
 
The difference at 96 weeks in UMSARS parts III and IV comparing exenatide to best medically 
treated patients, 
 
The difference in anti-parkinsonian or anti-orthostatic hypotension drugs at 96 weeks comparing 
exenatide to best medically treated patients, 
 
The difference in the number of falls at 96 weeks comparing exenatide to best medically treated 
patients,  
 
The difference in the proportion of patients reaching a score of 3 or more on UMSARS-I items 1 
(speech), 2 (swallowing), and 8 (falling) at 96 weeks comparing exenatide to best medically 
treated patients,  
 
The difference at 96 weeks in clinical global impression (CGI) and MoCA scores comparing 
exenatide to best medically treated patients. 
Data regarding walking will be collected over a week long period at baseline and at week 48 
prior to the visit via a CE marked sensor attached to the lower back  Axivity device. 


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5 
Trial design 
5.1 
Overall design 
This is a non-commercial, open label trial of a licensed drug designed to primarily provide 
preliminary efficacy and safety data for the use of Exenatide in MSA. This will be a simple parallel 
group design and include a 48-week exposure period. Detailed evaluations will take place at 
Screening, Baseline, 12, 24, 36, 48 and 96 weeks.  
Patients will be randomly allocated into 2 groups to receive either:  
 
Exenatide extended release 2mg subcutaneous injection once weekly for 48 weeks 
together with standard treatment options,  n~=25,  
or 
 
Standard treatment options, n~=25 
The control arm will attend all the same visits as the Exenatide group. Separate randomisation 
lists will be generated for patients with MSA-P or MSA-C.  
The control group of patients are very important in view of the continued neurodegenerative 
process of MSA that leads to a mean 7.8 point decline in UMSARS scores per year (Poewe et al. 
2015).  
All participants will be invited for face to face visits at all timepoints. If a participant is unable or 
unwilling to attend any of the follow up assessments (12,24,36,48,96 weeks), they may be 
offered the option of a home visit by 1 or more members of the trial clinical team if staffing 
levels permit. 
This trial will also assess the safety and tolerability of Exenatide when administered to patients 
with MSA. Encouraging results will be used as a basis for application for funding for a larger 
double blind placebo controlled RCT and will be used to inform upon sample size calculations 
for such a trial. This drug already has a license for the treatment of patients with Type II Diabetes 
and there is extensive safety data from phase 3 trials of its use in this patient group.  
 
.




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6 
Investigational Medicinal Products and Non-Investigational Medicinal 
Products 
6.1 
Name and description of IMP(s) 
Exenatide (extended-release for injectable suspension) - 
 2mg subcutaneous once 
weekly injection 
Bydureon BCise  2mg subcutaneous once weekly injection. 
 
Exenatide is a licensed treatment indicated in adults 18 years and older with type 2 diabetes 
mellitus to improve glycaemic control in combination with other glucose-lowering medicinal 
products including basal insulin, when the therapy in use, together with diet and exercise, does 
not provide adequate glycaemic control. This study will investigate Exenatide in a novel 
indication in Multiple System Atrophy. 
 
The Bydureon dual-chamber pen contains Exenatide powder and solvent in a Type 1 glass 
cartridge sealed at one end with a chlorobutyl rubber stopper and an aluminium seal, and at 
the other end with a chlorobutyl rubber piston. The two chambers are separated by a second 
chlorobutyl rubber piston. There is one needle supplied per pen. Each carton also contains one 
spare needle. Each pack contains 4 single-dose pre-filled pens and a multipack containing 12 (3 
packs of 4) single-dose pre-filled pens.  
From 31 March 2021, the Bydureon pen is being replaced by Astra Zeneca by a newer, easier 
to use device- the Bydureon BCise pen. The discontinuation of Bydureon is not due to quality 
or manufacturing issues and does not affect trial participants who are currently on Bydureon. 
The Bydureon BCise pen is a single chamber pen, with a needle already attached, containing 
the suspension and thus only needs shaking by the user to ensure the suspension is evenly mixed 
prior to administration. Each pack contains 4 single-dose pre-filled pens. 
 
6.2 
Source of IMP, Manufacture and  Distribution  
Exenatide (Bydureon or Bydureon BCise) will be sourced from routine hospital stock and their 
handling and management will be subject to standard procedures of the pharmacy. 
6.3 
Storage and handling of IMP(s) at site 
All IMP aspects of the trial at participating sites are the responsibility of the PI, who may delegate 
this duty to the local pharmacist or other appropriately trained personnel.  The delegation of 
duties must be recorded on the Staff Signature and Delegation of Tasks. 
Storage and handling (e.g., labelling) of the IMP will be completed in accordance with 
the relevant SPC and summary of drug arrangements.  Exenatide requires refrigerated 
storage (2-8°C). Once removed from the refrigerator, Exenatide needs to stand at 
room temperature for at least 15 minutes before administration. All patients will be 
instructed how to operate the pen device and to perform the injections. They will 
perform their first injection with supervision of the trial team at the end of the 
baseline visit. 


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For home visits, dispensing of IMP will be performed by trial pharmacy and transported to the 
patient in an appropriate cool bag with temperature logger by the clinical trial team.  The trial 
team member will check the temperature logger to ensure the temperature has stayed within 
the range 2-8°C.  If the temperature has fallen out of range the IMP must not be dispensed to 
the patient and should be returned to the trial pharmacy. 
 
Detailed instructions are contained in the summary of drug arrangements.  
 
6.4 
Accountability of IMP(s) 
The trial pharmacist within the hospital pharmacy will be accountable for trial drug supplies. 
There will be no additional reconstitution or other preparation required prior to dispensing 
from hospital stock.  
The IMP Drug Accountability Log must be completed to record each dose of IMP dispensed for 
each trial participant.  This log must be retained in the relevant section of the Pharmacy Site 
File, and a copy must be submitted to the sponsor upon request. It is the responsibility of the 
Pharmacy Lead to maintain drug accountability records.  
The patient will be instructed to return unused IMP to the research facility, which will then be 
returned to site pharmacy, to be then updated in the drug accountability log in the pharmacy 
site file. Following authorisation by the sponsor, drug destruction will be conducted in 
accordance to local practice and this will be documented in the drug destruction log in the 
hospital pharmacy file. 
Detailed instructions are contained in the summary of drug arrangements.  
6.5 
Concomitant medication 
Trial participants will be permitted to use any licensed medication throughout the course of the 
trial that is recommended by their referring Neurologist and is not contraindicated with trial IMP 
as per standard practice. Patients will be given advice in any necessary minor adjustments to 
their pre-existing MSA medications at each of their follow up visits and doses will be recorded 
and converted to a Levodopa equivalent dose (LED) as appropriate. No routine adjustment of 
MSA medications will be made by the Investigator(s) unless at the request of the patients. If 
possible, patients will be invited to attend the trial site at a similar time of day and after a similar 
duration since they took their usual MSA medications for each of the trial visits. 
Patients receiving warfarin or coumarin derivatives may be at risk of increased INR and 
associated bleeding; therefore INR should be monitored closely 
 
 
Patients on Warfarin will not be able to undergo Lumbar punctures. 
There have been rare reported events of altered renal function with Exenatide; therefore 
patients receiving the following concomitant medications should have their renal function 
closely monitored using blood tests at every follow up visit:  
 
angiotensin converting enzyme inhibitors,  


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angiotensin-II antagonists,  
 
non-steroidal anti-inflammatory medicinal products   
 
diuretics 
COVID-19 vaccinations that are administered after a patient has signed informed consent should 
be captured as a concomitant medication. If the vaccination is a multi-dose vaccination, each 
dose received should be entered as a separate concomitant medication.  
Concomitant medications will be 
local electronic health 
record system, EPIC.  
 
6.6 
Post-trial IMP arrangements 
The IMP will not be provided to trial 
 post-trial participation.  
7 
Selection of Participants 
The investigator should only enrol subjects who meet all inclusion and none of the exclusion 
criteria, are not put at undue risk by participating in the trial and can be expected to comply with 
the protocol. 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomisation. Previous 
clinical correspondence will be used to confirm eligibility criteria. Questions about eligibility 
criteria should be addressed PRIOR to attempting to randomise the participant.  
The eligibility criteria for this trial have been carefully considered and are the standards used to 
ensure that only medically appropriate participants are entered. Participants not meeting the 
criteria should not be entered into the trial for their safety and to ensure that the trial results 
can be appropriately used to make future treatment decisions for other people with similar 
diseases or conditions. It is therefore vital that exceptions are not made to these eligibility 
criteria. 
Participants will be considered eligible for enrolment in this trial if they fulfil all the inclusion 
criteria and none of the exclusion criteria as defined below. 
7.1 
Eligibility of trial participants  
7.2 
Trial participant inclusion criteria  
1. Male or female 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) 
2. 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.  
3. Participants who are able to walk at least 10 metres with or without assistance.  
4. Participants with an anticipated survival of at least three years in the opinion of the 
investigator.  


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5. Willing to adhere to the study drug regimen.  
6. Willing and able to meet all study requirements, including travel to Study Centre, 
procedures, measurements and visits, including: 
a. Caregiver/trial partner committed to facilitate participants involvement in the study 
if the participant is unable to attend appointments on their own.  
7. Females of childbearing potential and males with partners of childbearing potential 
agree to use an effective method of double contraception from the time consent is 
signed until at least 12 weeks after treatment discontinuation.  
8. For Females of childbearing potential; they must have had a negative pregnancy test 
within 7 days prior to being randomised.  Participants are considered not of child 
bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal 
9. 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.  
 
7.3 
Trial participant exclusion criteria  
1. Females who are pregnant, planning pregnancy or breastfeeding 
2. Women of child-bearing potential and males with partners of child bearing potential who do not 
practice an acceptable method of birth control [acceptable methods of birth control in this study 
are: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-
acting injectable contraceptive, partner's vasectomy, a double-protection method (condom or 
diaphragm with spermicide), total abstinence from intercourse with male partners. Abstinence is 
acceptable only as true abstinence: when this is in line with the preferred and usual lifestyle of 
the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), occasional abstinence and withdrawal are not acceptable methods of contraception. 
3. Subjects who meet any of the following criteria which tend to suggest advanced disease: 
A) Speech 
 
B) Swallowing 
 
C) Impairment in ambulation as assessed by a score of >3 on UMSARS question 7 
D)
8 
4. Participants with a clinically significant or unstable medical or surgical condition that, in the 
opinion of the investigator, might preclude safe completion of the study. 
5. Participants with active malignant neoplasms or history of malignant neoplasm in the last 5 years. 
6. Movement disorders other than MSA; e.g., Parkinson disease, dementia with Lewy bodies, 
essential tremor, progressive supranuclear palsy, spinocerebellar ataxia, spastic paraparesis, 
corticobasal degeneration, or vascular, pharmacological or post-encephalitic parkinsonism. 
7. Concurrent dementia defined by a score lower than 21 on the MoCA. 
8. 
-II  


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9. History of deep brain stimulation surgery. 
10. Patients with Body mass index <18.5.  
11. Currently active infection that cannot be stabilised before baseline visit.  
12. 
 or random blood 
glucose >11.1 mmol/L) 
13. End stage renal disease or severely impaired renal function with creatinine clearance <30ml/min 
14. History of severe cardiac disease (Angina, Myocardial infarction or cardiac surgery in preceding 2 
years) 
15. History of pancreatitis  
16. History of alcoholism 
1. Severe gastrointestinal disease including gastroparesis 
2. Ongoing treatment with sulphonylurea 
3.  Concurrent and/or recent involvement in other research or use of another experimental 
investigational medicinal product within 90 days of study enrolment 
4.  Known allergies to the IMP and excipients of IMP.  
7.4 
Recruitment 
Initial discussions with patients at scientific and patient support meetings show very high 
interest in this study. A cohort of patients at the National Hospital for Neurology and 
Neurosurgery and patients will be utilised for recruitment as well as working with hospitals from 
surrounding areas. Neurologists in the UK with an interest in MSA will be informed when the 
trial is open to recruitment and provided with details of eligibility criteria to allow referral of 
potential recruits to the clinical trial team.  
managers, the UCL Institute of Neurology, UCLH NHS Trust and local National Institute of Health 
Research Clinical Research Network portfolio websites. Contact details of the trial team will be 
included to allow potentially eligible interest patients to make direct enquires to the trial team.  
All participants will be pre-screened by recognised experts in Movement Disorders to avoid any 
variability in diagnoses; using the history of their symptoms, supported by all available clinical 
correspondence according to usual standard of care. 
It is anticipated that recruitment of 50 patients will be completed within 15 months of trial 
commencement. 
Participant recruitment at a site will only commence when the trial has  
1. 
 
2. 
 
 
Patients will be recruited from the National Hospital for Neurology & Neurosurgery, London. 
Patients attending their routine follow up appointments will be informed about the trial by their 
Neurologist and given a Patient Information Sheet, either by hand, by post or via email. This will 


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be documented in the medical records. Each potential patient will be pre-screened according to 
those inclusion/exclusion criteria which can be assessed ahead of obtaining informed consent.  
 
 
 
7.5 
Informed consent procedure 
It is the responsibility of the Investigator, or a person delegated by the Investigator to obtain 
written informed consent from each participant prior to participation in the trial, following 
adequate explanation of the aims, methods, anticipated benefits and potential hazards of the 
trial.  
The person taking consent will be GCP trained, suitably qualified and experienced, and will have 
been delegated this duty by the CI/ PI on the Staff Signature and Delegation of Tasks. 
 must be given for consideration by the participant before taking part. Consent 
will be sought at least 24 hours after being given the study documentation. It must be recorded 
in the 
when the participant 
information sheet (PIS) has been given to the participant.  
The Investigator or designee will explain that participants are under no obligation to enter the 
trial and that they can withdraw at any time during the trial, without having to give a reason. 
During the consent process it will be highlighted to the participant by the investigator that they 
will have a 50% chance of being allocated to randomly to active Exenatide treatment or as a 
control.  
No clinical trial procedures will be conducted prior to the participant giving consent by signing 
the Consent form. Consent will not denote enrolment into trial. Participants who are unable to 
write (eg due to severe tremor) will be able to indicate their informed consent verbally and a 
witness will sign the consent form on their behalf. 
A copy of the signed informed consent form will be given to the participant.  The original signed 
form will be retained in the trial file at site and a copy placed in the medical notes. 
The PIS and consent form will be reviewed and updated if necessary throughout the trial (e.g. 
where new safety information becomes available) and participants will be re-consented as 
appropriate.  
8 
Trial procedures  
 
The trial includes a screening visit (Visit 1), a baseline visit (Visit 2), a 12 week follow up (Visit 3), 
a 24-week follow-up visit (Visit 4), a 36 week follow up (Visit 5), 48-week follow-up visit (Visit 6), 
a 58-week telephone review  and a final 96-week follow-up visit (Visit 7). 
8.1 
Pre-treatment Assessments  
 
   
Screening assessments  Visit 1  


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Participants will attend the research centre for informed consent to the trial. The following trial 
y: 
 
Demographics recorded  
 
Medical History recorded  
 
Family History recorded 
 
All available brain imaging will be recorded 
 
Any previous genetic tests recorded e.g. if testing has been performed for 
Spinocerebellar ataxia or Fragile X tremor/ataxia syndrome  
 
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 and weight  
 
Vital signs 
 
Serum and urine pregnancy test (for women of child bearing potential) 
 
MoCA 
 
BDI-II  
 
Concomitant Medications  
At this visit the investigator will also ensure the patient is asked about speech/swallowing and 
mobility to assess exclusion criteria number 3. Eligible patients will wear a sensor attached by 
sticking plaster over their lower back for 1 week. They will bring this back to the trial team at the 
baseline visit or send to the trial team using a Stamped Addressed Envelope. 
Participants will be randomised to either the trial drug or control arm. 
 
 
Week 0 (Baseline assessments)  Visit 2  
Patients will attend the research centre for the following trial procedures: 
 
Physical Examination (if deemed necessary by trial clinician for clinical purposes) 
 
Neurological Examination (if deemed necessary by trial clinician for clinical purposes) 
 
Lumbar puncture for CSF collection   
 
Serum collection  
 
Fasting blood tests (glucose, insulin, c-peptide and triglycerides) 
 
Vital signs  
 
UMSARS  
 
COMPASS Select  
 
MSA-QoL scale 
 
Timed Motor Tests  
 
The Unified Dystonia Rating scale  
 
MoCA 
 
BDI-II  


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Concomitant Medications review  
 
Adverse Events review  
 
Participants randomised to the trial drug arm will be dispensed the trial medication and receive 
teaching on its use. 
 
 
All pre-treatment procedures will be carried out as specified in the schedule of assessments 
(appendix 1). 
 
8.2 
Randomisation Procedures  
 
All enrolled participants will be entered onto an enrolment log.  
Participant randomisation will be undertaken remotely at site using Sealed Envelope, an online 
service for the randomisation of participants in a clinical trial.  
Following participant consent, and confirmation of eligibility (see section 8.1 for pre-treatment 
assessments) the randomisation procedure described below will be carried out.  
Participants will be randomised to receive the trial drug added to their treatment or to continue 
to receive existing treatment alone. 
of birth, date of consent, criteria fulfilment and MSA phenotype strata into the Sealed Envelope 
secure website. A random sequence for study arm allocation will be computer generated by a 
randomisation service provider (Sealed Envelope.com).  Sealed Envelope will provide a unique 
trial identification code for each recruited participant. Blocking will be used within strata to 
enable achievement of approximately equal numbers in each group.  
Strata 1= Phenotype consistent with MSA-C. 
Strata 2= Phenotype consistent with MSA-P 
A list of the trial identification codes and treatment allocation will be stored in a secure cabinet 
with the study team. The randomisation list will be sufficiently long to enable continued 
randomisation should any patients drop out within the first 9 months. All randomisation 
procedures will take place during working hours. 
Participants are considered to be enrolled into the trial following: consent, pre-treatment 
assessments (see section 8.1), confirmation of eligibility, completion of the randomisation 
process, allocation of the participant trial number and treatment by the remote system. 
 
8.3 
Treatment Schedule 
For participants randomised to receive the trial drug they will receive 2mg Exenatide once-
weekly for 48 weeks via subcutaneous injection. Astra-Zeneca announced that they will 
discontinue manufacturing of Bydureon from March 2021 and that this would be replaced by 


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the Bydureon BCise. There is no difference to the dose of exenatide contained between the 
devices. Patients who have already started on Bydrureon will be reconsented and given new 
instructions about how to use the updated device. 
 
The first dose will be administered in clinic following injection teaching and the patient will be 
given sufficient number of pens to continue injections until their 12 week follow up visit. Each 
participant will be shown an online video instruction specifically for the Bydureon or Bydureon 
BCise pen injections, which they can revisit as necessary. Each subsequent injection will be given 
every 7 days at home by self-administration. Injections will be given into the abdomen, arm, 
thigh or buttocks. Participants will be given a dosing diary to record the time and day of all 
injections administered.  
The control group of patients are very important in view of the continued but variable rate of 
the neurodegenerative process of MSA.  
Patients will continue to see their treating neurologist at normally scheduled appointments. 
Adjustment to MSA medications will be permitted based on the clinical judgement of the 
treating neurologist and/or the clinical trial team to optimise symptom control throughout the 
duration of the trial. Doses of all medications will be recorded at each trial visit. 
8.3.1 Dose Modifications 
Patients experiencing abdominal pain consistent with a clinical diagnosis of pancreatitis will 
receive investigation and treatment according to NHS standard of care and the trial medication 
will be stopped pending confirmation or exclusion of the diagnosis. Confirmation of a diagnosis 
of acute pancreatitis will result in the trial medication being permanently stopped. 
 
Patients found to have an elevation in serum Amylase (>50% above baseline and >50% above 
the laboratory reference range) will have a clinical assessment and have the test repeated after 
1 week. If the amylase remains elevated, a clinical decision will be made whether to temporarily 
withdraw exenatide until the amylase return to the normal range or permanently withdraw 
exenatide.   
 
Patients developing clinical suspicion of thyroid malignancy will receive treatment according to 
NHS standard of care and the trial medication will be stopped. 
 
Patients experiencing excessive/undesirable weight loss (>10% of body weight during a 12 week 
interval) or unacceptable adverse effects will have a clinical assessment and a decision regarding 
temporary withdrawal of study medication will be made. 
8.4 
Subsequent assessments and procedures 
 
 
Week 4 (+/-1 week)   telephone call 
The study nurse will call the participants to ensure the participants are taking their medication 
according to the protocol requirements and completing their trial diary as required. They will 
also perform a concomitant medication and AE check.  


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Week 12 assessments  Visit 3  
At 12 weeks after baseline evaluation, each patient will be telephoned 1 week prior to remind 
them of their visit  
Participants will attend the research centre for the following trial procedures: 
 
Physical Examination (if deemed necessary by trial clinician for clinical purposes) 
 
Routine blood tests (FBC, U&E, LFT, glucose, amylase, HbA1c, PT and APTT) 
 
Serum collection  
 
Vital signs including weight 
 
UMSARS Part II (videotaped) 
 
UMSARS Part I, III and IV 
 
The Unified Dystonia Rating Scale  
 
MoCA  
 
Timed Motor tests 
 
BDI-II 
 
Concomitant Medications review  
 
Adverse Events review  
 
Dispensing of 12 exenatide (Bydureon or Bydureon BCise) pens (if randomised to receive 
exenatide). 
 All participants will be invited for face to face visits at all timepoints. If a participant is unable or 
unwilling to attend any of the follow up assessments (12,24,36,48,96 weeks), they may be 
offered the option of a home visit by one or more members of the trial clinical team if staffing 
levels permit. These participants will be asked to consent to home visits. Assessments will be 
performed as per protocol. Weight will be measured only if the participant is able to stand, and 
weighing scales are available. Dispensing of IMP will be performed by trial pharmacy and 
transported to the patient in an appropriate Cool Bag with temperature logger by the clinical 
trial team. 
 
 
Week 24 assessments  Visit 4 
At 24 weeks after baseline evaluation, each patient will be telephoned 1 week prior to remind 
them of their visit. They will be asked not to have eaten and to have drunk water only for 6 hours 
to enable fasting blood samples to be taken. 
Participants will attend the research centre for the following trial procedures: 
 
Physical Examination (if deemed necessary by trial clinician for clinical purposes) 
 
Neurological Examination (if deemed necessary by trial clinician for clinical purposes) 
 
Fasting blood tests (FBC, U&E, LFT, glucose, amylase, insulin, c-peptide, HbA1c) 
 
Serum collection  
 
Vital signs including weight 
 
UMSARS Part II (videotaped)  


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UMSARS Part I, III and IV 
 
Timed motor tests  
 
COMPASS Select  
 
COMPASS Change 
 
The Unified Dystonia Rating scale  
 
BDI-II 
 
MoCA 
 
Concomitant Medications review  
 
Adverse Events review  
 
Dispensing of 12 exenatide pens (if randomised to receive exenatide). 
 
 
 
Week 36 assessments  Visit 5 
At 36 weeks after baseline evaluation, each patient will be telephoned 1 week prior to remind 
them of their visit.  
Participants will attend the research centre for the following trial procedures: 
 
Physical Examination (if deemed necessary by trial clinician for clinical purposes) 
 
Routine blood tests (FBC, U&E, LFT, glucose, amylase and HbA1c) 
 
Serum collection  
 
Vital signs including weight 
 
UMSARS Part II (videotaped)  
 
UMSARS Part I, III and IV 
 
Timed motor tests  
 
The Unified Dystonia Rating scale  
 
BDI-II 
 
MoCA 
 
Concomitant Medications review  
 
Adverse Events review  
 
Dispensing of 12 exenatide (Bydureon or Bydureon BCise) pens (if randomised to receive 
exenatide). 
 
 
Week 48 assessments  Visit 6 
At 48 weeks after baseline evaluation, each patient will be telephoned 1 week prior to remind 
them of their visit. They will be asked not to have eaten and to have drunk water only for 6 hours 
to enable fasting blood samples to be taken. 
Participants will attend the research centre for the following trial procedures: 
 
Physical Examination (if deemed necessary by trial clinician for clinical purposes) 
 
Neurological Examination (if deemed necessary by trial clinician for clinical purposes) 


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Fasting blood tests (glucose, insulin and c-peptide) 
 
Routine blood tests (FBC, U&E, LFT, glucose, amylase, HbA1c, PT and APTT) 
 
Serum collection  
 
Lumbar puncture for CSF collection  
 
Vital signs including weight 
 
UMSARS Part II (videotaped)  
 
UMSARS Part I, III and IV 
 
Timed motor tests  
 
COMPASS Select  
 
COMPASS Change 
 
MSA-QoL scale 
 
The Unified Dystonia Rating scale  
 
BDI-II 
 
MoCA 
 
Concomitant Medications review  
 
Adverse Events review  
 
Axivity lumbar sensor 
If a patient cannot attend the clinical research facility and is being assessed via a home visit, no 
attempt will be made to perform a lumbar puncture and this missed assessment will be recorded 
as a protocol deviation. 
 
Week 58 (+/-1 week) telephone call 
The study nurse will call the participants to perform an adverse event check. 
 
Week 96 assessments  Visit 7 
At 96 weeks after baseline evaluation, each patient will be telephoned 1 week prior to remind 
them of their visit.  
Participants will attend the research centre for the following trial procedures: 
 
Physical Examination (if deemed necessary by trial clinician for clinical purposes) 
 
Neurological Examination (if deemed necessary by trial clinician for clinical purposes) 
 
Serum collection  
 
Vital signs including weight 
 
UMSARS Part II (videotaped)  
 
UMSARS Part I, III and IV 
 
Timed motor tests  
 
COMPASS Select  
 
COMPASS Change 
 
MSA-QoL scale 
 
The Unified Dystonia Rating scale  
 
BDI-II 
 
MoCA 


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Concomitant Medications review  
 
Adverse Events review  
 
8.5
Laboratory Assessments and Procedures
Local laboratories  
The following tests will be carried out at Local Laboratories:  
 
Routine bloods (FBC, U&E, LFT, glucose, amylase, HbA1c, PT and APTT) 
 
Fasting bloods (glucose, insulin, c-peptide, triglycerides, amylase, FBC, U&E, LFT and 
HbA1c) 
 
Urine pregnancy test  
These are all standard hospital laboratory tests and will be performed according to standard 
treatment processes.  
 
Research Samples  
Serum samples will be processed, aliquoted and frozen in accordance with laboratory manual. 
Patients may consent to their samples being kept for future research. Future analyses will be 
planned as appropriate in accordance with clinical results, future funding application and latest 
knowledge. 
8.6 
Clinical Procedures and Data Collection 
 
Medical history: review of past medical history, family history, previous imaging, previous 
genetics tests and MSA medication history.  
 
Physical examination:   The following sites will be examined:  chest, heart, abdomen, skin, 
and lymph nodes; and the following systems will be assessed:  musculoskeletal and 
neurological. 
 
Neurological examination: The following will be examined: mental status, level of 
consciousness, sensory function, motor function, cranial nerve function and reflexes.  
 
Electrocardiogram: A standard 12-lead electrocardiogram will be performed.  
 
measurement will be noted. Vital signs include systolic and diastolic blood pressure, 
respiratory rate, oxygen saturation, weight, temperature and pulse rate.  
 
Concomitant Medication: All over-the-counter or prescription medication, vitamins, and/or 
herbal supplements will be recorded. 


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The Montreal Cognitive Assessment is a 30-point test that assesses several cognitive 
domains to detect cognitive impairment.  
 
-II is a patient rated depression severity scale. 
 
The Unified MSA Rating Scale (UMSARS) is a multidimensional, reliable, and valid scale for 
semi quantitative assessment of MSA patients with high internal consistency and 
substantial-to-excellent interrater agreement and is sensitive to change.  It focuses on all 
aspects of the disorder, including autonomic, cerebellar, and parkinsonism manifestations. 
USMARS has an Activities of Daily Living score (UMSARS Part 1, 12 questions); a Motor 
Examination score (UMSARS Part 2, 14 questions); Autonomic examination score (UMSARS 
Part 3) and a global disability scale (UMSARS Part 4). Part 2 will be videotaped to ensure 
there is the option to retrospectively score the participants by blinded raters if there are 
concerns regarding bias in view of this being an open label trial. All videos will be stored in 
an appropriate secure encrypted storage facility which can only be accessed by members 
of the research team.  
 
The Composite Autonomic Symptom (COMPASS) Select is a subset of the full COMPASS 
consisting of 46 questions in 5 domains (orthostatic intolerance, secretomotor, bladder, 
constipation, and sleep), leading to a total score between 0 and 125, with a higher score 
indicating greater impairment 
 
The COMPASS Change Scale is a derivation of COMPASS-select in which the participants 
score their change in autonomic symptoms since their last exam. It comprises 26 
retrospective questions in which participants scored how much their autonomic symptoms 
had changed. It is divided into change of 6 autonomic function domains (or 5 in women) 
[i.e. orthostatic intolerance, sexual failure (erectile dysfunction, male only), bladder 
disorder, secretomotor disorder, constipation and sleep disorder] with a maximum score 
of 160 for men and 150 for women (Wenning GK et al., 2007).  
 
MSA-QoL scale is a validated 40 item self-completed questionnaire in which a participant is 
asked to record the problems due to their MSA over the preceding 4 weeks. 
 
Timed Motor Tests include a hand tapping task to evaluate the number of hand taps that 
an individual can perform within 30 seconds and a timed, sit, stand, walk task.  
 
The Unified Dystonia Rating scale is an objective assessment of the severity of dystonia in 
each body region.  
 
Axivity lumbar sensor device. This CE marked sensor will be worn over the lower back 
(lumbar region), attached using sticky-backed plastic by the research team at the clinic visit, 
and worn continuously over 1 week prior to the Baseline visit and after the 48 week visit. 
The sensor will be posted back to the research team at week 49 using a stamp-addressed 
envelope given out in clinic with clear written instructions and a telephone contact for 
problems or queries. All recordings will be stored with the unique participant identification 
number (PIN) as well as their date of birth and gender. Analysis will be performed by 
analytic protocols. 
 
 
 


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8.7 
Assessment of IMP/NIMP compliance 
The importance of compliance with the trial protocol will be explained to the participant at 
baseline and at each follow up visit. Compliance will be optimised by informing all participants 
of the most commonly experienced side effects and ways of minimising these. Participants will 
be given adequate instruction regarding administration of injections and will be provided with a 
diary to record administration of IMP throughout the trial.  
Compliance will be assessed by directly questioning patients at each visit, and if applicable carers 
will also be asked to provide estimates of compliance, along with review of the drug 
administration diary. Reasons for non-compliance will be sought and addressed as far as possible 
at each follow up visit.  
Biological samples will be collected from each participant at each visit. These will include serum 
samples to allow measurement of Exenatide levels if indicated. Participants will be aware that 
their compliance will be measurable on the basis of these results. All analyses will be performed 
at the end of the trial. Guidance for sample collection and transport can be found in the 
Laboratory Manual.  
8.8 
Discontinuation/withdrawal of participants 
In consenting to participate in the trial, participants are consenting to trial treatment, 
assessments, follow-up and data collection.  
Discontinuation of Trial Treatment for clinical reasons 
A participant may be withdrawn from trial treatment whenever continued participation is no 
for discontinuing treatment may include  
 
disease progression whilst on therapy 
 
unacceptable toxicity 
 
intercurrent illness which prevents further treatment 
 
patients withdrawing consent to further trial treatment 
 
 
Persistent non-compliance to protocol requirements 
The decision to withdraw a participant from treatment must be recorded in the CRF and medical 
notes and the sponsor when required should be notified in writing.  
In these cases participants remain within the trial for the purposes of follow-up for safety and or 
data analysis according to the treatment option to which they have been allocated. 
Participant withdrawal from trial treatment 
If a participant expresses their wish to withdraw from trial treatment, sites should explain the 
importance of remaining on trial follow-up and seek permission to allow use of routine follow-up 
data to be used for trial purposes. The importance of safety follow-up should be emphasised to 
the participant in the Participant Information Sheet. 


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The decision of the participant to withdraw from treatment must be recorded 
CRF and medical notes in the electronic health record system, EPIC. 
The participant may withhold their reason for withdrawal however, if the participant gives a 
reason for their withdrawal, this should be recorded. 
Withdrawal of Consent to Data Collection  
If a participant explicitly states they do not wish to contribute further data to the trial their 
decision must be respected and recorded 
system, EPIC. 
Loss to follow-up 
If a participant is lost to follow-up at a site every effort should be made to contact the 
 
8.9 
Replacements 
Participants who withdraw from the trial prior to Week 12 (visit 3) will be replaced and their 
replacement randomised to maintain adequate numbers of participants reaching the 12 week 
assessment.  
 
8.10 Stopping rules  
 
The trial may be stopped before completion for the following reasons: 
 
On the recommendation of the TSC or DMC 
 
On the recommendation of the sponsor and CI 
 
Individual participant stopping rules include: 
 
Unacceptable treatment toxicity or adverse event. 
 
Inter-current illness that prevents further treatment 
 
 Justifies the 
discontinuation of treatment 
 
If a stopping rule is reached safety data will be reviewed and a decision on continuation will be 
made by the TMG with input from the sponsor.  
 
8.11 Definition of End of Trial 
The expected duration of the trial is 4 years from recruitment of the first participant. The end of 
the trial is the date of the last follow up of the last participant.  
 


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9 
Recording and reporting of adverse events and reactions 
Collection, recording and reporting of adverse events (including serious and non-serious events 
 
9.1 
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial 
participant administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. Therefore an 
AE can be any unfavourable or unintended change in the structure 
(signs), function (symptoms) or chemistry (laboratory data) in a 
participant to whom an IMP or procedural intervention has been 
administered, including occurrences which are not necessarily caused by 
or related to that product. 
Adverse Reaction (AR) 
Any untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant.  
This includes medication errors, uses outside of protocol (including 
misuse and abuse of product) 
Serious Adverse Event 
(SAE), Serious Adverse 
Reaction (SAR) or 
Unexpected Serious 
Adverse Reaction  
Any adverse event, adverse reaction or unexpected adverse reaction, 
respectively, that: 
 
results in death, 
 
is life-threatening*, 
 
requires 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation**, 
 
results in persistent or significant disability or incapacity, or 
 
consists of a congenital anomaly or birth defect 
Some medical events may jeopardise the subject or may require an intervention to prevent one 
of the above characteristics/consequences. Such important medical events should also be 
considered as serious. 
*A life- threatening event, this refers to an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 
** Hospitalisation is defined as an in-patient admission, regardless of length of stay. 
Hospitalisation for pre-existing conditions, including elective procedures do not constitute an 
SAE. 
Suspected 
Unexpected Serious 
A serious adverse reaction, the nature, severity or outcome of which is 
not consistent with the Reference Safety Information. 


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Adverse Reaction 
(SUSAR) 
Reference Safety 
Information (RSI) 
A list of medical events that defines which reactions are expected for 
the IMP being administered to clinical trial subjects, and so do not 
require expedited reporting to the Competent Authority. It is contained 
in a specific section in the Summary of product characteristics (SmPC) 
or the Investigator Brochure (IB). 
 
 
9.2 
Recording adverse events 
All adverse events will be recorded in the in the 
the electronic health record system, EPIC and in the CRF. All adverse events will be recorded 
with clinical symptoms and accompanied with a simple, brief description of the event, including 
dates as appropriate from consent until 10 weeks after they finish IMP (phone call at 58 weeks). 
From the 58 week phone call and the 96 week visit only AEs related to IMP or other trial 
intervention need to be recorded in the CRF. 
 
9.3 
Assessments of Adverse Events 
Each adverse event will be assessed for severity, causality and seriousness as described below.  
9.3.1 Severity  
The severity of all AEs and/or ARs (serious and non-serious) in this trial should be graded using the study 
specific toxicity grading system and the National Institutes of Health Common Terminology Criteria for 


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Adverse Events (CTCAE) version 5.0. SUSARs will be coded via MedDRA for the purpose of expedited 
reporting to MHRA/REC. 
Where the specific event term is not listed in CTCAE please refer to the below table: 
Grade 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL**.  
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE.  
 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
9.3.2 Causality 
The assessment of relationship of adverse events to the administration of IMP is a clinical decision 
based on all available information at the time of the completion of the case report form.   
The following categories will be used to define the causality of the adverse event: 
 
Category 
Definition 
Related: 
A causal relationship between an IMP/investigational treatment and an 
adverse event is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. 
Not related 
There is no reasonable possibility of a causal relationship between an 
IMP/investigational treatment and an adverse event. 
 
 
9.3.3 Expectedness 
 


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Category 
Definition 
Expected 
An adverse event which is consistent with the information about the IMP listed in 
the current approved Reference Safety Information (RSI) for the trial. 
Unexpected 
An adverse event which is not consistent with the information about the IMP 
listed in current approved Reference Safety Information (RSI) for the trial. 
The RSI to be used to assess expectedness against the IMP is: 
SmPC for Bydureon (exenatide) 2 mg for prolonged-release suspension for injection in pre-filled 
pen (BCise) (AstraZeneca UK Limited).   
 
The following events listed below describe expected procedural/disease related AEs: The most 
frequent adverse reactions were mainly gastrointestinal related (nausea which was the most 
frequent reaction and associated with the initiation of treatment and decreased over time, and 
diarrhoea). In addition, injection site reactions (pruritus, nodules, erythema), hypoglycaemia 
(with a sulphonylurea), and headache occurred. Most adverse reactions associated with 
prolonged-release exenatide were mild to moderate in intensity. 
 
9.3.4 Seriousness 
All events are assessed for seriousness as defined for an SAE in section 9.1. Specific adverse events that 
require expedited reporting as SAEs are detailed in section 9.3.5. 
9.3.5 Other Notifiable Adverse Events  
Suspicion of chronic pancreatitis based on a rise in serum amylase greater than 50% above both 
baseline level AND the laboratory reference range will be notified in an expedited manner in the 
same way as an SAE.  
Overdose and potential drug induced liver injury (DILI) events must be handled as SAEs (see 
section 9.8).  
All safety events as described above will be treated as SAEs and reported in line with the 
procedures set-out in section 9.4 apart from regulatory reporting. 
9.4 
Procedures for recording and reporting Serious Adverse Events 
All serious adverse events (SAEs/SARs/SUSARs) will be recorded in the medical records and the 
SAE Recording Log.  The SAE Recording Log of SAEs will be reported to the 
sponsor at least once or twice per year. 
All SAEs will be recorded from baseline visit until 10 weeks after completion of IMP (phone call at 
58 weeks). From the 58 week phone call and the 96 week visit only SAEs related to IMP or other 
trial intervention need to be recorded in the CRF. 
All SAEs must be recorded on a Serious Adverse Event (SAE) Reporting Form. The CI/PI or 
designated individual will 
Reporting Form and the form will be 


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emailed to the Sponsor SAE@ucl.ac.uk and within 24 h of his / her becoming aware of the event. 
The Chief or Principal Investigator will respond to any SAE queries raised by the sponsor as soon 
as possible.  
 
 
 
 
Reporting Form (INV/S05) as amended for the trial.   
SAEs will be reported to the sponsor until the end of the trial. SAR and SUSAR will need to be 
reported to the Sponsor irrespective of how long after IMP administration the reaction has 
occurred.  
Participants must be followed up until clinical recovery is complete and laboratory results have 
returned to normal or baseline values, or until the event has stabilised. Follow-up should 
continue after completion of protocol treatment and/or trial follow-up if necessary.  
Follow-up SAE forms (clearly marked as follow-up) should be completed and emailed to the JRO 
as further information becomes available.  
 
 
Completed SAE forms must be sent within 24 hours of becoming 
aware of the event to the Sponsor  
Email forms to SAE@ucl.ac.uk  




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9.5 
Reporting SUSARs 
The sponsor will notify the main REC and MHRA of all SUSARs.  SUSARs that are fatal or life-
threatening must be notified to the MHRA and REC within 7 days after the sponsor has learned 
of them.  Other SUSARs must be reported to the REC and MHRA within 15 days after the sponsor 
has learned of them.   
9.6 
Development Safety Update Reports 
The sponsor will provide the main REC and the MHRA with Development Safety Update Reports 
office. The 
report will be submitted within 60 days of the Developmental International Birth Date (DIBD) of 
the trial each year until the trial is declared ended. 
9.7 
Pregnancy  
There is no safety data to inform on the use of Exenatide during pregnancy. Male participants 
and female participant of child-bearing potential will be advised to use an effective form of 
contraception whilst they are on the study. If it is subsequently discovered that a study subject 
is pregnant or may have been pregnant at the time of IMP exposure, including duration of at 
least 10 weeks after product administration, the IMP will be permanently discontinued in an 
appropriate manner.  
Protocol-required procedures for study discontinuation and follow-up must be performed on 
the subject unless contraindicated by pregnancy. Other appropriate pregnancy follow-up 
procedures should be considered if indicated. Trial follow up assessments will continue as per 
proto
may have followed Exenatide exposure during pregnancy.  
Pregnancy is not a SAE and should be reported through a Pregnancy Reporting Form. The 
pregnancy outcome may or may not be considered a SAE.  
If a female participant or the female partner of a male participant becomes pregnant at any 
point during the trial, a completed trial specific Pregnancy Reporting Form will be preferably 
emailed to the Sponsor SAE@ucl.ac.uk, within 24 hours of his / her becoming aware of the event 
in line with the Sponsors SOP (JRO/INV/S05). The Chief or Principal Investigator will respond to 
any queries raised by the sponsor as soon as possible.   
 
 
 
 
 
 
 
 
 
The Sponsor must be kept informed of any new developments involving the pregnancy through 
the completion of a follow-up Pregnancy Reporting Form. Any pregnancy that occurs in a female 
trial subject during a clinical trial should be followed to termination or to term. 
Completed Pregnancy Reporting Forms must be sent within 24 
hours of becoming aware of the event to the Sponsor  
Email forms to SAE@ucl.ac.uk  


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Consent to report information regarding the pregnancy must be obtained from the pregnant 
participant or pregnant partner. A trial-specific pregnancy monitoring information sheet and 
informed consent form for trial participants or pregnant partners must be used for this purpose.   
With consent additional information regarding the pregnancy will be collected and reported to 
the Sponsor, the Sponsor will advise on the length of follow up of the pregnancy/ child on a case 
by case basis.   
 
 
9.8 
Overdose  
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important and it must always be reported as a 
SAE. Overdoses will be fully described in the SAE report form and recorded on the deviation log. 
Overdoses can be observed from administration diaries, participant and carers comments.  
 
9.9 
Reporting Urgent Safety Measures and other safety events 
If any urgent safety measures are taken the CI/ PI shall immediately and in any event no later 
than 3 days from the date the measures are taken, give written notice to the MHRA, the relevant 
REC and Sponsor of the measures taken and the circumstances giving rise to those measures. 
 
9.10 Notification of Serious Breaches to GCP and/or the protocol (SPON/S15)  
 
 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
The sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach 
of  
(a) the conditions and principles of GCP in connection with that trial; or (b) the protocol relating 
to that trial, as amended from time to time, within 7 days of becoming aware of that breach. 
The sponsor will be notified immediately of any case where the above definition applies during 
 violations, urgent safety 
 
10 
Data management and quality assurance 
10.1 Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 2018. 
The Case Report Forms (CRFs) will not bear the s
data 


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identification and this will be clearly explained to the patient in the Patient information sheet.  
Patient consent for this will be sought. 
10.2 Data collection tools and source document identification 
The majority of study data will be collected from the sites on an electronic CRF and into the 
.  
Source data are contained in source documents and must be accurately transcribed on to the 
electronic CRF. Examples of source documents are electronic medical records which include 
laboratory and other clinical reports etc. 
A source document list will be implemented prior to the start of the trial to identify: 
which data is to be recorded directly onto the CRF;  
which data is not to be recorded in the CRF but only recorded in source documents, e.g., 
participant questionnaires and diary cards.  
It is the responsibility of the investigator to ensure the accuracy of all data entered in the eCRF. 
The delegation log will identify all those personnel with responsibilities for data collection and 
handling, including those who have access to the trial database. The electronic CRF will be 
purpose built and tested for completeness before activation of the site.  
 
10.3 Completing Case Report Forms  
All CRFs must be completed and signed by staff that are listed on the site staff delegation log 
and authorised by the CI to perform this duty.  The CI is responsible for the accuracy of all data 
reported in the CRF. Source data verification of a CRF page should be completed and all data 
queries answered prior to entry into the database where possible.  
10.4 Data handling and analysis 
A trial specific data management SOP will be in place for the trial. This will contain details of the 
software to be used for the database, the process of database design, coding, data entry, data 
quality checks, data queries, data security, database lock and data transfer. Data queries will be 
resolved by the trial manager through direct discussion with the trial team. A custom designed 
database will be created to store all trial data. The database will only be available to specified 
users who will require a username and password for access. 
Where data are transferred electronically this will be in accordance with the UK Data Protection 
Act 2018 as well as UCL Information Security Policy and Trust Information Governance Policy.  
There will be a documented record of data transfer and measures in place for the recovery of 
original information after transfer. 
 
11 
Statistical Considerations  
 


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11.1 Outcomes 
11.1.1 
Primary outcomes 
The primary 
 Atrophy Rating Scale 
(UMSARS) score (Parts I and II) at 48 week comparing Exenatide to best medically treated patients. 
The analysis will use ANCOVA to allow adjustment for baseline severity and MSA sub-type.
11.1.2 
 Secondary & Exploratory outcomes 
Key secondary outcomes would include proportion of patients with loss of independent 
ambulation by the end of week 48 and 96, defined by a score of 4 or more in UMSARS-I item 7 
(walking); difference at Week 48 and 96 in the MSA-QoL scale; difference at Week 48 and 96 in 
UMSARS Part I, II, III and IV; difference in anti-parkinsonian or anti-orthostatic hypotension  
drugs; number of falls; and the proportion of patients reaching a score of 3 or more on UMSARS-
I items 1 (speech), 2 (swallowing), and 8 (falling); difference in Week 48 and 96 in clinical global 
impression (CGI); difference at Week 48 and 96 in MoCA scores.  
 
11.2 Sample size and recruitment 
11.2.1 
Sample size calculation 
The recent rasagiline for MSA (MSA-Ras) trial evaluated rasagiline versus placebo using the 
UMSARS 
in the placebo group declined by mean 7.8 points (SD 10.4  Werner et al. 2015).  
Therefore, on the basis of this previously collected data and with a two-sided 5% significance 
level, we estimated that a sample size of 40 patients (20 per group) would be required to detect 
a difference of 5 total UMSARS points between the two groups, assuming a correlation between 
baseline and final disease severity of 0.85. These calculations were based on a common SD of 
10.4, 80% power and an overall type 1 error rate of 5%. A 5 point difference between groups 
would be a clinically important effect size. Based on a 20% dropout rate as reported from 
previous trials, the sample size would be 50 (25 per arm). 
11.2.2 
Planned recruitment rate 
The estimate recruitment period for the trial is 15 months.  
11.3 Randomisation methods 
A random sequence for study arm allocation will be computer generated by a randomisation 
service provider (SealedEnvelope.com). Sealed Envelope will provide a unique trial 
identification code for each recruited participant. Stratified randomisation will be performed 
with strata defined by MSA sub-type. Blocking will be used within strata to enable 
achievement of equal numbers in each group.  
Strata 1 = MSA of parkinsonian sub-type (MSA-P) 


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Strata 2 = MSA of cerebellar sub-type (MSA-C) 
birth, date of consent, criteria fulfilment and MSA sub-type strata into the 
SealedEnvelope.com secure website which will then allocate the appropriate trial 
identification code to the patient. 
 
11.4 Statistical analysis plan 
11.4.1 
Summary of baseline data and flow of participants 
A CONSORT diagram will be used to describe the course of patients through the trial. Baseline 
characteristics will be summarised by randomised group. Summary measures for the baseline 
characteristics of each group will be presented as mean and standard deviation for continuous 
(approximate) normally distributed variables, medians and interquartile ranges for non-normally 
distributed variables, and frequencies and percentages for categorical variables. The impact of 
missing data and non-compliance will be investigated. 
 
11.4.2 
Primary outcome analysis 
The primary outcome 
(UMSARS) score (Parts I and II) at 48 weeks. The primary analysis will compare exenatide 
patients to be best medically treated patients using a regression (ANCOVA) model that adjusts 
for baseline severity and MSA subtype. All modelling assumptions will be checked. The statistical 
analysis will be based on all participants as randomised, irrespective of subsequent compliance 
with allocated treatment (intention to treat analysis). The impact of missing data and non-
compliance will be investigated as appropriate. 
11.4.3 
Secondary outcome analysis 
Key secondary outcomes would include loss of independent ambulation by end of study, defined 
by a score of 4 or more in UMSARS-I item 7 (walking); MSA-QoL scale UMSARS parts I, II, III and 
IV at week 48 and 96; use of anti-parkinsonian or anti-orthostatic hypotension drugs; number of 
falls; and the proportion of patients reaching a score of 3 or more on UMSARS-I items 1 (speech), 
2 (swallowing), and 8 (falling) ; clinical global impression (CGI) at week 48 and 96; MoCA scores 
at week 48 and 96. These outcomes will be analysed using appropriate statistical methods, 
adjusting for baseline values where possible. Again, all assumptions will be checked.  
11.4.4 
Sensitivity and other planned analyses 
Sensitivity analyses will be performed to identify differences between patients who drop-out 
or have missing data and patients with complete data for each variable. 
 


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Protocol Version 6.0 Dated 13 June 2024 
11.5 Other statistical considerations 
Any deviation(s) from the original statistical plan will be described and justified in the final 
report. 
12 
Record keeping and archiving 
At the end of the trial, all essential documentation will be archived securely by the CI and trial 
sites for a minimum of 25 years from the declaration of end of trial.  
Essential documents are those which enable both the conduct of the trial and the quality of 
the data produced to be evaluated and show whether the site complied with the principles of 
Good Clinical Practice and all applicable regulatory requirements.  
The sponsor will notify sites when trial documentation can be archived. All archived documents 
must continue to be available for inspection by appropriate authorities upon request.  
13 
Oversight Committees  
13.1 Trial Management Group (TMG) 
The TMG will include the Chief Investigator and trial staff.  The TMG will be responsible for 
overseeing the trial.  The group will meet to discuss trial progress every 3 months as stated in 
the TMG terms of reference.  
The TMG will review recruitment figures, SAEs and substantial amendments to the protocol prior 
to submission to the REC and/or MHRA.   
 
13.2 Trial Steering Committee (TSC) 
The role of the TSC is to provide overall supervision of the trial.  The TSC will review the 
recommendations of the Data Monitoring Committee and, on consideration of this information, 
recommend any appropriate amendments/actions for the trial as necessary.  The TSC acts on 
behalf of the funder(s) and Sponsor. 
13.3 Data Monitoring Committee (DMC) 
 
The role of the DMC is to provide advice on data and safety aspects of the trial but where all 
members are independent.  The membership, frequency of meetings, activity (including review 
of trial conduct and data) and authority will be covered in the DMC terms of reference. The IDMC 
will consider data in accordance with the statistical analysis plan and will advise the TSC through 
its Chair. 
14 
Direct Access to Source Data/Documents 
The investigator(s)/ institution(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents.  Trial participants 
are informed of this during the informed consent discussion.  Participants will consent to provide 
access to their electronic health records and medical notes. 


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15 
Ethics and regulatory requirements 
The sponsor will ensure that the trial protocol, participant information sheet, consent form, GP 
letter and submitted supporting documents have been approved by the appropriate regulatory 
body (MHRA in UK) and an appropriate research ethics committee, prior to any participant 
recruitment. The protocol, all other supporting documents including and agreed amendments, 
will be documented and submitted for ethical and regulatory approval as required. Amendments 
will not be implemented prior to receipt of the required approval(s).  
Before the site may be opened to recruit participants, the Chief Investigator or designee must 
have HRA approval and capacity and capability confirmed in writing from their Trust Research & 
Development (R&D).  It is the responsibility of the CI/ PI or designee at each site to ensure that 
all subsequent amendments gain the necessary approvals, including HRA approvals (where 
required) at the site. It is the responsibility of the CI or designee at each site to ensure that all 
subsequent amendments gain the necessary approvals, including NHS Permission (where 
immediate action if thought necessary to protect the health and interest of individual 
participants 
(see 
section 
9.9 
for 
reporting 
urgent 
safety 
measures). 
 
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary 
date on which the favourable opinion was given, and annually until the trial is declared ended. 
The chief investigator will prepare the APR. 
Within 90 days after the end of the trial, the CI/Sponsor will ensure that the main REC and the 
MHRA are notified that the trial has finished.  If the trial is terminated prematurely, those reports 
will be made within 15 days after the end of the trial. 
The CI will supply the Sponsor with a report of the clinical trial which complies with the format 
as defined by the EMA. This will then be uploaded to EudraCT for availability to the MHRA and 
a copy of the report will be submitted to the main REC, within 1 year after the end of the trial.  
16 
Monitoring requirement for the trial 
The sponsor will determine the appropriate level and nature of monitoring required for the trial.  
Risk will be assessed on an ongoing basis and adjustments made accordingly. The degree of 
monitoring will be proportionate to the objective, purpose, phase, design, size, complexity, 
blinding, endpoints and risks associated with the trial. A trial specific oversight and monitoring 
plan will be established for studies. The trial will be monitored in accordance with the agreed plan. 
17 
Finance 
The trial is being funded by the John Black Charitable Foundation and the Van Andel Research 
Institute. It also has financial support from the Defeat MSA Alliance from the USA. The trial will 
benefit from support for recruitment via the MSA Trust in the UK. 


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Protocol Version 6.0 Dated 13 June 2024 
18 
Insurance 
University College London holds insurance against claims from participants for injury caused by 
their participation in the clinical trial. Participants may be able to claim compensation if they can 
prove that UCL has been negligent. However, as this clinical trial is being carried out in a hospital, 
the hospital continues to have a duty of care to the participant of the clinical trial.  University 
negligence on the part of hospital employees. This applies whether the hospital is an NHS Trust 
or otherwise.   
Participants may also be able to claim compensation for injury caused by participation in this 
clinical trial without the need to prove negligence on the part of University College London or 
another party.  Participants who sustain injury and wish to make a claim for compensation 
should do so in writing in the first instance to the Chief Investigator, who will pass the claim to 
 
Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance 
cover for harm caused by their employees and a copy of the relevant insurance policy or 
summary shall be provided to University College London, upon request. 
19 
Publication policy 
The results of this trial will be submitted for publication in a peer reviewed journal, in addition 
to reports at appropriate specialist conferences. The results of the trial will be disseminated 
regardless of the direction of effect. 
Authorship will be granted to individuals making a substantial contribution to the design, setup 
or conduct of the trial and/or analysis and interpretation of trial data. 
The latest version of the trial protocol will be made available as Supplementary material upon 
publication of the final trial report.  
All proposed publications will be discussed with and reviewed by the Sponsor prior to publishing 
other than those presented at scientific forums/meetings.  
20 
References 
 
 
-like Peptide 1 (GLP) Receptor as a 
 
18.  
 
Athauda, Dilan, Seema Gulyani, Hanuma Karnati, Yazhou Li, David Tweedie, Maja Mustapic, Sahil 
-Derived Exosomes to Examine Molecular Mechanisms That 
Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD 
 


Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
Page 51 of 58 
Protocol Version 6.0 Dated 13 June 2024 
 
Athauda, Dilan, Kate Maclagan, Natalia Budnik, Luca Zampedri, Steve Hibbert, Simon S. Skene, Kashfia 
Chowdhury, Iciar Aviles-Olmos, Patr
Exenatide Have on Non-
58.  
 
Athauda, Dilan, Kate Maclagan, Simon S Skene, Martha Bajwa-joseph, Dawn Letchford, Kashfi 
-Blind, Placebo Controlled Trial of 
Exenatide Once-
 
 
Aviles-Olmos, Iciar, John Dickson, Zinovia Kefalopoulou, Atbin Djamshidian, Peter Ell, Therese Soderlund, 
 
 
Aviles-Olmos, Iciar, John Dickson, Zinovia Kefalopoulou, Atbin Djamshidian, Joshua Kahan, Peter Ell 
Fmedsci, Peter Whit
 
 
Bassil, Fares, Marie-Hélène Canron, Anne Vital, Erwan Bezard, Pierre-Olivier Fernagut, and Wassilios G. 
32 (suppl. 
 
Bassil, Fares, Marie-Hélène Canron, Anne Vital, Erwan Bezard, Yazhou Li, Nigel H. Greig, Seema Gulyani, 
Dimitrios Kapogiannis, Pierre-
Exendin-
36.  
 
Bergenstal, Richard M, Carol Wysham, Leigh Macconell, Jaret Malloy, Brandon Walsh, Ping Yan, Ken 
Sitagliptin or Pioglitazone as an Adjunct to Metformin for Treatment of Type 2 Diabetes (DURATION-2): 
9739): 431 39.  
 
Blevins, Thomas, John Pullman, Jaret Malloy, Ping Yan, Kristin Taylor, Christine Schulteis, Michael 
-5: Exenatide Once Weekly Resulted in Greater 
Improvements in Glycemic Control Compared with Exenatide Twice Daily in Patients with Type 2 
10.  
 
-1 Agonists: Understanding 
Their Safety and Tolerability.
18.  


Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
Page 52 of 58 
Protocol Version 6.0 Dated 13 June 2024 
 
Cork, Simon C., James E. Richards, Marie K. Holt, Fiona M. Gribble, Frank Reimann, and Stefan Trapp. 
-like Peptide-1 Receptor Expressing Cells in the 
31.  
 
Terruso, Giuseppe Salemi, Giorgia Famoso, Paolo Aridon, and Giovanni Savettieri. 2009. 
-
660 64.  
 
Dodel, Richard, Annika Spottke, Alexander Gerhard, Alexander Reuss, Sylvia Reinecker, Nicole Schimke, 
Claudia Trenkwalder, et al. 2010
-Year Therapy in Multiple-System-Atrophy: Effect on 
Clinical Symptoms and [ 11 C] (R) -PK11195 PET (MEMSA-
107.  
 
Drucker, Daniel J, John B Buse, Kristin Taylor, David M Kendall, Michael Trautmann, Dongliang Zhuang, 
Lisa Porter, and DURATION-
Treatment of Type 2 Diabetes: A Randomised, Open-Label, Non-
(9645): 1240 50.  
 
Egan, Amy G, Eberhard Blind, Kristina Dunder, Pieter A de Graeff, B Timothy Hummer, Todd Bourcier, 
-Based Drugs--
The New England Journal of Medicine 370 (9): 794 97.  
 
Fanciulli, Alessandra, and Gregor K
-
New England Journal of Medicine 372 (3): 249 63.  
 
Fernagut, Pierre-Olivier, Benjamin Dehay, Aline Maillard, Erwan Bezard, Paul Perez, Anne Pavy-Le Traon, 
Olivier Rascol, Alexandra Foubert-
System Atrophy: A Prototypical Synucleinopathy for Disease-
Neurobiology of Disease 67 (July). Academic Press: 133 39.  
 
Fineman, Mark S, K F Mace, M Diamant, T Darsow, B B Cirincione, T K Booker Porter, L a Kinninger, and 
-Exenatide Antibodies: Safety, Efficacy and Cross-
Reactivity with Long-
54. 
https://doi.org/10.1111/j.1463-1326.2012.01561.x. 
Gilman, S., G. K. Wenning, P. A. Low, D. J. Brooks, C. J. Mathias, J. Q. Trojanowski, N. W. Wood, et al. 
670 76.  


Short title: Exenatide once-weekly as a treatment for Multiple System Atrophy   Sponsor code:  125591 
 
 
 
 
 
 
 
 
 
 
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Protocol Version 6.0 Dated 13 June 2024 
 
Greig, Nigel H, David Tweedie, Lital Rachmany, Yazhou Li, Vardit Rubovitch, Shaul Schreiber, Yung-Hsiao 
(1 Suppl). Elsevier: S62-75.  
 
Low, Phillip A, Stephen G Reich, Joseph Jankovic, Clifford W Shults, Matthew B Stern, Peter Novak, 
19.  
 
Low, Phillip A, David Robertson, Sid Gilman, Horacio Kaufmann, Wolfgang Singer, Italo Biaggioni, Roy 
Double-Blind, Placebo-
ology 13 (3): 268 75. 
https://doi.org/10.1016/S1474-4422(13)70301-6. 
-to-Head Comparisons of Glucagon-like Peptide-1 Receptor 
-Blackwell: 317 32.  
 
Pablo-Fernandez, E. De, F. Sierra-Hidalgo, J. Benito-León, and F. Bermejo-
136 (6): 732 36.  
 
Poewe, Werner, Robert A. Hauser, and Anthony Lang. 2015
Nonmotor Scores of the MDS-
92. 
 
Poewe, Werner, Klaus Seppi, Cheryl J Fitzer-Attas, Gregor K Wenning, Sid Gilman, Phillip A Low, Nir 
giline in Patients with the Parkinsonian Variant of Multiple System 
Atrophy: A Randomised, Placebo-
52.  
 
Talbot, Konrad, Hoau-Yan Wang, Hala Kazi, Li-Ying Han, Kalindi P Bakshi, Andres Stucky, Robert L Fuino, 
IGF-1 Resistance, IRS-
(4). American Society for Clinical Investigation: 1316 38. 
 
Wenning, Gregor K., Francois Tison, Klaus Seppi, Cristina Sampaio, Anja Diem, Farid Yekhlef, Imad 
Ghorayeb
1402.  
 


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Protocol Version 6.0 Dated 13 June 2024 
Wenning GK et al. Progression of dysautonomia in multiple system atrophy: a prospective study of self-
perceived impairment.Eur J Neurol. 2007 Jan;14(1):66-72. 
 
Wenning, Gregor K, Felix Geser, Florian Krismer, Klaus Seppi, Susanne Duerr, Sylvia Boesch, Martin 
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74.  









SAP_001.pdf: 
Statistical Analysis Plan for the Analysis of the Exenatide Trial 
1 
 
Title: An open label, single site, 48 week, randomised controlled trial evaluating the safety and 
efficacy of Exenatide once-weekly in the treatment of patients with Multiple system Atrophy 
NCT Number: NCT04431713 
Document Date: 6 April 2023 
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
2 
 
The Exenatide MSA Trial 
Statistical Analysis Plan 
Version 1.0 
6 April 2023 
 
1 
Administrative information 
1.1 Trial full title 
A Phase IIa, open label, single-site, 48 week randomised controlled trial evaluating the safety and 
efficacy of Exenatide once-weekly in the treatment of patients with Multiple System Atrophy. 
 
1.2 Purpose 
This Statistical Analysis Plan describes a protocol-specified analysis of the investigational medicinal 
product Trial. 
 
1.3 Protocol version 
This SAP has been written based on information contained in the study protocol version 4.0, dated 14 
Sep 2021. Full details of the trial design, population, intervention, comparison and outcome variables 
may be found in the protocol. 
 
1.4 Trial registration 
This trial was prospectively registered with ClinicalTrials.gov (NCT04431713).  
 
1.5 Authorship 
This SAP has been written by Dr Chen Qu and Professor Gareth Ambler (Lead Statistician), following 
the guidelines of Gamble et al (JAMA 2017. doi:10.1001/jama.2017.18556). 
 
1.6 SAP revisions 
There have been no revisions. This is version 1.0.  
 
 
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
3 
 
1.7 Signatures 
The undersigned confirm that the following Statistical Analysis Plan has been agreed and accepted 
and that the Trial Statistician agrees to conduct the analysis in compliance with the approved 
Statistical Analysis Plan. Major deviations from the Plan will be agreed in advance before 
implementation. All deviations from the Plan will be explained, documented and reported accordingly. 
 
Authorised by: 
Signature 
Date 
 
 
 
Professor Thomas Foltynie 
  Chief Investigator 
 
 
 
 
 
 
 
 
Professor Gareth Ambler 
  Lead Statistician 
 
 
 
 
 
 
 
 
Dr Christopher Kobylecki 
  IDMC Chair 
 
 
 
 
 
 
 
 
Dr Alan Whone 
  TSC Chair 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
4 
 
2 
Table of Contents 
1 
Administrative information ............................................................................................................. 2 
1.1 
Trial full title ............................................................................................................................ 2 
1.2 
Purpose ................................................................................................................................... 2 
1.3 
Protocol version ...................................................................................................................... 2 
1.4 
Trial registration ...................................................................................................................... 2 
1.5 
Authorship .............................................................................................................................. 2 
1.6 
SAP revisions ........................................................................................................................... 2 
1.7 
Signatures ............................................................................................................................... 3 
2 
Table of Contents ............................................................................................................................ 4 
3 
Introduction .................................................................................................................................... 5 
3.1 
Background ............................................................................................................................. 5 
3.2 
Principle research objectives .................................................................................................. 5 
4 
Study Method ................................................................................................................................. 5 
4.1 
Trial design .............................................................................................................................. 5 
4.2 
Randomisation ........................................................................................................................ 5 
4.3 
Sample size.............................................................................................................................. 5 
5 
Statistical Principles ........................................................................................................................ 6 
5.1 
Confidence intervals and p-values .......................................................................................... 6 
5.2 
Adherence to intervention ..................................................................................................... 6 
5.3 
Analysis Populations ............................................................................................................... 6 
6 
Trial Population ............................................................................................................................... 7 
6.1 
Recruitment and retention ..................................................................................................... 7 
6.2 
Baseline characteristics ........................................................................................................... 7 
7 
Analysis ........................................................................................................................................... 8 
7.1 
Outcomes ................................................................................................................................ 8 
7.1.1 
Primary outcome ............................................................................................................ 8 
7.1.2 
Secondary outcomes ....................................................................................................... 8 
7.1.3 
Exploratory outcomes ..................................................................................................... 8 
7.1.4 
Timing of outcomes ........................................................................................................ 9 
7.2 
Primary outcome Analysis .................................................................................................... 10 
7.3 
Secondary outcome analyses ............................................................................................... 10 
7.4 
Sensitivity analyses ............................................................................................................... 10 
7.5 
Subgroup analyses ................................................................................................................ 10 
7.6 
Missing data .......................................................................................................................... 11 
7.7 
Adverse event reporting ....................................................................................................... 11 
7.8 
Software ................................................................................................................................ 11 
8 
Summary of Changes .................................................................................................................... 11 
9 
Appendix - Questionnaires scoring ............................................................................................... 12 
9.1 
The Unified Multiple System Atrophy Rating Scale (UMSARS) score ................................... 12 
9.2 
MSA health-related Quality of life (MSA-QoL) scale ............................................................. 12 
9.3 
Clinical Global Impression - Improvement (CGI-I) ................................................................ 12 
9.4 
Montreal Cognitive Assessment (MoCA) .............................................................................. 12 
 
 
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
5 
 
3 
Introduction 
3.1 Background 
Multiple System Atrophy (MSA) has a prevalence of 4.4 in 100,000 individuals and there are no 
effective treatments that can slow down or modify the course of disease progression. There is thus an 
urgent unmet need for novel treatments that may slow or halt disease progression in MSA. Recent 
studies have shown encouraging results of using Exenatide in further neurodegenerative diseases. A 
simple randomised trial was therefore needed to compare use of Exenatide against standard 
treatment option in MSA. A full description of the trial is contained in the protocol. 
 
3.2 Principle research objectives 
To collect pilot data from which to estimate the effectiveness of Exenatide in modifying disease 
progression of patients with MSA. 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.  
 
 
4 
Study Method 
4.1 Trial design  
This is a non-commercial, open label trial of a licensed drug designed to primarily provide preliminary 
efficacy and safety data for the use of Exenatide in MSA. This will be a simple parallel group design 
and include a 48-week exposure period. Detailed evaluations will take place at Screening, Baseline, 
12, 24, 36, 48 and 96 weeks.  
 
4.2 Randomisation 
Patients will be randomly assigned in a 1:1 ratio to receive the Exenatide together with standard 
treatment options or to receive the standard treatment options alone. Randomisation will be stratified 
by MSA phenotype strata using block randomisation to enable achievement of approximately equal 
numbers in each group. Full details can be found in the randomisation protocol.  
 
4.3 Sample size  
The recent rasagiline for MSA (MSA-Ras) trial evaluated rasagiline versus placebo using the UMSARS 
total (Parts 1 and II) as the primary efficacy measure after 48 weeks treatment. Patients in the placebo 
group declined by mean 7.8 points (SD 10.4 – Werner et al. 2015).  
 
Therefore, on the basis of this previously collected data and with a two-sided 5% significance level, we 
estimated that a sample size of 40 patients (20 per group) would be required to detect a difference of 
5 total UMSARS points between the two groups, assuming a correlation between baseline and final 
disease severity of 0.85. These calculations were based on a common SD of 10.4, 80% power and an 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
6 
 
overall type 1 error rate of 5%. A 5-point difference between groups would be a clinically important 
effect size. Based on a 20% dropout rate as reported from previous trials, the sample size would be 50 
(25 per arm). 
 
 
5 
Statistical Principles 
5.1 Confidence intervals and p-values 
All statistical tests and confidence intervals will be 2-sided. Significance will be considered at the 5% 
level and confidence intervals will be at the 95% level. 
 
5.2 Adherence to intervention 
Compliance will be assessed by directly questioning patients at each visit, and if applicable carers will 
also be asked to provide estimates of compliance, along with review of the drug administration diary. 
Reasons for non-compliance will be sought and addressed as far as possible at each follow up visit. 
 
5.3 Analysis Populations 
The ‘intention-to-treat’ population will include all randomised patients according to the treatment to 
which they were randomised to receive. Any patients that have withdrawn from the trial, and 
withdrawn permission to keep and use their data, will be necessarily excluded. The ‘per-protocol’ 
population will also exclude any patients randomised to standard treatment who have sourced 
exenatide outside of the trial. 
 
 
 
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
7 
 
6 
Trial Population 
6.1 Recruitment and retention 
A CONSORT diagram will be presented to provide a detailed description of participant numbers at 
each time point during the trial. In addition, a table summarising the number of patients who have 
been lost to follow up at each stage of the trial and reasons for loss to follow up (if supplied) will be 
presented.  
 
6.2 Baseline characteristics 
The demographic information collected at baseline will be presented in a table summarised separately 
by study arm. Numerical variables will be summarised using either means and standard deviations or 
medians and interquartile ranges. Categorical variables will be summarised using numbers and 
proportions. The number of missing observations will be reported. No statistical tests will be 
performed to assess baseline differences between study arms.  
The following baseline characteristics of patients will be summarised by randomised allocation:  
a) 
Age 
b) 
Sex 
c) 
Ethnicity 
d) 
Weight 
e) 
Physical Examination 
f) 
Neurological Examination 
g) 
Vital Signs 
h) 
HOMA index 
 
 
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
8 
 
7 
Analysis 
7.1 Outcomes 
7.1.1 Primary outcome 
The primary outcome is the total Unified Multiple System Atrophy Rating Scale (UMSARS) score (Parts 
I and II) at 48 weeks. 
 
7.1.2 Secondary outcomes 
• 
Patients with loss of independent ambulation by the end of the study, defined by a score of 4 
in UMSARS-I item 7 (walking);  
• 
Multiple System Atrophy health-related Quality of life (MSA-QoL) scale at week 48;  
• 
UMSARS score (Parts III and IV) at week 48; 
• 
Anti-parkinsonian or anti-orthostatic hypotension drugs comparing exenatide at week 48;  
• 
The number of falls at week 48;  
• 
Patients reaching a score of 3 or more on UMSARS-I items 1 (speech), 2 (swallowing), and 8 
(falling) at week 48;  
• 
Clinical global impression (CGI) at week 48; 
• 
Montreal Cognitive Assessment (MoCA) scores at week 48;  
• 
Safety of exenatide in MSA based on Adverse event reporting. 
 
7.1.3 Exploratory outcomes 
• 
UMSARS score (Parts I and II) at 96 weeks;  
• 
MSA-QoL scale at 96 weeks;  
• 
UMSARS score (Parts III and IV) at 96 weeks;  
• 
The use of Anti-parkinsonian or anti-orthostatic hypotension drugs at 96 weeks; 
• 
The number of falls at 96 weeks; 
• 
Patients reaching a score of 3 or more on UMSARS-I items 1 (speech), 2 (swallowing), and 8 
(falling) at 96 weeks; 
• 
CGI and MoCA scores at 96 weeks. 
 
Serum will be collected at baseline and 12 weeks, 24 weeks, 36 weeks, 48 weeks and 96 weeks for 
biomarker analysis. CSF will be collected at baseline and 48 weeks for biomarker analysis. Further 
details on the scoring and ranges of all outcomes can be found in the Appendix. 
 
 
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
9 
 
7.1.4 Timing of outcomes 
Table 1 provides an overview of primary and secondary outcomes and the time points at which they 
will be collected. 
 
Table 1: Data collection measures and time points. 
 
Measure 
0 
4* 
12 
24 
36 
48 
58* 
96 
Screening measures 
Physical Examination 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
Neurological Examination  
✓ 
 
 
✓ 
 
✓ 
 
✓ 
Vital Signs including weight 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
Fasting blood test 
✓ 
 
 
✓ 
 
✓ 
 
 
Eligibility confirmation 
✓ 
 
 
 
 
 
 
 
Primary outcome 
UMSARS Part 1, 3 and 4  
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
UMSARS Part 2 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
Secondary outcomes 
MSA-QoL scale 
✓ 
 
 
 
 
✓ 
 
✓ 
MoCA  
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
Serum collection  
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
CSF collection  
✓ 
 
 
 
 
✓ 
 
 
Other measures 
BDI-II  
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
COMPASS Select  
✓ 
 
 
✓ 
 
✓ 
 
✓ 
COMPASS Change  
 
 
 
✓ 
 
✓ 
 
✓ 
Timed Motor Tests  
✓ 
 
 
✓ 
 
✓ 
 
✓ 
The Unified Dystonia Rating  
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
IMP administration 
✓ 
 
 
✓ 
✓ 
✓ 
 
 
Adverse Events/SAEs review  
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Concomitant Medication 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
*: Telephone call 
 
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
10 
 
7.2 Primary outcome Analysis 
The primary outcome is the total Unified Multiple System Atrophy Rating Scale (UMSARS) score (Parts 
I and II) at 48 weeks. The primary analysis will compare exenatide patients to be best medically treated 
patients using a two-level mixed model that includes the total UMSARS scores from four time-points 
(12 weeks, 24 weeks, 36 weeks and 48 weeks) with interaction terms between the intervention and 
time-point indicator variables to enable estimation of the effect of intervention at 48 weeks. This 
model will also adjust for baseline UMSARS score and MSA subtype using fixed effects. 
 
In detail, the primary analysis will involve fitting the model 
 
𝑈𝑀𝑆𝐴𝑅𝑆𝑖𝑗= 𝛽0 + 𝛽1𝑇𝑅𝑇𝑖+ 𝛽2𝑗𝑇𝐼𝑀𝐸𝑗+ 𝛽3𝑗𝑇𝑅𝑇𝑖× 𝑇𝐼𝑀𝐸𝑗+ 𝛽4𝑈𝑀𝑆𝐴𝑅𝑆0𝑖+ 𝛽5𝑀𝑆𝐴𝑖+ 𝑢𝑖+ 𝜖𝑖𝑗 
 
to patients 𝑖= 1, . . , 48  and time-points 𝑗= 12, 24, 38 and 48  weeks, where 𝑈𝑀𝑆𝐴𝑅𝑆𝑖𝑗 and 
𝑈𝑀𝑆𝐴𝑅𝑆0𝑖 are the UMSARS total scores for patient 𝑖 at time-point 𝑗 and baseline respectively, 𝑇𝑅𝑇𝑖 
is the intervention group indicator (0=standard; 1=Exenatide), 𝑇𝐼𝑀𝐸𝑗 are time-point indicators, 𝑀𝑆𝐴𝑖 
is a MSA subtype indicator, and ui ~ 𝑁(0, 𝜎𝑢2) and ϵij ~ 𝑁(0, 𝜎2) are error terms. All modelling 
assumptions will be checked. 
 
7.3 Secondary outcome analyses 
The effect of the intervention on secondary outcomes will be assessed using appropriate single-level 
regression models, i.e. linear regression models for numerical outcomes, logistic regression models 
for binary outcomes, and Poisson models for count outcomes (or negative binomial models, if their 
use is indicated). All models will be adjusted for MSA subtype; models for numerical outcomes will 
also be adjusted for baseline outcomes if available. All analyses of secondary and other outcomes 
should be considered as supportive analyses. 
 
7.4 Exploratory outcome analyses 
The effect of the intervention on exploratory outcomes will be assessed using the same models as 
used for the secondary outcomes.  
 
7.5 Sensitivity analyses 
Several sensitivity analyses will be performed for the primary outcome. These are: 
• 
The effect of the intervention will be assessed using a single-level linear regression model, 
adjusted for MSA subtype and baseline severity. 
• 
If adherence is deemed to be an issue, per-protocol and complier average causal effect (CACE) 
analyses will be performed.  
 
7.6 Subgroup analyses 
There are no planned subgroup analyses.  
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
11 
 
7.7 Missing data 
Withdrawals from the study, loss to follow up and other missing outcome data will be summarised 
separately by randomised arm. Potential bias due to missing data will be investigated by comparing 
the baseline characteristics of patients with and without missing values. From this, predictors of 
missingness may be identified and used to perform an additional analysis that includes these 
predictors as covariates in the primary analysis model.  
 
Multiple imputation may also be performed, if deemed appropriate. The imputation model will 
include outcome data from all time-points, as well as baseline characteristics.  
 
In addition, imputation may be performed under the assumption that the missing data are MNAR. 
Two strategies may be investigated: 
• 
Delta-adjustment: This approach initially uses (standard) multiple imputation to impute missing 
values but then the imputed values are modified using a ‘delta-adjustment’. Different values of 
delta may be specified, and these can differ by trial arm. 
• 
Reference-based sensitivity analyses: A range of different assumptions regarding the missing 
data can be investigated using this approach, which is implemented in the Stata package mimix 
(Cro et al, 2016). 
 
7.8  Adverse event reporting 
The number, nature and severity of serious adverse events (if any) will be reported separately by study 
arm at each follow up time point. The number of patients who experience adverse events will likewise 
be reported separately by study arm.  
 
7.9  Software  
All the statistical analysis will be performed using Stata version 17 (or above). 
 
 
8 
Summary of Changes  
This Statistical Analysis Plan does not propose any major changes to the statistical approach described 
in the protocol. Of note, is that the primary analysis proposed in this document uses outcomes from 
four time-points; however, the effect of intervention will still be estimated at 48 weeks. Any changes 
to the Statistical Analysis Plan made after this document has been signed off need to be recorded. In 
addition, significant changes will need to be approved before implementation.  
 
 
 


Statistical Analysis Plan for the Analysis of the Exenatide Trial 
12 
 
9 
Appendix - Questionnaires scoring 
9.1 The Unified Multiple System Atrophy Rating Scale (UMSARS) score 
The Unified MSA Rating Scale (UMSARS) comprises four components: a historical review of disease-
related impairments (Part I, 12 items), motor examination (Part II, 14 items), autonomic examination 
(Part III), and global disability scale (Part IV). A single score using a 0 (no impairment) to 4 (severe 
impairment) scale was generated for each item. UMSARS total is calculated as the sum of the Part I 
and Part II items; all items must be answered to have a score.  
• 
Wenning GK, Tison F, et al.. Multiple System Atrophy Study G (2004) Development and 
validation of the unified multiple system atrophy rating scale (UMSARS). Mov Disord 19:1391–
1402. 
 
9.2 MSA health-related Quality of life (MSA-QoL) scale 
MSA-QoL is a validated 40 item self-completed questionnaire (on a 5-point scale ranging from 0-4). 
Score is calculated as the sum of the items. Missing values for MSA-QoL will be scored as zero unless 
more than four items are missing, in which case the participant is to be excluded. 
• 
Schrag A, et al.. Measuring health-related quality of life in MSA: the MSA-QoL. Mov 
Disord. 2007;22(16):2332–2338. 
 
9.3 Clinical Global Impression - Improvement (CGI-I) 
CGI-I is an observer-rated score (on a 8-point scale ranging from 0-7).  
• 
https://en.wikipedia.org/wiki/Clinical_Global_Impression 
 
9.4 Montreal Cognitive Assessment (MoCA) 
MoCA is a screening test for assessing cognitive impairment. It is a 30-question test and cover eight 
cognitive domains. Total scores on the MoCA range from 0 to 30, a score of 26 and above is considered 
to be normal.  
• 
Nasreddine ZS, Phillips NA, et al. The Montreal Cognitive Assessment, MoCA: a brief screening 
tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–699