Investigating the Tolerability and Feasibility of Transcutaneous Vagus Nerve Stimulation Following Aneurysmal Subarachnoid Haemorrhage
Phase: NA
Conditions: Subarachnoid Haemorrhage From Cerebral Aneurism Rupture
Sponsor: Sheffield Teaching Hospitals NHS Foundation Trust

 
tVNS in aSAH, Protocol, Version 2 16.12.23, STH22772, IRAS: 334282 
 
 
 Investigating the tolerability and 
feasibility of transcutaneous vagus 
nerve stimulation following aneurysmal 
subarachnoid haemorrhage 
 
tVNS in aSAH 
 
 
 
Sponsor: Sheffield Teaching Hospitals NHS Foundation Trust 
 
Funded by: University of Sheffield 
 
 
 
Chief/Principal Investigator: Dr Ali Ali, Professor Arshad Majid 
 
Co-Investigators:  Mr Matthew Myers 
 
 
 
 
 
 
 
 
 

 
tVNS in aSAH, Protocol, Version 2 16.12.23, STH22772, IRAS: 334282 
Project Details 
 
Investigator Details: 
 
Mr Matthew Myers 
Academic Neurosurgery Trainee 
Matthew.myers3@nhs.net 
 
Chief Investigators: 
 
Professor Arshad Majid 
Professor of Cerebrovascular Neurology 
Honorary Consultant Neurologist Sheffield Teaching Hospitals   
Arshad.majid@sheffield.ac.uk 
 
Dr Ali Ali 
Senior Clinical Lecturer Cerebrovascular Disease 
Honorary Consultant Stroke and Geriatrics Sheffield Teaching Hospitals 
Ali.ali@sheffield.ac.uk 
 
Co-Investigators: 
 
Professor Su Li 
Professor of Neuroimaging 
University of Sheffield 
S.Li@sheffield.ac.uk 
 
Sponsor Details: 
Sheffield Teaching Hospitals NHS Foundation Trust 
 
Project Title: 
Investigating the tolerability and feasibility of transcutaneous vagus nerve stimulation 
following aneurysmal subarachnoid haemorrhage 
 
STH Project Reference Number: 
STH22772 
 
Protocol Version Number and Date: 
Version V1 Date 17/10/2023 
 
STH Directorate Affiliation: 
Neurosciences 
 
Confidentiality Statement: 
This document contains confidential information that must not be disclosed to 
anyone other than the Sponsor, the Investigator Team, HRA, host organisation, and 
members of the Research Ethics Committee, unless authorised to do so by the Chief 
Investigator. 
 
 

 
tVNS in aSAH, Protocol, Version 2 16.12.23, STH22772, IRAS: 334282 
Table of Contents 
 
1. 
Study Synopsis/Profile ...................................................................................................... 4 
2. 
Research Questions .......................................................................................................... 5 
3. 
Abstract/Summary ........................................................................................................... 7 
4. 
Aims of the Study ............................................................................................................. 7 
5. 
Background ....................................................................................................................... 8 
6. 
Plan of the Investigation ................................................................................................... 9 
6.1 
Methodology ............................................................................................................ 9 
6.2 
Design ....................................................................................................................... 9 
6.3 
Setting ..................................................................................................................... 10 
6.4 
Participants ............................................................................................................. 10 
6.5 
Sample Size ............................................................................................................. 10 
6.6 
Recruitment ............................................................................................................ 10 
6.7 
Outcome Measures ................................................................................................ 11 
6.8 
Subject Withdrawal, Breaking the Blind and Trial Discontinuation Rules .............. 12 
6.9 
Intervention ............................................................................................................ 12 
6.10 
Study Protocol ........................................................................................................ 14 
7. 
Data Management .......................................................................................................... 16 
7.1 
Statistical Analysis .................................................................................................. 16 
7.2 
Statistical Opinion ................................................................................................... 16 
7.3 
Confidentiality ........................................................................................................ 17 
7.4 
Data Collection, Handling and Storage Record Keeping ......................................... 17 
7.5 
Data Storage ........................................................................................................... 17 
8. 
Study Management ........................................................................................................ 18 
8.1 
Project Plan ............................................................................................................. 18 
8.2 
Project Management .............................................................................................. 18 
9. 
Expertise ......................................................................................................................... 18 
10. 
Ethical Issues ............................................................................................................... 19 
10.1 
Ethical Considerations: ........................................................................................... 19 
10.2 
Declaration of Helsinki ............................................................................................ 19 
10.3 
Guidelines for Good Clinical Practice ...................................................................... 19 
10.4 
Expenses and Benefits ............................................................................................ 19 
10.5 
Other Ethical Considerations .................................................................................. 20 

 
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11. 
Service Users and Patient and Public Involvement .................................................... 20 
12. 
Dissemination ............................................................................................................. 20 
13. 
Taking the Work Forward ........................................................................................... 20 
14. 
Intellectual Property (IP) ............................................................................................ 20 
15. 
Costing Schedule ........................................................................................................ 21 
16. 
Funding Arrangements ............................................................................................... 21 
17. 
References .................................................................................................................. 21 
 
1. Study Synopsis/Profile  
 
Study title Investigating the tolerability and feasibility of 
transcutaneous vagus nerve stimulation following 
aneurysmal subarachnoid haemorrhage 
Study short title tVNS in aSAH 
Study design Two-arm randomised controlled trial 
Study participants Inclusion criteria: 
• Age >18 
• Admitted to STH neurosurgery 
• Confirmed aneurysmal SAH on vascular imaging 
• Within 5 days of ‘Securing’ aneurysm (i.e., 
successfully coiled or surgically following rupture) 
Exclusion criteria: 
• Current or prior use of a vagus nerve stimulation  
• Symptomatic bradycardia or PPM insertion 
• Complete heart block 
• Implantation of any other electrical stimulator (e.g. 
DBS) 
Planned sample size 30 participants (15 in each arm) 
Planned study period 36 months 
Planned recruitment 
period 
24 months 
Study assessments 
• Deliver TVNS using the parasym device for 45 
minutes twice daily for 5 days following aSAH 
intervention (coiling or clipping) 
o Pulse width 25ms, frequency device standard 
(25 Hz), at maximum tolerated intensity, or 

 
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20MA for patients who cannot report the 
maximum tolerated intensity 
• Clinical follow-up on discharge and at 1 month 
Objectives Primary  
To establish the tolerability, and feasibility of tVNS in 
patients following aSAH, including; 
• Monitor tolerability for tVNS 
o Symptom severity scores of mild or moderate 
in less than 1/3 of participants able to report 
symptoms 
• Assess study feasibility 
o recruit >1 patient per month of recruitment 
o >80% of recruited patients completing primary 
outcome measures 
Secondary  
• Monitor safety criteria for tVNS 
o No SAEs reported to tVNS 
o Unexpected AEs in less than 1/3 of 
participants 
• Explore clinical outcomes including: 
o rates of clinical or radiological DCI 
o inpatient mortality 
o inpatient length of stay 
o Rate of complications: seizures, 
hyponatraemia, rebleed, hydrocephalus 
• Outcome measures using questionnaires on 
discharge and at 1-month  
o Disability assessment: modified Rankin Score, 
Barthel Index 
o Assess frequency and severity of headache: 
Likert scale 
• Explore mechanisms of action: 
o Inflammatory markers at baseline and 5 days 
• Explore response to tVNS: 
o Near-infrared cerebral spectroscopy  
o Heart rate variability 
o Pupillary reactivity 
 
2. Research Questions 
 
Is transcutaneous nerve stimulation a tolerable and feasible intervention to 
potentially improve clinical outcomes in aneurysmal subarachnoid haemorrhage 
(aSAH)? 

 
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3. Abstract/Summary 
 
Background 
 
Subarachnoid haemorrhage (SAH) is a type of brain bleed, which can be 
complicated by issues including delayed cerebral ischaemia (DCI) which causes 
stroke like symptoms, such as weakness, in up to 30% of patients.1 Current 
treatments for DCI focus on improving blood supply but fail to address other 
important factors including reducing inflammation.2  
 
Stimulation of a nerve in the neck called the vagus nerve, which can be done 
through the skin (transcutaneous vagus nerve stimulation, tVNS) is known to relax 
blood vessels and reduce inflammation and is approved in other conditions such as 
epilepsy.3,4 In animals, vagus nerve stimulation improves survival after aSAH, and is 
being studied in humans to reduce headaches after aSAH.5,6  
 
There is a theoretical role of tVNS in improving outcome after aSAH. We aim to 
study whether tVNS is tolerated, and feasible in aSAH.  
 
 
Methods  
 
This is a single centre, pilot randomised controlled trial (RCT); the participants will 
receive either tVNS or ‘sham’ tVNS, twice daily for 45 minutes for 5 days. We will 
monitor tolerability (symptoms) and feasibility (recruitment rates) for recruited 
patients. Secondary outcomes will include rates of side effects, complications from 
SAH, outcomes on discharge and 4 week follow up, and exploration of mechanisms 
of action and response to tVNS including levels of serum inflammatory markers (IL-
1B, IL-4, IL-6, IL-10 and TNFa), functional near infra-red spectroscopy (f-NIRS), 
heart rate variability (HRV) and pupillary light reactivity (PLR).  
 
 
Results  
 
Rates of complications, side effects and recruitment will be reported descriptively 
and we will undertake simple between-group statistical analyses on secondary 
outcome measures. If proven to be tolerated and feasible, this study will provide the 
basis for a future larger trial design.  
4. Aims of the Study 
 
The aims of the study will be to conduct a pilot RCT to investigate whether tVNS is a 
tolerable and feasible treatment for acute aSAH. To understand this we will recruit 
participants who have recently undergone acute securing procedures follow acute 
aSAH (coiling or clipping of aneurysm) to a 5 day programme of intervention (active 
tVNS vs sham) and collect outcome data (primary and secondary as per outcomes 
section). We will evaluate whether pre-defined success criteria are achieved for 
tolerability and feasibility and explore signals of effect on clinical outcome measures 
and mechanistic measures. Non-invasive vagal nerve stimulation has not been 

 
tVNS in aSAH, Protocol, Version 2 16.12.23, STH22772, IRAS: 334282 
studied in the acute period following aSAH outside of the remit of reducing 
headache. This should offer critical insights as to whether this intervention has 
potential to take forward to a larger phase 2/3 clinical study.  
5. Background 
 
Delayed cerebral ischaemia (DCI) is a multifactorial sequela of aneurysmal 
subarachnoid haemorrhage (aSAH) which occurs in up to 30% of patients, usually 
within 14 days of ictus.1 Diagnosis is by means of clinical and radiological 
assessment of a new neurological deficit in the absence of other causes.2 Alongside 
rebleeding, DCI is the strongest predictor of in-hospital mortality after aSAH and has 
a significant impact on morbidity.1 
 
The pathophysiology of DCI is complex and poorly understood, but emerging 
evidence supports a multifactorial model which includes arterial vasospasm, 
inflammatory processes, localised coagulopathy, and failure of cerebral 
autoregulation – this represents a vasculopathic progress, rather than purely 
vasospasm.7 Current management strategies for DCI focus on overcoming 
vasospasm, primarily by inducing hypertension, although this fails to address other 
important factors in the disease pathophysiology such as the inflammatory process.2 
Interventions that target a multiple pathophysiological pathways may offer greater 
clinical benefits. 
 
Several studies are ongoing to address the utility of novel therapeutic targets in DCI. 
Vagus nerve stimulation (VNS) is known to have vasodilatory and anti-inflammatory 
effects and is licensed in other conditions including migraine and epilepsy.3,4 In 
animal models, transcutaneous VNS (tVNS) has been found to reduce aneurysm 
rupture rates and improve survival after aSAH.8 Studies are ongoing to establish its 
efficacy in reducing post-SAH headache.5 However, there have been no studies 
investigating the use of tVNS in delayed cerebral ischaemia. 
 
 

 
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6. Plan of the Investigation  
 
6.1 Methodology  
 
This is a single centre, pilot, randomised controlled trial. 30 participants who have 
suffered an aneurysmal subarachnoid haemorrhage and had their aneurysm secured 
(coiled or clipped successfully).  
 
The intervention will take place for 45 minutes twice a day for 5 days after securing 
the aneurysm. The placebo group will receive the same intervention, but the device 
will be in ‘sham’ mode (i.e. attached to the earlobe).  
 
It is not known whether tVNS is tolerable, and feasible in aSAH, but standard device 
settings will be used in accordance with a majority of other studies. Similarly, the 
optimal therapeutic duration is not known – 45 minutes twice a day is a similar usage 
to other studies. A 5-day course has been chosen because it covers the highest risk 
period for DCI and is feasible for the research team to deliver. 
 
6.2 Design 
 
This is a single centre pilot, single blind, randomised, placebo – controlled study. 
 
This has been chosen as it will demonstrate feasibility and tolerability, whilst 
providing early data to indicate whether tVNS may provide benefit in this setting, 
supporting the development of a larger RCT to establish whether it is a statistically 
significant benefit.  
 
Patients may be able to tell the different between an activated device and sham 
(where the device is applied to the earlobe instead of the tragus). However, they will 
not experience both settings, and we will make no clear distinction of exactly what 
they should feel.  
 
 

 
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6.3 Setting 
 
The patients will be inpatients under Neurosurgery at the Royal Hallamshire 
Hospital. All outcome measures will be collected at recruitment, discharge and 1 
month following discharge. They will undergo the TVNS intervention as an inpatient 
for 5 days. 
 
6.4 Participants 
 
Inclusion criteria: 
• Age >18 yrs 
• Admitted to STH neurosurgery 
• Confirmed aneurysmal SAH on intracranial vascular imaging 
• Within 3 days of ‘Securing’ aneurysm (i.e., successfully endovascularly coiled 
or surgically clipped following rupture) 
Exclusion criteria: 
• Current or prior use of a vagus nerve stimulation device 
• Symptomatic bradycardia 
• Complete heart block 
• Presence of other implanted electrical stimulator (e.g. DBS) 
• Pregnancy 
 
6.5 Sample Size 
 
A sample size of at least 30 has been chosen based on the number or participants 
required for the purposes of a feasibility assessment.9 It is also a practically feasible 
number of participants to recruit based on annual admission numbers of patients to 
the RHH and the timeframe of the recruitment period.  
 
6.6 Recruitment 
 
Potential participants with aSAH will be identified on admission to neurosurgery at 
RHH and approached about the study by the clinical treating team on the basis of 
convenience sampling. If they are interested in the study, they will be provided with 
an information sheet again and the opportunity to discuss the study with a member 
of the research team. If they are willing to take part in the study written informed 
consent will be obtained, after a screening consent support tool is used to ensure the 
patient had adequate comprehension. 
 
Capacity to consent to the study would be determined by the treating clinical team and 
confirmed by the research team according to the principles of the mental capacity act 
(MCA, 2005). Where the patient lacks capacity to consent (including sedated/intubate 
patients), a personal or nominated consultee can provide advice on what they feel the 
patients’ wishes would be if they had capacity. The treating clinical team would 

 
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introduce the study to the consultee and an information leaflet given to them. The 
consultee would then have the option to sign a consent form if they believed the patient 
would agree to participate. In accordance with the MCA 2005, ongoing consent or 
assent would be sought from the individual or consultee at each study visit, before any 
research activity at the that visit is undertaken. Consultees may advise at any point 
that they believe the person’s wishes about participation have changed and they 
should therefore be withdrawn from the study. Agitated patients will not receive the 
intervention if they are unable to tolerate it.  
 
6.7 Outcome Measures 
 
Primary Outcome Measures – success criteria: 
o Monitor tolerability for tVNS 
§ 
Symptom severity scores of mild or moderate in less than 1/3 of 
participants able to report symptoms (based on Likert Scale 1-5; 
1 representing no issues; 5 representing severe symptoms) 
o Assess study feasibility 
§ 
recruit >1 patient per month of recruitment 
§ 
>80% of recruited patients completing primary outcome 
measures at 4 weeks follow up 
 
These outcome measures will be collected during the participants inpatient stay over 
the intervention period using a data collection proforma (appendix) and taken from 
recruitment records kept contemporaneously. Safety assessment of SAEs / AEs will 
be collected each intervention day by our research team.  
 
Secondary Outcome Measures:  
o Monitor safety criteria for tVNS 
§ 
No SAEs reported to tVNS 
§ 
Unexpected AEs in less than 1/3 of participants 
o Explore clinical outcomes including: 
§ 
rates of clinical or radiological DCI (%) 
§ 
inpatient mortality (%) 
§ 
inpatient length of stay (days) 
§ 
rate of complications: seizures, hyponatraemia, rebleed, 
hydrocephalus (%) 
o Outcome measures using questionnaires on discharge and at 1-month  
§ 
Disability assessment: modified Rankin Score, Barthel Index 
§ 
Assess frequency and severity of headache: Likert scale 
o Explore mechanisms of action: 
§ 
Inflammatory markers at baseline and 5 days 
o Explore response to tVNS: 
§ 
Near-infrared cerebral spectroscopy  
§ 
Heart rate variability 
§ 
Pupillary reactivity 

 
tVNS in aSAH, Protocol, Version 2 16.12.23, STH22772, IRAS: 334282 
 
These will be measured during the inpatient hospital stay up until discharge (Figure 
1). 
 
o Outcome measures using questionnaires at on discharge and at 4 
week follow-up 
§ 
Disability assessment: modified Rankin Score, Barthel Index 
§ 
Assess frequency and severity of headache: Likert scale (1-10 
where 1 is non-existent and 10 is extremely severe) 
o Explore mechanisms of action measured at baseline and at the end of 
intervention (5 days): 
§ 
Inflammatory marker analysis at baseline and 5 days (IL-1B, IL-
6, IL-10, TNFa) 
§ 
Concurrent WCC, CRP and infection will be recorded at these 
time points as these may confound results 
o Explore response to tVNS: 
§ 
Near-infrared cerebral spectroscopy  
§ 
Heart rate variability (HRV) parameters using a commercially 
available heart rate monitor - (SDRR – standard deviation of the 
inter-beat-interval ms; RMSSD – the root mean square of 
successive differences between heartbeats ms; LF power – 
power of HRV distributed in the low frequency (0.04 – 0.15) 
band indicative of sympathetic nervous activity; HF power – 
power of HRV distributed in the high frequency (0.15 – 0.4) band 
indicative of parasympathetic nervous activity; LF/HF ratio) 10-12 
§ 
Pupillary reactivity (constriction and dilatation amplitudes mm; 
constriction speeds ms, latency ms)13. Confounders including 
eyedrops that may influence pupil size will be recorded 
 
6.8 Subject Withdrawal, Breaking the Blind and Trial Discontinuation Rules 
 
Participants will be advised that they can withdraw from the study at any time without 
giving a reason and without this affecting their clinical care. Any data already 
collected will be analysed with permission from the patient. A member of the 
research team will confirm the patient is happy to continue with the longitudinal study 
at their clinical follow up appointments. 
 
We will record data including number of patients admitted with aneurysmal SAH, 
number eligible, number recruited, dropout rates, and reasons for these. Participants 
will be given the opportunity to get involved in a public patient involvement group 
(PPI) at completion of the study.  
 
6.9 Intervention 
 
We are using tVNS settings that are widely used in other neurological conditions 
(epilepsy, migraine)14. These include: 

 
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o Pulse width - 25ms 
o Frequency – device default (20 or 25Hz) 
o Intensity – below pain threshold.  
o Frequency – 45 minutes twice daily. On the basis of similarity to other 
studies, practicalities on the ward and clinical scenario 
 
We have chosen a duration of 5 days based on the usual clinical pathway of 
inpatient management at the Royal Hallamshire Hospital, and have chosen to deliver 
the treatment twice daily to optimise the dose. This is a pilot study with feasibility 
outcomes and as such we will be exploring the feasibility of this treatment regimen.  
 
The Parasym Device will be applied to the left tragus (figure 1) as this is the most 
common site for tVNS delivery in neurological studies and is associated with few 
afferents to the heart.  
 
The intervention is aimed at supplementing routine clinical care, and as such, the 
doses of tVNS can be interrupted for care activities (therapy sessions, examinations, 
assessments etc) and resume afterwards. The overall minute duration will aim to 
remain 45 minutes twice daily.  
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Anatomy of the ear and the tragus (a). Parasym attached to the tragus (b) 
 
 
The active intervention will be compared to sham tVNS where the vagal nerve 
stimulator will be attached to the earlobe instead of the tragus, in keeping with 
evidence that this does not cause vagus nerve stimulation and is in line with sham 
methods used in other studies. We do not anticipate that patients will have the 
intervention long enough to become familiar with the common sensations associated 
with true tVNS intervention. At the end of the intervention period, participants will be 
asked if they thought they had received true of sham tVNS to understand the 
blinding ability of the sham.  
 
We will use the FNIRS Lumo ecosystem (Gower labs) to assess cerebral blood flow 
in the frontal lobes. We will complete a protocol where 6 optodes are placed 
bilaterally over the frontal and prefrontal cortices. We will complete and record 
resting state signals of oxyhaemoglobin and deoxyhaemoglobin for 5 minutes while 
patients are layed in bed with their eyes closed (or wearing an eye patch). Following 
the 5-minute rest phase, vagal nerve stimulation or sham stimulation will start 
 
 B 

 
tVNS in aSAH, Protocol, Version 2 16.12.23, STH22772, IRAS: 334282 
depending on the participants randomisation and signal acquisition will continue for 5 
minutes. After this time, the stimulation will cease and a further 5 minutes of resting 
signal acquisition will be completed. The data acquired during this protocol will 
undergo processing (adjustment for background and physiological noise) and data 
analysis using recommended software (Homer 2/3). Data analysis will look to 
compare signal acquisition between resting and stimulation states and will evaluate 
any lasting effects of stimulation following termination. We will perform this on the 
first and last day of the intervention, before and after stimulation respectively. 
 
We will be using Reflex Pupillometry to measure pupillograms in response to a light 
stimulus during an intervention session for all participants. This will be done at a 
different time to the Lumo FNIRS assessment. Recording of the pupillary response 
will follow the following protocol; 3 baseline measures taken 1 minute apart prior to 
stimulation will represent baseline pupillograms (which will be averaged). Following 
this, stimulation (active or sham) will start and 3 times pupillograms will be measured 
at 1 minute intervals following initiation. After completion of the treatment session, 3 
further pupillograms separated by 1-minute intervals will be measured - that will 
constitute the recovery phase.  We acknowledge that environmental influences 
(ambient light intensity, equipment noise and administered medications may 
confound pupillography, however this analysis is exploratory. 
6.10 Study Protocol 
 
Patients (or their representatives if they lack capacity) who are eligible for entry into 
the will be approached by the treating clinical teams with information about the study. 
Those who are interested will be given an information sheet and time to consider the 
study. Those keen to participate will sign a consent form (or assent form for those 
that lack capacity) and baseline outcome measures will be performed.  
 
Enrolled participants will be issued with a study number and randomised 2:1 
(SealedEnvelope Ltd) stratified according to age (<65 and ≥ 65 years). They will then 
receive either active tVNS stimulation (tragus) or sham (earlobe), twice daily for 45 
minutes per session for 5 days. We do not anticipate discharges from hospital earlier 
than 5 days as this is not routine practice in the neurosurgical unit.  
 
Primary outcome measures of tolerability and feasibility will be collected daily by 
researchers delivering the intervention, and secondary outcome measures will be 
collected at the end of intervention or on hospital discharge as detailed in figure 2.  
 
Following discharge from hospital participants will return for follow up clinic 
assessment at 4 weeks where questionnaire measures of functional recovery and 
adverse event reporting will be undertaken. After this the participants involvement in 
the study will be complete.  
 
 
 

 
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Figure 2: Study Schedule for Outcome Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT = End of 
treatment; BI = 
Barthel Index; 
fNIRS = Functional near infra-red spectroscopy 
 
 
 
Baseline 
visit 
 
Visit 
1  
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
(EOT) 
discharge 
At 4 
weeks 
Eligibility 
screening 
X 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
Randomisation 
X 
 
 
 
 
 
 
 
Socio-
demographic 
data 
X 
 
 
 
 
 
 
 
Clinical data 
collection 
X 
 
 
 
 
 
X 
 
Questionnaires: 
Disability - 
mRS, BI, 
headache likert 
scale  
X 
 
 
 
 
 
X 
X 
Reporting of 
side effects, 
adverse events 
and tolerability 
 
X 
X 
X 
X 
 
X 
X 
Intervention 
reporting – 
settings 
delivered, 
duration of 
intervention 
 
X 
X 
X 
X 
 
 
 
Pupillometry + 
recording of 
prescribed eye 
drops 
X 
 
 
 
 
X 
 
 
Heart rate 
variability 
 
X 
 
 
 
 
X 
 
 
fNIRS 
X 
 
 
 
 
X 
 
 
Monitor blood 
test results 
(secondary 
outcome 
measures), 
collection of 
data on 
WCC/CRP and 
infection status 
X 
X 
X 
X 
X 
 
X 
 
Inflammatory 
marker analysis 
X 
 
 
 
 
X 
 
 

 
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7. Data Management 
 
7.1 Statistical Analysis 
 
The analyses will be undertaken on statistical software (PRISM) and will compare 
the two groups. Rates of complications and outcomes will be reported descriptively. 
Data integrity will be checked by two researchers and inputted contemporaneously. 
Each researcher will be trained in outcome measures prior to study initiation. 
 
We anticipate approximately 50% of participants will be unable to complete 
questionnaires due to confusion / low GCS etc. This is exploratory and if this is the 
case then these outcome measures will not be taken forward in the next stages of 
future trials. Otherwise we anticipate very few missing data in terms of the primary 
outcome measures and the objectively measured secondary outcomes due to the 
fact that we will have a researchers based on the neurosurgical units throughout the 
recruitment and intervention periods collecting and recording data. 
 
7.2 Statistical Opinion 
 
This is a pilot study which hopes to form the basis of further grant funding for a larger 
study. This is a provisional study to demonstrate tolerability and feasibility. Further 
statistical advice would be sought should further funding be granted for future study. 
Primary outcome data will be reported descriptively (proportions, %).  
 
Continuous data will be compared using parametric or non-parametric analyses 
depending on whether data distribution is normal or not. Categorical data will be 
compared using Chi-square or one-way ANOVA. However, due to the small sample 
size, appropriate power to detect significant differences for these measures will not 
be reached. This is primarily an exploratory study and most data will be reported 
descriptively. 
Between group differences in baseline characteristics will be compared using 
parametric (T-Tests) and non-parametric (Mann – Whitney U, Chi squared) tests, 
depending on normality of distribution.  
A secondary outcome of this study is safety of TVNS in patients who have suffered a 
subarachnoid haemorrhage. Utilising the definition of SAE, if no SAE’s are reported 
which are deemed related to tVNS by the research team, then we can be 95% 
confident that the true SAE rate lies between 0 and 12%.15 
 
 
 
 
 

 
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7.3 Confidentiality  
 
Participant information (socio-demographic, clinical, outcome measure assessment) 
will be recorded on paper clinical research forms that will be furnished with a study 
number rather than the patient identifiers. This will then be transferred to an encrypted 
electronic database stored on a password protected Sheffield Teaching Hospitals 
research laptop, access to which will be restricted to researchers entering data and 
performing statistical analyses. Each study participant will be assigned a unique ID 
number, which will be the only "identifier" linked to data collected. A separate 
enrolment log will be kept updated by the researcher and held within a study file 
separate to the study site file. This will link these numbers to the participant’s 
personally identifiable information. In this way, the participants’ data will be "pseudo-
anonymised" and no identifiable information will be kept with the actual study data. 
 
The research laptop, study site file and enrolment log will be stored in a locked office 
at Sheffield Teaching Hospitals, RHH. Participants will undergo baseline and follow up 
data collection at the stroke unit at the RHH. Rooms there are private and data 
collection will be conducted in a confidential manner. 
 
7.4 Data Collection, Handling and Storage Record Keeping 
 
Data from the study will be inputted directly onto paper documents that will act as the 
source documents and be stored in a locked cabinet in a locked room. 
Data analysis will take place on a STH laptop that is password protected. 
The PI will check all source documents before submitting to minimise the chance of 
any data errors. 
 
7.5 Data Storage 
 
Data will be collected and retained in accordance with the Data Protection Act 1998. 
Paper copies of source data and consent forms will be stored in locked cupboard in 
the Royal Hallamshire Hospital. Electronic data collected will be stored on a 
password protected computer in the STH computer network. The data will be 
accessible only to the study team and the trust approved research and governance 
auditors. The data will be stored within the STH archiving facility for 5 years after 
completion of the study.  
 
 
 
 
 

 
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8. Study Management  
 
8.1 Project Plan 
 
Activity 
Time Frame 
Ethical Approvals 
August 2023 – January 2024 
Recruitment 
January 2024 – June 2025 
Closed to Recruitment, in Follow up 
July 2025  
Closed to Recruitment, Follow up 
complete 
August  2025 
Data Analyses 
August 2025 – October 2025 
Write up 
November – December 2025 
Dissemination 
January 2026 onwards 
 
8.2 Project Management 
 
The principal investigator will have overall responsibility for the study and will 
supervise, monitor and review any work undertaken by the research team. They will 
also be responsible for the data collection and analysis of the outcome measures. All 
SAH patients in the eligible time frame will be approached.  
9. Expertise 
 
 
Mr Matthew Myers is an academic neurosurgery ST2 trainee in Sheffield Teaching 
Hospital NHS Foundation Trust since 2022.   
 
Dr Ali and Professor Majid are academic consultants in neurology stroke and 
Geriatrics and have experience in running clinical trials and supervising academic 
fellows, MSc and PhD students.  
 
The project team (Dr Ali, Prof Majid) will meet twice monthly to discuss problems that 
arise with recruitment and data analysis. The Principal Investigators will have overall 
responsibility for the study and will supervise, monitor and review work undertaken, 
the data collected and analysis performed. 
 
 
 

 
tVNS in aSAH, Protocol, Version 2 16.12.23, STH22772, IRAS: 334282 
10. 
Ethical Issues 
 
10.1 Ethical Considerations: 
 
The Investigator asking for consent and the Participant Information Sheet (PIS) will 
inform the potential participant that participation is entirely voluntary and their medical 
care will not be affected by their decision. The PIS and Informed Consent Form (ICF) 
will be given to the potential participant, and they will be given adequate time to read 
and understand the information and ask any questions prior to consenting. They will 
be informed that they have the right to withdraw at any time without giving reason and 
this will not affect their medical care or legal rights. The participants’ rights to 
information and consent, confidentiality and privacy are and will be respected and 
upheld throughout the duration of this study. For any eligible patients who lack capacity 
and cannot consent form themselves, consent will be sought from the next of kin or 
personal representatives. The decision to include patients who lack capacity has been 
taken as it is likely this will form a significant proportion of the aSAH population, and 
thus to ensure our research is generalisable to as many that benefit as possible 
including this group is critical. We have a wealth of evidence demonstrating the safety 
of this intervention in acute stroke and other acute neurological conditions [Redgrave 
et al]. All members of the research team have undergone GCP training. If assent to 
participate has been obtained from personal representatives and the participant 
regains capacity during the intervention period then informed consent from the 
participant themselves will be obtained prior to continuation with study activities. 
Participants are free to withdraw from the study at any time without giving a reason 
and without it affecting their clinical care or legal rights. The study data already 
collected will be withdrawn up until the time it is anonymised. 
 
10.2 Declaration of Helsinki 
 
The CI will ensure that this study is conducted in accordance with the principles of 
the Declaration of Helsinki. 
 
10.3 Guidelines for Good Clinical Practice 
 
The CI will ensure that this study is conducted in accordance with relevant 
regulations and the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH)-Good 
Clinical Practice. 
 
All research active staff will have completed the GCP training or re-fresher training 
within the last 3 years (in line with STH Trust Requirements). 
 
10.4 Expenses and Benefits 
 
There is no anticipated direct benefit of this study to participants, but it is hoped the 
study will help support the use of a novel technology to improve outcomes after SAH. 

 
tVNS in aSAH, Protocol, Version 2 16.12.23, STH22772, IRAS: 334282 
10.5 Other Ethical Considerations 
 
PIS, PIL and consent forms attached, which state participation is entirely voluntary, 
will always be provided to the patient, or NOK if the patient is unconscious and then 
given to the patient when they have capacity. The participant or legal representative 
will be given adequate time to ask questions and read the additional documentation. 
They have the right to withdraw at any time without giving a reason and this will not 
affect their future medical care. 
 
There is no anticipated direct benefit of this study to participants, but it is hoped that 
the information obtained will help to identify a biomarker for therapeutic application in 
future trials.  
11. 
Service Users and Patient and Public Involvement 
 
The research team have met with the PPI stroke panel on 17th November 2023 and 
received positive feedback with discussion points actioned. 
12. 
Dissemination 
 
The overall findings of this study will be presented locally to the academic 
directorates of Neuroscience. The research team will also aim to present the findings 
at international scientific meetings and will write up the findings for publication in 
peer – reviewed journals. The study will be registered with Sheffield Teaching 
Hospitals and will be advertised on the University of Sheffield website under the 
Biomedical Research Centre page and be registered on ClinicalTrials.org.  
13. 
Taking the Work Forward 
 
The pilot data generated from this project will contribute towards future grant 
submissions. This pilot work would look to generate an application to fund a multi-
centre trial involving a larger number of participants to evaluate the effect of tVNS on 
reducing complications following SAH. We would look to apply to an NIHR funding 
stream for the funding of a further study to establish whether tVNS has a statistically 
significant impact on improving outcomes after SAH.  
14. 
Intellectual Property (IP) 
 
No IP is anticipated from the completion of this study.  
 
 

 
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15. 
Costing Schedule 
 
The funding for this project will be provided by the stroke research account within the 
Academic Directorate of Neurosciences at Sheffield Teaching Hospitals.  
Matthew Myers is an academic trainee funded by the NIHR with dedicated academic 
time. He will be involved at all stages of the project. Masters students may be 
recruited to assist in participant recruitment and data collection. No additional 
members of staff will need to be funded.  
The necessary devices, including TVNS and lumos, are already available to the 
department and research team at no additional cost.  
16. 
Funding Arrangements 
 
The funding for this project will be provided by the stroke research account within the 
Academic Directorate of Neurosciences at Sheffield Teaching Hospitals. 
17. 
References 
 
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2018;49(2):333-340. doi:10.1161/STROKEAHA.117.019328 
2. 
Steiner T, Juvela S, Unterberg A, et al. European Stroke Organization 
guidelines for the management of intracranial aneurysms and subarachnoid 
haemorrhage. Cerebrovasc Dis. 2013;35(2):93-112. doi:10.1159/000346087 
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Johnson RL, Wilson CG. A review of vagus nerve stimulation as a therapeutic 
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