Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06374693 |
| Other study ID # |
STH22772 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 14, 2024 |
| Est. completion date |
August 2025 |
Study information
| Verified date |
April 2024 |
| Source |
Sheffield Teaching Hospitals NHS Foundation Trust |
| Contact |
Dr Ali Ali |
| Phone |
+4401142159114 |
| Email |
Ali.ali[@]sheffield.ac.uk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
After a subarachnoid haemorrhage, complications are common and increase the overall rate of
disability and death from the condition. Despite some advances in preventing, detecting and
treating these complications, the rates of complications and associated risks remain high.
Further research into ways to reduce complications of subarachnoid haemorrhage.
Transcutaneous vagus nerve stimulation (tVNS) is a technique where a small handheld device is
attached to an earpiece which stimulates the nerves to the ear. This is given for short
periods and may help improve blood flow and reduce inflammation in the brain. The
intervention has been safely used and licensed in seizures, headache and severe depression.
This study will look to see if it is feasible and tolerable to have tVNS twice daily for 5
days after subarachnoid haemorrhage, and whether it can help reduce the risk of complications
from subarachnoid haemorrhage.
The participant will be randomly allocated to receive either tVNS or a dummy intervention,
known as sham.
The researchers will collect some personal and clinical details such as diagnosis,
medications, age, blood test results, as well as some details about the subarachnoid
haemorrhage.
The researchers will also complete brief questionnaires with the participant to assess
symptoms. They will take measurements of heart rate, pupil response, and brain activity using
a cap. The participant will then be randomly allocated to either receive the tVNS or sham
intervention.
Next, the research team will apply the earpiece to their ear twice a day for 45 minutes, for
a total of 5 days.
At the end of the 5-day study period, the intervention will be complete. The researchers will
arrange a follow-up meeting on discharge and at 6 weeks, to assess the participants symptoms
and recovery.
Previous studies have shown that tVNS is safe and well tolerated, including a recent review
of tVNS studies which evaluated the side effects experienced by 1322 patients receiving tVNS.
The main side effects include localised tingling/numbness/pain/redness around the ear (17%),
headaches (3%), dizziness (1%), facial droop (1%), nausea (1%), nasal discharge (2%). Rarely,
palpitations or a slow heart rate may occur.
They will continue to receive full medical treatment and observation alongside the study.
They are free to withdraw from this study if they find it too demanding on top of their other
activities.
Description:
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 the investigators 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). The investigators
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 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.
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.
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 the investigators will make no clear distinction of exactly what they
should feel.
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 (Royal
Hallamshire Hospital, Sheffield) and the timeframe of the recruitment period.
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 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.
The investigators are using tVNS settings that are widely used in other neurological
conditions (epilepsy, migraine)14. These include:
- Pulse width - 25ms
- Frequency - device default (20 or 25Hz)
- Intensity - below pain threshold.
- Frequency - 45 minutes twice daily. On the basis of similarity to other studies,
practicalities on the ward and clinical scenario
The investigators 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 the investigators 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.
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. The
investigators 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.
The investigators will use the FNIRS Lumo ecosystem (Gower labs) to assess cerebral blood
flow in the frontal lobes. The investigators will complete a protocol where 6 optodes are
placed bilaterally over the frontal and prefrontal cortices. The investigators will complete
and record resting state signals of oxyhaemoglobin and deoxyhaemoglobin for 5 minutes while
patients are laid 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 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. The investigators
will perform this on the first and last day of the intervention, before and after stimulation
respectively.
The investigators 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.
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. The investigators 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.
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.
