Neuro-navigated TMS for Chronic SCI Patients
Conditions: Spinal Cord Injuries
Sponsor: King's College Hospital NHS Trust

 
 
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Neuro-navigated TMS for Chronic SCI patients 
 
Chief Investigator 
Mr Aminul Ahmed (Consultant Neurosurgeon and Senior Lecturer, King’s 
College London) 
 
e-mail:  aminul.ahmed@kcl.ac.uk 
Tel: 020 7848 6469  
Sponsor(s) 
 
 
Research & Innovation Department 
King’s College Hospital NHS Foundation Trust 
161 Denmark Hill, London, SE5 9RS 
 
Neurosurgery Department  
King’s College Hospital NHS Foundation Trust 
Denmark Hill Road, London, SE5 9RS 
 
King’s College London University 
Funder (s): 
AO Spine 
IRAS Reference 
-- 
 
Protocol Version 1.0 {28/02/2023} 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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CONTENTS 
 
STUDY SUMMARY ...................................................................................................................................... 4 
1 
INTRODUCTION…………………………………………………………………………………………………………………………………….5 
2             BACKGROUND ........................................................................................................................................... 5 
3 
OBJECTIVES ................................................................................................................................................ 7 
4 
STUDY DESIGN ........................................................................................................................................... 7 
5 
CONSENT, ELIGIBILITY & RECRUITMENT ................................................................................................. 10 
6 
PATIENT AND PUBLIC INVOLVEMENT (PPI) ............................................................................................. 11 
7 
FUNDING AND SUPPLY OF EQUIPMENT .................................................................................................. 11 
8 
DATA HANDLING AND MANAGEMENT .................................................................................................... 11 
9 
PEER AND REGULATORY REVIEW ............................................................................................................ 12 
10 
ADVERSE EVENTS AND INCIDENT REPORTING ........................................................................................ 12 
11 
MONITORING AND AUDITING ................................................................................................................. 16 
12 
TRAINING ................................................................................................................................................. 16 
13 
INDEMNITY ARRANGEMENTS .................................................................................................................. 16 
14 
ARCHIVING............................................................................................................................................... 17 
15 
REFERENCES ............................................................................................................................................ 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
CAG 
Confidential Advisory Group 
CI 
Chief Investigator 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
GAfREC 
Governance Arrangement for NHS Research Ethics 
HRA 
Health Research Authority 
HTA 
Human Tissue Authority 
ICF 
Informed Consent Form 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
TMF 
Trial Master File 
nTMS 
Neuro-navigated Transcranial magnetic stimulation 
SCI 
Spinal cord injury 
ISNCSCI 
International standards for neurological classification of spinal 
cord injury 
EM-SCI 
European Multicentre study about Spinal cord injury 
PPI 
Public patient involvement 
 
 
 
 

 
 
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STUDY SUMMARY 
STUDY OVERVIEW 
Full title 
Validating neuro-navigated TMS stimulation in SCI patients: a 
feasibility study towards a gene therapy for SCI.  
Objectives 
Primary objective: Whether neuro-navigated Transcranial Magnetic 
Stimulation can be used as an additional outcome measure to EM-
SCI assessments in a Spinal Cord Injury trial? 
 
Secondary objective: Whether nTMS stimulation combined with MRI 
Tractography can be used as an adjunct outcome tool with EM-SCI 
assessments for a planned first in human SCI gene therapy trial. 
Type of trial 
Single site observational study 
Trial design and methods 
Recruited patients will undergo nTMS and MRI Tractography in 
addition to full EM-SCI assessments. Comparisons will be made to 
assess the sensitivity of TMS as an outcome measure and whether it 
can be used as an adjunct whilst assessing SCI patients.  
Health condition(s) or 
problem(s) studied 
Chronic cervical and thoracic spinal cord injuries (greater than 6 
months from injury). 
Target sample size 
20 patients 
Trial duration per 
participant: 
1 month 
Main inclusion/exclusion 
criteria: 
Inclusion Criteria: 
- Single traumatic event at least 6 months prior to recruitment  
- ISNCSCI grade A, B, C or D  
- Able to participate in EM-SCI and nTMS assessments and capable of 
informed consent 
 
Exclusion Criteria:  
- History of Malignancy 
- History of other Neurological disease 
- Pregnancy 
- Other cord lesions or tethering 
- Cord transaction or penetrating injury 
Statistical methodology 
and analysis: 
Analysis will be performed in house using SPSS statistical software 
(IBM SPSS software version 28).   
STUDY TIMELINES 
Study Duration/length 
6 months 
Expected Start Date 
February 2023 
End of Study definition 
and anticipated date 
31 August 2023 
 
 
 
 
 
 
 

 
 
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1 INTRODUCTION 
This is an exciting time for translating experimental Advanced Therapies into treatments for spinal 
cord injury (SCI). There are currently no regenerative therapies available that target the underlying 
biology. Over the last 5 years we have developed a viable gene therapy approach for treating SCI in 
pre-clinical models. We are on the cusp of translating this therapy to first-in-human studies. We are 
leading a programme to establish a world-first regenerative gene therapy for traumatic SCI affecting 
upper limb mobility (since recovery of arm/hand function is one of the highest patient priorities). 
Our team will develop an innovative trial design involving neurosurgical delivery of the gene therapy 
into the spinal cord, followed by specialist neuro-rehabilitation.   
For a clinical trial to have the best chance of success, we need to address key steps which include 
validation of new assessment methods for the clinical trial. Our aim is to determine whether neuro-
navigated Transcranial Magnetic Stimulation (nTMS) can be used as an adjunct to standard 
assessments of function in SCI patients. Following two patient and public involvement events 
(patient focus group and feedback for project design with our rehabilitation partners), we will recruit 
chronic SCI subjects to carry out European Multicenter Study about SCI (EM-SCI) assessments. EM-
SCI assessments are well established assessment tools for SCI patients and include the EM-SCI ‘core’ 
assessments (ISNCSCI, WISCI-III, Walk Test, SCIM 3) and EM-SCI ‘additional’ assessments (GRASSP, 
Pain score, neurophysiology). We will compare and validate nTMS with EM-SCI assessments in stable 
chronic SCI patients with both cervical and thoracic injuries. nTMS with combined Tractography MRI 
of the cortico-spinal tract (the main motor pathway of the spinal cord) will allow functional 
characterisation and density measurements of this tract in SCI patients.  
2 BACKGROUND AND RATIONALE 
 
Worldwide, more than 20 million people live with the devastating consequences of a traumatic 
SCI, with >250,000 new injuries suffered each year1,2. Along with loss of sensory and motor 
function and paralysis, many patients suffer incontinence, chronic pain and depression. SCI 
therefore imposes severe limitations on mobility, independence, full participation in society and 
quality of life. SCI also has a high financial burden, with healthcare costs among the highest of any 
medical condition (estimated at £1.4 billion per annum in the U.K.)2. Current treatments rely on 
early surgical intervention for mechanical decompression, symptomatic relief, supportive care 
and rehabilitation. There are currently no adequate therapies available. SCI therefore represents 
a clear unmet need for which new treatment options are vital. 
Most spinal cord injures occur in the neck (cervical) region, causing upper limb paralysis. 
Regaining use of the hands (the ability to reach, grip, hold and pick up objects) would enable 
independent living, is the highest rated patient priority, and would have immense impact for 
reducing healthcare burden and improving quality of life. King’s College Hospital has one of the 

 
 
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largest neurosurgical units in the United Kingdom. It provides specialist acute input for all SCI 
covering a catchment of over 4 million people. Over the last 5 years it has admitted and treated 
an average of 65 SCI patients per year, with around half of these patients with a traumatic SCI. 
KCH’s rehabilitation partner is the world-renowned National Spinal Injuries Centre (NSCIC) at 
Stoke Mandeville, and KCH is NSIC’s largest referring centre. There is an urgent need to find novel 
interventions to improve outcome in SCI patients both within our large patient population at 
King’s and also the wider SCI community. 
We have pioneered the use of Chondroitinase ABC (ChABC) for treating SCI, since the first in vivo 
demonstration that local intrathecal ChABC injections could restore sensorimotor hindlimb 
function to paralysed rats, to the recent development of an advanced gene therapy approach for 
restoring upper limb function (Figure 1)3,4. ChABC has the largest body of pre-clinical evidence 
supporting efficacy than any other experimental treatment for SCI and is considered a leading 
candidate for clinical translation, with efficacy demonstrated by many labs worldwide and in 
numerous species, including mice, rats, dogs and primates. We developed a vector-based gene 
therapy strategy for ChABC and demonstrated improved function in pre-clinical SCI contusion 
models. With this approach we are addressing the ambitious challenge of developing 
regenerative therapies that enable functional reconnection of damage nerve fibres and engage 
paralysed muscles. GMP grade vectors are being produced and regulatory approvals are being 
sought for a first-in-human clinical trial.  
 
Key to the success of the trial is the ability to assess the functional changes in SCI patients. The 
EM-SCI ‘core’ (ISNCSCI, WISCI-III, Walk Test, SCIM) and EM-SCI ‘additional’ assessments 
(GRASSP, Pain score, neurophysiology) are validated assessment tools utilized widely used in SCI 
trials5. While the state of art in the field is at the cusp of a breakthrough trial, we believe an 
additional assessment with neuro-navigated Transcranial Magnetic Stimulation (nTMS) will 
improve the chance of trial success since it will have greater sensitivity to pick up subtle changes. 
Moreover, we can select participants with residual CST function more likely to respond to a 
neuroplasticity- promoting treatment. nTMS is a non-invasive method using a magnetic field to 
stimulate the underlying cerebral cortex. In SCI, non-navigated TMS has been used to both assess 
function and as an adjunct to rehabilitation to promote recovery6,7. 

 
 
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nTMS allows for an individual location of the magnetic stimulation within an acceptable margin 
of error derived from the registration process. When compared with non-navigated TMS, the 
navigated TMS allows for more spatially discrete cortical stimulation and more stable motor 
evoked potentials with significantly higher amplitudes and shorter latencies8. Also, when 
different navigation methods are compared, ‘E-field’ navigation proved to be superior to line-
navigation method9. At King’s, we use an E-Field nTMS. We combine nTMS with MRI tractography, 
a 3D modelling technique used to visually represent nerve tracts using data collected by diffusion 
MRI. This accurately delineates the location of the motor cortex. The advantage for this is pairing 
a positive TMS cortical response with a defined subcortical tract that carries that same motor 
information, thus confirming a true positive response. 
3 OBJECTIVES 
3.1 
Primary Objective  
Can neuro-navigated Transcranial Magnetic Stimulation be used as an additional outcome 
measure to EM-SCI assessments in a Spinal cord injury trial?  
 – Compare EM-SCI assessment with nTMS in ten chronic thoracic SCI patients  
– Compare EM-SCI assessment with nTMS in ten chronic cervical SCI patients 
3.2 
Secondary Objectives  
nTMS stimulation combined with MRI Tractography can be used as an adjunct outcome tool with 
EM-SCI assessments for a planned first in human SCI gene therapy trial.  
Specifically, nTMS will demonstrate sensitivity for cortico-spinal tract function, giving a novel tool 
for stratifying and selecting patients for SCI trials. 
4 STUDY DESIGN 
This is a pilot study in the assessment of nTMS as an adjunct tool in measuring outcome within 
chronic spinal cord injury patients. Initial PPI events will be performed where patients will be 
engaged in obtaining feedback on study design and protocol for both the pilot nTMS study and 
the potential subsequent Gene therapy trial. Following these events, suitable patients who meet 
the inclusion criteria and have displayed interest in participation will be consented for the 
study. Patients will then attend for a single day of assessments as follows:  
1 – The International Standards for Neurological Classification of Spinal Cord 
Injury (ISNCSCI). The International Standards for Neurological Classification of Spinal Cord 
Injury (ISNCSCI) assessment protocol consists of two sensory examinations, a motor 
examination, and a classification framework (the impairment scale) to quantify the severity of 
the spinal cord injury. The grading is from A to E, with A being a complete injury with no motor 
or sensory function and E being normal sensory function. Patients recruited will vary between A 
and D to give an indication of variability in the motor response to allow comparisons between 
injury severity.   

 
 
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2 – Neurophysiology. Three standard neurophysiological measures will be registered: MEP 
(motor evoked potentials), SSEP (somatosensory evoked potentials) and NCV (nerve conduction 
velocity). MEPs and SSEPs of the tibialis and ulnar nerves quantify the status of the efferent and 
afferent pathways in the spinal cord. The NCV will be used to exclude peripheral nerve lesions.  
3 – Functional Tests. Assessment of the walking ability of patients with movement disorders is 
an important outcome measure in rehabilitation. The Walking Index for Spinal Cord Injury II 
(WISCI II) has been validated in SCI patients, The WISCI II has an original scale that quantifies a 
patient's walking ability; a score of 0 indicates that a patient cannot stand and walk and the 
highest score of 20 is assigned if a patient can walk more than 10m without walking aids of 
assistance. In addition, the following two time tests will be performed: Timed Up & Go (TUG) 
test and 10-metre walking test (10MWT).  
4 - Spinal Cord Independence Measure 3 (SCIM 3). The Spinal Cord Independence Measure 
(SCIM) is a disability scale developed specifically for patients with spinal cord lesions. It focuses 
on the requirement of personal assistance and/or technical aids with domains in self-care, 
respiration and sphincter management and mobility. The score is between 0 and 100.  
5 - Graded and Redefined Assessment of Strength, Sensibility and Prehension version 1 
(GRASSP v1)10. The GRASSP is an outcome measure to assess hand function in patients with a 
cervical spinal cord injury. It consists of three domains: 1. Strength, 2. Sensation and 3. 
Prehension: including relevant finger positioning performance with 6 Activities of Daily Living. 
The score is between 0 and 116.  
6 - MRI Tractography followed by neuro-navigated Transcranial Magnetic Stimulation will be 
undertaken. The rationale is that nTMS will provide a more sensitive characterisation of a 
functional CST in SCI patients11. Moreover, nTMS provides spatial resolution of the tracts which 
standard neurophysiology cannot determine. The addition of MRI tractography allows accurate 
neuro-navigated localisation of the CST and quantification of the fibre density of the CST. 
After acquisition of the MRI scans, nTMS-seeded tractography will be performed. nTMS positive 
motor responses will be used as regions of interest and another region of interest will be placed 
in the brainstem at the level of the superior cerebellar peduncle. This technique will provide 
somatotopic tractography. DTI-derived metrics (Fractional Anisotropy (FA), Axial Diffusivity 
(AD), Radial Diffusivity (RD), Mean Diffusivity (MD) and Hindrance Modulated Orientation 
Anisotropy (HMOA)), number of fibres and volume will be calculated for both CSTs. Our 
hypothesis is that an abnormal cortical excitability will correlate with abnormal CST metrics 
supporting microstructure impairment. This may be particularly true with the tract specific 
metric, HMOA.  
Comparisons between EM-SCI and nTMS/tractography assessments will be made to determine 
if nTMS can be used as an adjunct which is more sensitive in the assessment of SCI patients.  For 
instance, nTMS can induce motor evoked potentials in patients with no active movement 
detected in neurological examination and this can have an impact in terms of prognostication of 
motor recovery, which is especially important for SCI trials.   
 

 
 
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Consent and recruitment of 20 patients who 
meet the inclusion criteria 
(Month 1-3) 
Patient attends King’s College Hospital for a 
single day of assessments, including MRI head, 
TMS and full EM-SCI assessments. 
(Month 3-9) 
No further follow up or participation is required, 
once the data has been analysed and manuscript 
prepared, consenting patients will be notified of 
study outcome 
(Month 9-12) 
Identification of eligible patients - Cervical 
and thoracic SCI patients more than 6 
months post injury.  
(Month 1-3) 

 
 
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5 CONSENT 
The Informed Consent form must be approved by the REC and must be in compliance with GCP, local 
regulatory requirements and legal requirements. The investigator or designee must ensure that each 
trial participant, or his/her legally acceptable representative, is fully informed about the nature and 
objectives of the trial and possible risks associated with their participation. Participants reserve the 
right to withdraw consent at any point without reason. 
Alternatively, recognising many centres have transitioned to virtual outpatient appointments and may 
not see a participant in person until the day of surgery, verbal informed consent can be obtained by 
telephone. This must be countersigned by a second investigator, to confirm that the individual 
received a verbal description of the study, had received the PIS, and had had sufficient time to consider 
the information and an opportunity to ask questions, and voluntarily agreed to participate in this 
study.   
 
ELIGIBILITY CRITERIA 
5.1 
Inclusion Criteria 
- Single traumatic event at least 6 months prior to recruitment  
- ISNCSCI grade A, B, C or D  
- Able to participate in EM-SCI and nTMS assessments and capable of informed consent 
5.2 Exclusion Criteria 
- History of Malignancy 
- History of other Neurological disease 
- Pregnancy 
- Other cord lesions or tethering 
- Cord transaction or penetrating injury 
 
RECRUITMENT 
Participants will be identified and recruited from spinal cord injury follow up clinics at King’s College 
Hospital, where eligible patients will be approached. Patients will also be approached via Participant 
identification centres, with Stoke Mandeville Hospital (National spinal injuries unit) the agreed site 
for patient referrals.  

 
 
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6 PATIENT AND PUBLIC INVOLVEMENT (PPI) 
Two Public Patient Involvement (PPI) events have taken place in the planning and preparation of this 
study. The first event took place in the National Spinal Injuries Centre at Stoke Mandeville 
(NSIC), England in November 2022. This was followed by an event in the National spinal injuries 
unit in Glasgow (February 2023).  
Both involved presentations on Gene therapy as a novel treatment option for spinal cord injury and 
neuro navigated TMS as an assessment tool in chronic SCI. Participants were also consulted on the 
study design including the proposed full day of assessments planned. 
Feedback from the PPI event’s was overwhelmingly positive, with participants supportive of new 
studies that may further the management of SCI patients. Moreover no concerns were raised against 
the study design, and participants felt the full day of assessments was definitely feasible. All 
participants if eligible felt they would be interested in partaking within the neuro TMS trial despite 
any potential risks.  
7 FUNDING AND SUPPLY OF EQUIPMENT  
The study funding has been reviewed by the KCH R&I Office, and deemed sufficient to cover the 
requirements of the study.  
 
The research costs for the study have been supported by AO Spine.   
 
8 DATA HANDLING AND MANAGEMENT 
Personal data will be obtained with full consent and transparency of its use. Confidentiality will be 
maintained through de-identification of participants. 
 
Data will be made de-identifiable and stored in a secure university/hospital computer at King’s College 
Hospital and King’s College London, and only shared between accredited members of the direct care 
team via encrypted email. Personal data once no longer required will be erased in accordance with 
GDPR guidance, any remaining data/information will remain non-identifiable. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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9 PEER AND REGULATORY REVIEW 
The study will undergo initial peer review within the research team.  
The study was deemed to require regulatory approval from the following bodies - HRA and REC. Each 
approval will be obtained before the study commences.  
10 ADVERSE EVENTS AND INCIDENT REPORTING 
 
10.1 Definitions of Adverse Events  
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or study participant, 
which does not necessarily have a causal relationship with the 
intervention/treatment/procedure involved.  
Serious Adverse Event 
(SAE). 
Any adverse event 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 
*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. 
10.2 
Assessments of Adverse Events  
Each adverse event will be assessed for severity, causality, seriousness and expectedness as described 
below. 
Severity  
Category 
Definition 
Mild 
The adverse event does not interfere with the participant’s daily routine, and 
does not require further procedure; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the participant’s routine, or 
requires further  procedure, but is not damaging to health; it causes moderate 
discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is clearly 
damaging to health 
 

 
 
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Causality 
The assessment of relationship of adverse events to the procedure 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 
Definitely: 
There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
Probably: 
There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the event occurred 
within a reasonable time after administration of the study procedure). However, 
the influence of other factors may have contributed to the event (e.g. the 
participant’s clinical condition, other concomitant events). 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the event did 
not occur within a reasonable time after administration of the study procedure). 
There is another reasonable explanation for the event (e.g. the participant’s 
clinical condition). 
Not related 
There is no evidence of any causal relationship. 
Not Assessable 
Unable to assess on information available. 
 
Expectedness 
Category 
Definition 
Expected 
An adverse event which is consistent with the available information about the 
intervention/treatment/procedure in use in this study.   
Unexpected 
An adverse event which is not consistent with the available information about the 
intervention/treatment/procedure in use in this study* 
* this includes listed events that are more frequently reported or more severe than previously 
reported 
10.3 Procedures for recording adverse events  
- 
All adverse events will be recorded in the medical records in the first instance. 
- 
All Adverse events will be recorded in the CRF following consent. 
- 
All adverse events will be recorded with clinical symptoms and accompanied with a 
simple, brief description of the event, including dates as appropriate.  
- 
 

 
 
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10.4 Procedures for recording and reporting Serious Adverse Events  
All serious adverse events will be recorded in the medical records and the CRF.   
All SAEs (except those specified in section 16.2 as not requiring reporting to the Sponsor) must be 
recorded on a serious adverse event (SAE) form. The CI/PI or designated individual will complete an 
SAE form and the form will be emailed to the R&I Office (kch-tr.researchqualityassurance@nhs.net) 
within 1 working day of becoming aware of the event.  
Where the event is unexpected and thought to be related to the intervention/treatment/procedure 
this must be reported by the Investigator to the REC and Health Research Authority, using the SAE 
Report form for non-CTIMPs (available from the HRA website) within 15 days.   
10.5 Serious Adverse Events that do not require reporting  
You may choose not to report some particular SAEs to the CI/R&I Office, for example if they are 
expected to occur on a regular basis and offer no further new information to your safety profile or are 
related to the disease area of the participants. It should be specified that where the frequency or 
severity of these events is unusual they must be reported. These events must continue to be recorded 
in the medical records, CRF however you may state that you will not complete an SAE form and 
forward it to the CI/R&I Office. Provide the rationale for doing so.    
10.6 Reporting Urgent Safety Measures  
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 relevant REC, Health Research 
Authority and R&I office of the measures taken and the circumstances giving rise to those measures. 
10.7 Protocol deviations and notification of protocol violations 
A deviation is usually an unintended departure from the expected conduct of the study protocol/SOPs, 
which does not need to be reported to the sponsor.   The CI will monitor protocol deviations. 
 
 A protocol violation is a breach which is likely to effect to a significant degree – 
(a) the safety or physical or mental integrity of the participants of the study; or 
(b) the scientific value of the study. 
The CI and R&I Office should be notified immediately of any case where the above definition applies 
during the study conduct phase.   
 
 

 
 
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Flow Chart for SAE reporting  
AE occurs 
Assign Severity Grade 
Was the event Serious? 
No 
Yes 
Yes 
No 
Submit SAE form to: 
 KCH R&I Office 
Sponsor within 5 working days 
 
Record in medical records,  
and CRF in accordance with the protocol  
 
Record in medical records 
and CRF 
Is the event specified as an adverse event which does not require immediate reporting as an SAE?  
See section 15.5.  
Record in medical records, CRF  
Complete an SAE report form 

 
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10.8 Trust incidents and near misses 
An incident or near miss is any unintended or unexpected event that could have or did lead to harm, 
loss or damage that contains one or more of the following components: 
a. It is an accident or other incident which results in injury or ill health. 
b. It is contrary to specified or expected standard of patient care or service. 
c. It places patients, staff members, visitors, contractors or members of the public at 
unnecessary risk. 
d. It puts the Trust in an adverse position with potential loss of reputation. 
e. It puts Trust property or assets in an adverse position or at risk. 
Incidents and near misses must be reported to the Trust through DATIX as soon as the individual 
becomes aware of them. 
A reportable incident is any unintended or unexpected event that could have or did lead to harm, loss 
or damage that contains one or more of the following components: 
 
a) It is an accident or other incident which results in injury or ill health. 
b) It is contrary to specified or expected standard of patient care or service. 
c) It places patients, staff members, visitors, contractors or members of the public at 
unnecessary risk. 
d) It puts the Trust in an adverse position with potential loss of reputation. 
e) It puts Trust property or assets in an adverse position or at risk of loss or damage. 
11 MONITORING AND AUDITING 
The Chief Investigator will ensure there are adequate quality and number of monitoring activities 
conducted by the study team. This will include adherence to the protocol, procedures for consenting 
and ensure adequate data quality.  
 
The Chief Investigator will inform the sponsor should he/she have concerns which have arisen from 
monitoring activities, and/or if there are problems with oversight/monitoring procedures. 
 
 
12 TRAINING 
The Chief Investigator will review and provide assurances of the training and experience of all staff 
working on this study.  Appropriate training records will be maintained in the study files 
13 INDEMNITY ARRANGEMENTS 
KCH will provide NHS indemnity cover for negligent harm, as appropriate and is not in the position to 
indemnify for non-negligent harm. NHS indemnity arrangements do not extend to non-negligent harm 
and NHS bodies cannot purchase commercial insurance for this purpose; it cannot give advance 
undertaking to pay compensation when there is no negligence attributable to their vicarious liability. 
The Trust will only extend NHS indemnity cover for negligent harm to its employees, both substantive 
and honorary, conducting research studies that have been approved by the R&D Department. The 
Trust cannot accept liability for any activity that has not been properly registered and Trust approved. 
Potential claims should be reported immediately to the R&I Office 
 

 
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King’s College London holds insurance against claims from participants for harm caused by their 
participation in this clinical study. Participants may be able to claim compensation if they can prove 
that KCL has been negligent. However, if this clinical study is being carried out in a hospital, the 
hospital continues to have a duty of care to the participant of the clinical study. King’s College London 
does not accept liability for any breach in the hospital’s duty of care, or any negligence on the part of 
hospital employees. This applies whether the hospital is an NHS Trust or otherwise. 
14 ARCHIVING 
Research data generated will be stored for up to 5 years following the end of the study. Physical 
consent forms and some physical personal will also be retained and stored for this time period.   
15 REFERENCES 
 
1 
Injury, G. B. D. T. B. & Spinal Cord Injury, C. Global, regional, and national burden of 
traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global 
Burden of Disease Study 2016. Lancet Neurol 18, 56-87, doi:10.1016/S1474-4422(18)30415-
0 (2019). 
2 
McDaid, D., Park, A. L., Gall, A., Purcell, M. & Bacon, M. Understanding and modelling the 
economic impact of spinal cord injuries in the United Kingdom. Spinal Cord 57, 778-788, 
doi:10.1038/s41393-019-0285-1 (2019). 
3 
Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord 
injury. Nature 416, 636-640, doi:10.1038/416636a (2002). 
4 
Burnside, E. R. et al. Immune-evasive gene switch enables regulated delivery of 
chondroitinase after spinal cord injury. Brain 141, 2362-2381, doi:10.1093/brain/awy158 
(2018). 
5 
Schuld, C. et al. Computer implementation of the international standards for neurological 
classification of spinal cord injury for consistent and efficient derivation of its subscores 
including handling of data from not testable segments. J Neurotrauma 29, 453-461, 
doi:10.1089/neu.2011.2085 (2012). 
6 
Awad, B. I., Carmody, M. A., Zhang, X., Lin, V. W. & Steinmetz, M. P. Transcranial magnetic 
stimulation after spinal cord injury. World Neurosurg 83, 232-235, 
doi:10.1016/j.wneu.2013.01.043 (2015). 
7 
Nardone, R. et al. Descending motor pathways and cortical physiology after spinal cord injury 
assessed by transcranial magnetic stimulation: a systematic review. Brain Res 1619, 139-
154, doi:10.1016/j.brainres.2014.09.036 (2015). 
8 
Julkunen, P. et al. Comparison of navigated and non-navigated transcranial magnetic 
stimulation for motor cortex mapping, motor threshold and motor evoked potentials. 
Neuroimage 44, 790-795, doi:10.1016/j.neuroimage.2008.09.040 (2009). 
9 
Sollmann, N. et al. Comparison between electric-field-navigated and line-navigated TMS for 
cortical motor mapping in patients with brain tumors. Acta Neurochir (Wien) 158, 2277-2289, 
doi:10.1007/s00701-016-2970-6 (2016).