Preoperative Paravertebral Block in Cancer Surgery of the Lung: ParaSOL a Prospective Randomized Controlled Clinical Trial
Phase: PHASE2
Conditions: Thoracic Neoplasm, Chronic Pain Post-Procedural, Acute Post-thoracotomy Pain, Anesthesia, Local
Sponsor: Guy's and St Thomas' NHS Foundation Trust

 
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1. Protocol Details 
1.1 Protocol Title: 
Preoperative paravertebral block in cancer surgery of the lung: ParaSOL a prospective randomised 
controlled clinical trial 
1.2 Names (Titles), titles and contact details of:  
Sponsor 
Name of Sponsoring Organisation/s: Guy’s & St Thomas’ NHS Foundation Trust 
Name of Sponsor Representative: Elizabeth Bruna 
Address: R&D Department, 16th Floor, Tower Wing, London, SE1 9RT 
Telephone: 0207 188 7188 Extn 51682 
Fax: 0207 188 8330 
Email: R&D@gstt.nhs.uk 
 
 
Chief Investigator  
Name: Dr Cheng Ong 
Address: Department of Anaesthesia, 2nd Floor Borough Wing, Guy’s Hospital, Great Maze Pond, 
London SE1 9RT 
Telephone: 07973128344 
Fax: 0207 188 6116 
Email: cheng.ong@gstt.nhs.uk 
 
Name and address of Investigator(s)  
Name: Dr Craig Johnstone 
Address: Department of Anaesthesia, 2nd Floor Borough Wing, Guy’s Hospital, Great Maze Pond, 
London SE1 9RT 
Telephone: 07897909257 
Fax: 0207 188 6116 
Email: craig.johnstone@gstt.nhs.uk 
 
 
1.3 Protocol Details 
 
Version number 
1.0 
Final/draft 
 
Final 
Date 
 
 
11/07/2019 
 
 
 
 

 
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2. Signature Page 
 
 
The Chief Investigator and the R&D (sponsor office) have discussed this protocol. The investigators 
agree 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, 
the UK Data Protection Act (1998), the Trust Information Governance Policy (or other local 
equivalent), the Research Governance Framework (2005’ 2nd Edition; as amended), the Sponsor’s 
SOPs, and other regulatory requirements as amended. 
 
Chief investigator 
Dr Cheng Ong 
 
 
 
Signature 
Date 
Sponsor Representative 
 
 
 
GSTFT 
Signature 
Date 
 
 
 
 
This Protocol template is intended for use with UK sites only. 
 
 

 
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3. List of Abbreviations and Definitions 
 
AE 
 
 
Adverse Event  
 
 
AR 
 
 
Adverse Reaction 
ASR 
 
 
Annual Safety Report 
CA 
 
 
Competent Authority 
CI 
 
 
Chief Investigator 
CRF 
 
 
Case Report Form 
CRO 
 
 
Contract Research Organisation 
DMC 
 
 
Data Monitoring Committee 
EC 
 
 
European Commission 
GAfREC  
 
Governance Arrangements for NHS Research Ethics Committees 
ICF 
 
 
Informed Consent Form 
ISRCTN  
 
International Standard Randomised Controlled Trial Number 
MA 
 
 
Marketing Authorisation 
MS 
 
 
Member State 
Main REC 
 
Main Research Ethics Committee 
NHS R&D 
 
National Health Service Research & Development   
PI 
 
 
Principle Investigator 
QA 
 
 
Quality Assurance 
QC 
 
 
Quality Control 
Participant 
 
An individual who takes part in a clinical trial 
RCT 
 
 
Randomised Controlled Trial 
REC 
 
 
Research Ethics Committee 
SAE 
 
 
Serious Adverse Event 
SDV 
 
 
Source Document Verification 
SOP 
 
 
Standard Operating Procedure  
SSA 
 
 
Site Specific Assessment 
TMG 
 
 
Trial Management Group 
TSC 
 
 
Trial Steering Committee 
 
 
 
 
 

 
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4. Summary/Synopsis 
Title  
 
 
Preoperative paravertebral block in cancer surgery of the lung: 
ParaSOL a prospective randomised controlled clinical trial 
Protocol Short Title/Acronym 
 
ParaSOL 
Protocol Version number and Date 
 
V0.1 28/06/2019 
Is the study a Pilot? 
 
No 
IRAS Number 
 
244767 
REC Reference 
 
 
 
 
 
Study Duration 
 
24 months 
Methodology 
 
Double-blind randomised controlled study 
Sponsor name 
 
Guy’s and St Thomas’ NHS Foundation Trust 
Chief Investigator 
 
Dr Cheng Ong 
Funder Name 
 
European Society of Regional Anaesthesia (ESRA) 
Medical condition or disease under 
investigation 
 
Paravertebral analgesia in lung cancer surgery 
Purpose of clinical trial 
 
Does the contribution of a preemptive preoperative ultrasound-guided 
paravertebral analgesic blockade (PVB) ‘pre-PVB LA’, administered in 
addition to a postoperative PVB local anaesthetic infusion ‘post-PVB 
LA’, reduce the severity of acute postoperative pain? 
Primary objective 
 
The primary outcome is the proportion of patients with clinically 
relevant moderate-to-severe pain (NRS ³ 3) related to the surgical site 
at rest at 24h 
Secondary objective (s) 
 
Secondary outcomes are acute pain as measured by NRS, cumulative 
48h morphine requirement, mobilization, respiratory and in-hospital 
complications, length of hospital stay, quality of life and chronic post-
surgical pain (CPSP). 
Number of Subjects/Patients 
 
100 subjects 
Trial Design  
 
Population: 
Adults ≥18 years of age, having elective primary lung cancer surgery by 
video-assisted thoracoscopy for a single lobectomy 
 
Intervention: 
After general anaesthesia, but before surgery, ultrasound-guided pre-
PVB injection will be performed by the anaesthetist. 
 The pre-PVB injectate will be 20ml 0.5% levobupivacaine (pre-PVB 
LA). 
At the end of surgery, the surgeon will administer a standard post-PVB 
LA injection and infusion. 
 

 
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Comparison: 
After general anaesthesia, but before surgery, ultrasound-guided pre-
PVB injection will be performed by the anaesthetist. 
 The pre-PVB injectate will be 20ml normal saline (pre-PVB saline). 
At the end of surgery, the surgeon will administer a standard post-PVB 
LA injection and infusion. 
 
 
Endpoints 
 
PRIMARY OUTCOME 
1. The proportion of patients with clinical relevant moderate-to-severe 
pain (NRS ³ 3) related to the surgical site at rest at 24h (1). 
SECONDARY OUTCOMES 
1. Acute postoperative pain related to the surgical site as measured by 
a numerical rating scale (NRS) at rest and on coughing, preoperatively, 
and after arrival in recovery at 1, 6, 24 and 48h (2).  
2. Cumulative morphine requirement over 48h post arrival in recovery. 
3. Time to first mobilization (walking 50m without the aid of another 
person), measured at baseline pre-operatively and postoperatively on 
daily assessment.  
4. Incidence of in-hospital complications (AF, MI, unplanned ICU 
admission) and respiratory complications, as defined by the Melbourne 
Group Scale (3).  
5. Length of hospital stay 
6. Quality of life (QoL) score at pre-operative assessment, 3 and 6 
months postoperatively as measured by the EORTC-QLQ-C30 version 3 
(4–6). 
7. Presence of chronic post-surgical pain (CPSP) (binary yes/no) 
fulfilling CPSP criteria at 3 and 6 months post-surgery as assessed by 
DN4 (7–9). 
 
Main Inclusion Criteria 
 
• 
Elective radical primary lung cancer VATS surgery for single 
lobectomy  
• 
ASA I-III 
• 
Age ≥18 
 
Main Exclusion Criteria 
 
• 
Planned open thoracotomy, wedge resection, bilobectomy, 
pneumonectomy, chest wall resection or total pleurectomy 

 
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• 
Local anaesthetic or opioid allergy 
• 
Coagulation disorders 
• 
Inability to comply with study questionnaire completion 
• 
Pre-existing pain in chest area or pre-existing pain conditions 
• 
Local infection/tumour at proposed PVB site 
• 
Previous lung surgery 
• 
Planned surgery within 3 months of the primary lung resection 
Statistical Methodology and Analysis 
 
Baseline risk factors and demographics of the overall study participants 
will be reported, stratified by their treatment allocation group in 
accordance to CONSORT guidelines. Patient outcomes will be analysed 
according to intention-to-treat. 
Primary outcome: 
The proportion of patients with clinically relevant moderate-to-severe 
pain (Numerical Rating Scale [NRS] ≥ 3) related to the surgical site at 
rest at 24h in treatment (pre-PVB LA) and control (pre-PVB saline) arms 
will be compared using the chi-square test for equality of two 
proportions 
Secondary outcomes: 
For all secondary outcomes, the distributions of outcome variables will 
be assessed for normality. To compare outcomes between treatment 
and control arms, we will use Student’s t test to for normally-
distributed continuous outcome variables, the Mann-Whitney test for 
non-normally distributed continuous and ordinal outcome variables, 
and chi-square tests for binary outcome variables. 
 
5. Introduction 
 
In the UK, there has been an increase in lung cancer operations, especially in high risk and elderly 
patients, improving survival from 10.6% in 2008 to 15.1% in 2013 (10–13). Lung cancer surgery is 
associated with severe acute pain, a high incidence of respiratory complications and chronic post-
surgical pain (CPSP)(3). Severe acute postoperative pain is a strong predictor of CPSP (14–17). The 
improvement of perioperative outcomes in elderly patients, the benefits of regional anaesthesia and  
reduction of chronic pain are investigative priorities of the Anaesthesia and Perioperative Care 
Setting Partnership (18). 
Enhanced recovery strategies include video-assisted thoracoscopic surgery (VATS), a minimally 
invasive alternative to open thoracotomy, which may be associated with less postoperative pain 
(11,15,19–21). Regional anaesthesia, by thoracic epidural analgesia (TEA) or paravertebral analgesic 
blockade (PVB) is superior to systemic opioids in reducing acute pain after thoracotomy surgery (22–
27).  
Preemptive analgesia describes the aim of minimizing central spinal pain transmission by noxious 
stimuli arising from events at surgery, by administering an analgesic technique prior to surgical 
incision (28,29). Regional blockade affects central sensitization, allowing analgesia to outlast the 

 
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pharmacological sensory blockade (29). 
Compared to TEA initiated after surgery, acute pain severity is reduced by preemptive TEA (30). 
There are conflicting reports on the benefit of preemptive analgesia in other types of surgery 
(23,28–31), but TEA and PVB may prevent CPSP in thoracotomy and breast surgery (32). Some small 
studies have shown that pre-PVB reduces acute postoperative pain (24,33,34). 
Paravertebral blockade is known to be as effective as TEA for acute postoperative analgesia 
following thoracic surgery, whilst having a lower incidence of pulmonary complications, hypotension 
and nausea (26,27). It is conventional practice in many centres for the surgical administration and 
placement of a catheter at the end of surgery for postoperative LA infusion (post-PVB) as the sole 
method of regional analgesia (35). Preoperative PVB is less common: anaesthetists may use a 
landmark technique, single or multiple injections and different volumes/strengths of LA 
(24,33,34,36–38).  
Ultrasound guidance for pre-PVB injection increases accuracy (39,40).  In an audit using this 
technique with post-PVB compared to post-PVB only, we demonstrated reduced pain numerical 
rating scale (NRS) scores in elective VATS patients, (mean NRS at 24h 2.5 vs 4.5), and a reduction in 
the proportion of patients who experienced moderate-to-severe pain of NRS ≥ 3 from 83% to 50% at 
24h (41).  
We therefore aim to evaluate the contribution of ultrasound-guided pre-PVB, administered in 
addition to the post-PVB LA infusion, in reducing the severity of acute postoperative pain, 
perioperative opioid requirement, development of CPSP, and improving patient outcome in lung 
cancer patients undergoing VATS. 
 
6. Trial Objectives and purpose 
Study Aim 
We aim to determine whether ultrasound-guided preemptive PVB local anaesthetic (pre-PVB 
LA), administered in addition to the post-operative PVB (post-PVB) local anaesthetic (LA) 
infusion, reduces acute postoperative pain, opioid requirement, chronic pain, and improves 
surgical recovery, in thoracoscopic surgery for lung cancer. 
 
PRIMARY OUTCOME 
1. The proportion of patients with clinical relevant moderate-to-severe pain (NRS ³ 3) related to 
the surgical site at rest at 24h (1). 
 
SECONDARY OUTCOMES 

 
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1. Acute postoperative pain related to the surgical site as measured by a numerical rating scale 
(NRS) at rest and on coughing, preoperatively, and after arrival in recovery at 1, 6, 24 and 48h 
(2).  
2. Cumulative morphine requirement over 48h post arrival in recovery. 
3. Time to first mobilization (walking 50m without the aid of another person), measured at 
baseline pre-operatively and postoperatively on daily assessment.  
4. Incidence of in-hospital complications (AF, MI, unplanned ICU admission) and respiratory 
complications, as defined by the Melbourne Group Scale (3).  
5. Length of hospital stay 
6. Quality of life (QoL) score at pre-operative assessment, 3 and 6 months postoperatively as 
measured by the EORTC-QLQ-C30 version 3 (4–6). 
7. Presence of chronic post-surgical pain (CPSP) (binary yes/no) fulfilling CPSP criteria at 3 and 6 
months post-surgery as assessed by DN4 (7–9). 
 
 
7. Study Design & Flowchart 
 
7.1 Study Design 
 
EXPERIMENTAL DESIGN (Table 1) 
Table 1 ParaSOL in PICOT Format  
Research 
question 
ParaSOL is a double-blinded randomised controlled trial 
investigating the question: 
Does the contribution of a preemptive preoperative 
ultrasound-guided PVB ‘pre-PVB LA’, administered in addition 
to a postoperative PVB local anaesthetic infusion ‘post-PVB 
LA’, reduce the severity of acute postoperative pain? 
Population 
Adults ≥18 years of age, having elective primary lung cancer 
surgery by video-assisted thoracoscopy for a single lobectomy 
Intervention 
After general anaesthesia, but before surgery, ultrasound-
guided pre-PVB injection will be performed by the anaesthetist. 
 The pre-PVB injectate will be 20ml levobupivacaine (pre-PVB 
LA). 
At the end of surgery, the surgeon will administer a standard 
post-PVB LA injection and infusion. 

 
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Comparison 
After general anaesthesia, but before surgery, ultrasound-
guided pre-PVB injection will be performed by the anaesthetist. 
 The pre-PVB injectate will be 20ml normal saline (pre-PVB 
saline). 
At the end of surgery, the surgeon will administer a standard 
post-PVB LA injection and infusion. 
Outcome 
The primary outcome is the proportion of patients with 
clinically relevant moderate-to-severe pain (NRS ³ 3) related to 
the surgical site at rest at 24h 
Secondary outcomes are acute pain as measured by NRS, 
cumulative 48h morphine requirement, mobilization, 
respiratory and in-hospital complications, length of hospital 
stay, quality of life and CPSP. 
Time 
Data collection will be until 6 months after surgery 
 
Fig 1 Flow of participants in the trial 

 
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Our study is a parallel group design of a control and intervention group. The anticipated journey of 
participants through the trial is illustrated in Fig 1. Both study groups will receive a preoperative 
paravertebral block injection after general anaesthesia and before surgery, and a local anaesthetic 
paravertebral block injection and infusion at the end of surgery. Only the intervention group will be 
administered a local anaesthetic preoperative paravertebral block injection; the control group will be 
administered a saline placebo preoperative paravertebral injection. 
 
The paravertebral infusion will be managed as per standard Trust protocol. The data collection will 
continue with follow-up after the participant is discharged from hospital for 6 months after the date 
of surgery. It is conventional to follow-up patients for at least 6 months for pain and pain related 
outcomes when studying the incidence of chronic pain. Adverse events will be collected throughout 
the study period. 
 
 

 
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Table 3 Study assessments 
Assessments 
Pre-
operative 
baseline 
Intra-
operative 
Post-operative 
Hours 
1   6  24  48 
Follow-up  
Hospital 
Dis-
charge 
 
 
3 
months 
 
 
6 
months 
Pain NRS at 
rest 
X 
… 
X   X   X    X 
 
… 
X 
X 
Pain NRS on 
coughing 
X 
… 
 X   X   X    X 
… 
X 
X 
Opioid 
requirement 
X 
X 
X   X   X    X 
… 
X 
X 
Mobilisation 
X 
 
… 
…   …   X   X    
… 
… 
… 
EORTC- QLQ- 
C30 
X 
… 
…  …  …   … 
… 
X 
X 
Respiratory 
and in-hospital 
complications  
X 
… 
X 
X 
… 
… 
DN4 
X 
… 
…  …  …  … 
… 
X 
X 
 
8. Subject Selection 
 
This single-centre study will be conducted at Guy’s Hospital, a large tertiary thoracic centre for 
London, Sussex, Kent and Berkshire. In 2015, 459 lung cancer resection operations were 
performed; 8% of all lung cancer resections in England (42).  
The source of subjects are adults presenting for elective primary lung cancer surgery, by video-
assisted thoracoscopy (VAT) for a single lobectomy. We chose to study only those participants 
who would be chosen by standard surgical criteria as suitable for VAT or key-hole surgery, and 
not to include open thoracotomy patients (a much bigger surgical incision and trauma), because 
pain outcomes are likely to be influenced by the surgical incision. A VAT procedure is commonly 
practised at our centre, with the intention of improving postoperative recovery in lung cancer 

 
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patients. It is the procedure of choice over an open thoracotomy. 
Our unit performed 350 VAT lung cancer resections in 2016. We estimate that 50% (175) will be 
eligible from our study criteria, and agreement to recruitment to be 60% (105). We envisage that 
recruitment will take at least 12 months with a conservative estimate of 18 months, with final 
six-month follow-up at 24 months.  
8.1 Subject Inclusion Criteria 
 
Inclusion Criteria 
• 
Elective radical primary lung cancer VATS surgery for single lobectomy  
• 
ASA I-III 
• 
Age ≥18 
 
8.2  Subject exclusion criteria (with justification if necessary – for example consider contra-
indications to trial treatments, incompatible concurrent treatments, recent involvement in 
other research 
Exclusion Criteria 
• 
Planned open thoracotomy, wedge resection, bilobectomy, pneumonectomy, chest wall 
resection or total pleurectomy 
• 
Local anaesthetic or opioid allergy 
• 
Coagulation disorders 
• 
Inability to comply with study questionnaire completion, and non-English speakers 
• 
Pre-existing pain in chest area or pre-existing pain conditions 
• 
Local infection/tumour at proposed PVB site 
• 
Previous lung surgery 
• 
Planned surgery within 3 months of the primary lung resection 
 
Criteria for discontinuation/withdrawal or modifying allocated treatment: 
• 
Participant request to withdraw from the study. 
• 
Intraoperative identification of infection/tumour in paravertebral space 
 
 
The exclusion of pre-existing pain in the chest area pre-existing conditions is consistent with the 2016 
IMMPACT research design recommendations for chronic pain trials. 
 
9. Study Procedures 
9.1 Subject Recruitment 
Eligible patients will be identified in the catchment outpatient clinics 4-6 weeks before surgery by 
the direct care team. The participant information sheet (PIS) will be introduced in the standard 
surgical booklet given by the surgeon (see appendix), further supported by a web resource link. 
Participation will be completely voluntary, and the participants will not be paid. 

 
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At the preoperative assessment clinic 2-3 weeks before surgery, a face-to-face discussion with the 
research nurse will support the PIS; the opportunity to ask any questions and contact a member of 
the research team will be given. The subject will therefore have this period until their admission to 
decide to take part. At the discussion, those patients that lack capacity to comply with questionnaire 
completion will be excluded from the trial. 
Sufficient time will be given to discuss and ask any questions before taking consent. If the patient 
consents to participate in the study, written informed consent will be obtained, by a member of the 
research team prior to or on the day of surgery. If the patient decides to enter the trial, they will be 
asked to sign two original copies of the consent form; a research team member will countersign the 
form. The patient will retain one original copy of the signed consent form, and the second original 
copy will be photocopied. The photocopy will be kept in the patient medical records, and the original 
will be kept in the Investigator site file. A letter will be sent to the patient’s GP to inform them about 
the study (see appendix). 
9.2 Screening Procedures 
Patients will be identified by standard surgical criteria, by the surgeons, for elective lung cancer 
resection of a single lobe by VAT, at the outpatient clinics.  
The research team will use the inclusion and exclusion criteria to determine the eligible patients, and 
entered into the screening log. The research nurse will be authorized to complete this task. 
 
9.3 Randomisation Procedures 
Participants will be randomised on the day of surgery to the ‘pre-PVB LA’ or ‘pre-PVB saline’ arm, by 
a study investigator, with a 1:1 randomisation ratio using ‘Castor EDC’ online software. Each subject 
will receive a unique randomization code in an envelope that will only be opened during the 
preparation of the pre-PVB injectate. 
 
9.4 Masking & other measures taken to avoid bias  
9.4.1 Masking 
Blinding of allocations: 
A non-blinded research nurse, will prepare the pre-PVB injectate in a standard syringe according to 
the allocation, labelled by participant number, in a theatre location concealed from the operating 
room and staff. The local anaesthetic will be taken from standard theatre pharmacy stock. ParaSOL 
is not a Medicines for Human Use Trial (non-CTiMP). 
The anaesthetist, the surgeon and theatre team, recovery staff, and the researchers performing all 
the outcome assessments will be separate and blinded to the group allocation. The intervention LA 
injectate is identical in appearance to the placebo injectate of saline (identical placebo). After the 
operation, the PVB catheter will be taped as normal before connecting the standard post-PVB LA 

 
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infusion pump, and no visible difference will be seen by the patient.  
We have elected to perform an interventional placebo intervention as opposed to a sham control to 
minimize observer bias. The main risk of pre-PVB saline insertion, pneumothorax, is insignificant to 
the chest surgery. 
On occasions where patient safety relies on it (e.g. suspected LA side effects), unblinding will be 
permissible by protocol. 
9.5 Schedule of Treatment of each Visit  
The interventions will take place at a single hospital admission for the participant and two follow-up 
episodes at 3 and 6 months (Table 3). 
Assessments 
Pre-
operative 
baseline 
Intra-
operative 
Post-operative 
Hours 
1   6  24  48 
 
Pain NRS at 
rest 
X 
… 
X   X   X    X 
 
 
Pain NRS on 
coughing 
X 
… 
 X   X   X    X 
… 
Opioid 
requirement 
X 
X 
X   X   X    X 
… 
Mobilisation 
X 
 
… 
…   …   X   X    
… 
Respiratory 
and in-hospital 
complications  
X 
… 
X 
X 
 
Preoperative assessment: 
The patient will be evaluated by a study investigator at the beginning of their hospital stay after 
routine admission procedures on the ward. 
Conduct of Anaesthesia 

 
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Patients will be anaesthetised by experienced consultant thoracic anaesthetists who regularly 
perform PVB, trained by supervised practice, practical workshops, and adherence to the Trust PVB 
guideline. 
For all patients, AAGBI standard monitoring and BIS monitoring will be applied at the start of 
anaesthesia. Patients will be preoxygenated and fentanyl 1 μg kg-1, propofol target-controlled 
infusion targeting a BIS value of 40-60, and rocuronium 0.5 mg kg-1 will be administered.  
After general anaesthesia, participants will be placed in the lateral operative position and the pre-
PVB injection will be performed by the anaesthetist. Using a transversal in-plane technique, 10ml of 
pre-PVB study injectate will be administered each at T3/4 and T7/8 levels using a 18G Sonoplex 
100mm Tuohy needle (39).  
Standard perioperative analgesia is shown in Table 2.  
Table 2 Standardised analgesia  
 
Analgesia according to hospital protocol 
Intraoperative 
Paracetamol 1 g IV 
Fentanyl IV, unrestricted supplementation allowed 
Surgically-placed post-PVB LA and infusion: 30ml 0.25% 
levobupivacaine and 0.125% plain bupivacaine 3-10 ml/h 
Recovery analgesia 
Morphine IV boluses 2mg every 5 min  
Morphine IV PCA 1mg bolus, 5 min lockout 
PVB infusion continued 
Postoperative 
analgesia 
Morphine IV PCA  
Paracetamol 1 g 6hrly  
Ibuprofen 400mg 8hrly if not contraindicated 
PVB infusion continued until 4h after chest drain removal 
Morphine immediate release tablets 10 mg PRN when PCA 
discontinued 
 
Conduct of surgery 
VATS will be performed via the standard surgical technique, the Copenhagen approach, which is 3-4 
surgical port incisions at T4-8, and a single 28F chest drain in the T7/8 intercostal space (43). 

 
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Surgical Post-PVB 
In both study groups, before final wound closure, the surgeon will administer a post-PVB LA injection 
using a 18G Tuohy needle, and introduce a catheter under direct  vision, followed by LA infusion 
(Table 2) (44) . We deem placement of catheters by this method to be superior to ultrasound-guided 
placement (40). Chest drains will be removed according to standard indications (no air leak, output 
<400ml/24h, no active bleeding or chylothorax), and the post-PVB will be continued until 4h 
afterwards. 
9.6 Follow Up Procedures  
Timing of study assessments are shown in Table 3. After discharge, the standard questionnaires will 
be performed by phone (supported by reminder letter/email) to minimise disruption to the patient, 
at 3 months and 6 months after surgery. 
 
 
Follow-up: 
3 months 
 
6 months 
Pain NRS at 
rest 
… 
X 
Pain NRS on 
coughing 
X 
X 
Opioid 
requirement 
X 
X 
EORTC- QLQ- 
C30 
X 
X 
DN4 
X 
X 
 
9.8 End of Study Definition 
The end of the study is marked by the final 6 month follow-up of the final participant. 
 
10. Assessment of Safety 

 
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10.1 Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, 
users or other persons 
Note 1: Local bleeding from the insertion of a paravertebral needle or 
catheter will not be classified as an adverse event. Local anatomical spread 
of the local anaesthetic will not be classified as an adverse event. 
Serious Adverse Event 
(SAE) 
Any adverse event that: 
• 
Led to death, 
• 
Led to serious deterioration in the health of the subject, that either 
resulted in  
• a life-threatening illness or injury, or 
• a permanent impairment of a body structure or a body function, 
or 
• in-patient or prolonged hospitalisation, or 
• medical or surgical intervention to prevent life-threatening illness 
or injury or permanent impairment to a body structure or a body 
function, 
Note 2: Planned hospitalisation for a pre-existing condition, or a procedure 
required by the CIP (clinical investigation plan), without serious 
deterioration in health is not considered a SAE.  
An adverse event does not include: 
• 
Medical or surgical procedures; the condition that leads to the procedure is an adverse event. 
• 
Pre-existing disease, conditions, or laboratory abnormalities present at the start of the study 
that do not worsen in frequency or intensity. 
• 
The disease being studied, lung cancer, or signs/symptoms associated with the disease unless 
more severe than expected for the subject’s condition. 
 
 
 
10.1.1 Safety Reporting requirements and timelines 
Please refer to Appendix 1 for further information with regards to Safety Reporting 
Term 
Reporter 
Reported to 
Reporting Timeline from 
awareness of the event 
Adverse Event (AE) 
Investigator 
Sponsor 
As agreed with sponsor 
Serious Adverse Event 
(SAE) 
Investigator 
Sponsor 
Immediately, no more than 24hrs 
of becoming aware of the event   

 
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10.2 Assessment of adverse events 
10.2.1 Severity and Seriousness 
Category 
Definition 
Mild 
The adverse event does not interfere with the subjects daily routine, and does 
not require intervention; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the subjects routine, or 
requires intervention, 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 
Note: A severity rating of severe does not necessarily categorise the event as an 
SAE. 
 
Seriousness as defined for an SAE in section 10.1.1.  
10.2.2 Causality 
The assessment of relationship of adverse events to the study procedure and the investigational 
device will be 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 
Yes 
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 procedure). However, the influence of other 
factors may have contributed to the event (e.g. the patient’s clinical condition, 
other concomitant events). 
No 
There is no evidence of any causal relationship. 
 
10.2.3 Expectedness 
Category 
Definition 

 
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Expected 
An adverse event that is consistent with the information about the intervention 
listed in the Investigator Brochure or clearly defined in this CIP. 
Unexpected 
An adverse event that is not consistent with the information about the 
intervention listed in the Investigator Brochure  
The reference document to be used to assess expectedness against the intervention is the IB. The CIP 
will be used as the reference document to assess disease related and/or procedural expected events.  
10.2.4 Investigator Responsibilities 
All AEs and SAEs will be recorded in the medical records and CRF following consent. 
All SAEs will need to be reported to the sponsor on a SAE form unless stated in the CIP that some 
expected SAEs will not be reported to the sponsor, with a justification as to why they will not be 
reported.   
The Chief or Principal Investigator will complete the sponsor’s serious adverse event form and the 
form will be emailed to the sponsor R&D@gstt.nhs.uk immediately (or within 24 hours but certainly 
no later than 24 hours) 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 
You may choose not to report EXPECTED SAEs to the sponsor for example if they are expected to occur 
on a regular basis and offer no further new information to your safety profile. These events must 
continue to be recorded in the source data and CRF, however you may state that you will not complete 
an SAE form and forward it to the sponsor.  
All deaths will be reported to the sponsor irrespective of whether the death is related to disease 
progression, or an unrelated event. These reports will be provided immediately (or within 24hours) 
upon notification.  
The investigator shall keep detailed records of all adverse events relating to the clinical trial which are 
reported to them by trial participants or users. The investigator shall document all relevant 
information on sponsor provided AE logs, SAE forms and DD forms.  
All SAEs, SADEs should be reported to R&D@gstt.nhs.uk  
10.3 Foreseeable Adverse Events 
 
The intervention is the administration of the paravertebral local anaesthetic block, after the patient is 
under anaesthesia. An ultrasound scan is used to aid the correct site of administration of the block, 
and is an advance to increase safety, as well to increase the success of the block. This is performed by 
an anaesthetist experienced in the technique, which is accepted practice in many of the operations at 
our centre. There are two adverse events which may be anticipated: 
1. Inadvertent spread of local anaesthetic (minor adverse event): 
- to the opposite side via epidural spread as evidenced by numbness on the opposite side of the body 

 
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- cranial spread to cause a Horner’s or Harlequin sign 
Both these adverse events do not require treatment, above the management of a routine 
paravertebral infusion, and can occur routinely with conventional postoperative paravertebral 
infusions.  
From our routine practice, these adverse events occur uncommonly. This will be recorded as an 
expected AE in the CRF, and will not be reported to the sponsor. 
 
2. Local anaesthetic toxicity from intravascular injection or absorption from paravertebral space 
This is a rare adverse event which can theoretically occur from the administered injection or the 
postoperative paravertebral infusion. There is a standard hospital protocol for treatment of suspected 
local anaesthetic toxicity which can be initiated in the event of haemodynamic instability. Our 
institution has had a long history (over two decades) of administration of paravertebral local 
anaesthetic infusions, but a case of toxicity has never been demonstrated in the thoracic surgery 
patient population. In the literature, though moderately high plasma levels of local anaesthetic have 
been demonstrated in children, symptoms and signs of toxicity have not been demonstrated. 
This event will be recorded in the CRF as a serious AE and an AE form will be completed to be 
forwarded to the sponsor. 
 
11.0 Ethics Reporting 
Reports of related and unexpected SAEs should be submitted to the Main REC within 15 days of the 
chief investigator becoming aware of the event, using the NRES template. The form should be 
completed in typescript and signed by the chief investigator. The main REC will acknowledge receipt 
of safety reports within 30 days. A copy of the SAE notification and acknowledgement receipt should 
be sent to the R&D Directorate.  
Any SAE’s that are expected and do not require reporting for this study are described above in 10.1.   
Ethics & Regulatory Approvals 
Appropriate Sponsorship will be sought from Guy’s and St Thomas’ NHS Foundation Trust and REC 
and HRA approval will be sought from XXXX  
12.0 Compliance and Withdrawal  
12.1 Subject compliance  
 
The intervention does not require active compliance from the patient, as the PVB is administered 
when the patient is under general anaesthesia. 
 

 
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12.2 Dropout / Withdrawal of Subjects  
 
Subjects will be withdrawn from the trial if there is a loss of capacity, a refusal to proceed with the 
study, if the patient is admitted to the intensive care unit and is under sedation and therefore unable 
to comply with follow-up questionnaires. 
 
In this case, the data collected will be kept, but further study data will not be collected. 
 
12.3 Protocol Compliance 
If there is a deviation from protocol it will be documented and reported to the sponsor. 
In the unlikely event of a deviation, a report to the CI should be made immediately as to how to 
proceed. The CI will discuss the case with the research team in a meeting to review the response. 
 
13 
Data 
13.1 Data to be collected 
 
 
Assessments 
Source of 
data 
(data 
form) 
Baseline 
before 
surgery 
Intra-
operative 
Post-
operative 
Hours 
1   6  24  48 
Follow-up  
Hospital 
Dis-
charge 
 
 
3 months 
 
 
6 months 
Eligibility and 
written 
informed 
consent 
Patient 
notes 
(descript-
ive) 
X 
 
 
 
 
 
Demographic 
data and  
medical 
history 
Patient 
notes 
(descript-
ive) 
X 
 
 
 
 
 
Randomisation 
Database 
(binary) 
X 
Day of 
surgery 
 
 
 
 
 

 
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Paravertebral 
insertion data 
Patient 
notes and 
procedure 
(descript-
ive) 
 
X 
 
 
 
 
Intraoperative 
data 
Patient 
notes 
(descript-
ive) 
 
X 
 
 
 
 
Pain NRS at 
rest and 
coughing 
Standard 
question-
aire 
(numeric) 
X 
… 
X   X   X    X 
 
… 
X 
X 
Opioid 
analgesic 
requirement 
Patient 
notes 
(continuo
us) 
X 
X 
X   X   X    X 
… 
X 
X 
Mobilisation 
(Time to 
standard 
distance) 
Patient 
notes 
(numeric) 
X 
 
… 
…   …   X   X    
… 
… 
… 
Respiratory 
and in-hospital 
complications  
Patient 
notes 
 
… 
X 
X 
… 
… 
Hospital length 
of stay 
Patient 
notes 
(numeric) 
 
 
 
X 
 
 
Mortality (if 
applicable) 
Patient 
notes 
(binary) 
 
 
 
X 
X 
X 
EORTC- QLQ- 
C30  
Standard 
question-
X 
… 
…  …  …   … 
… 
X 
X 

 
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aire  
(numeric) 
DN4 pain 
questionnaire 
Standard 
question-
aire 
(numeric) 
X 
… 
…  …  …  … 
… 
X 
X 
Adverse 
events (if 
applicable) 
Patient 
notes and 
procedure 
(descript-
ive) 
 
 
 
X 
X 
X 
Protocol 
deviations (if 
applicable) 
Patient 
notes and 
procedure
(descript-
ive) 
 
 
 
X 
X 
X 
 
 
 
Consent and eligibility will be evaluated by the research team. Data recording will be collected by the 
research nurses. 
 
To maximise completeness of data, the research team will review the patients at the beginning of the 
day for expected hospital location, review patients after their surgery for data completeness, 
highlighting the patients at nurse handover, and posting coloured laminates for instructions of the 
analgesia pumps. In the period after hospital discharge, patients will receive questionnaires by post 
and email, and receipt and completion followed up by a phone call. 
 
 
13.2 Data handling and record keeping 
  
The data will be stored on on-site, on protected research laptops within the research department in 
locked rooms, with limited and restricted access. The data collected will be pseudo-anonymised, 
with an enrolment number allocated to the participant's data. This allocation data will be held within 
the research department's laptop, with security as outlined in the previous question.  
14 Statistical Considerations 
The research team statistician, Dr D Wong will analyse the data. 

 
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14.1  Sample size calculation (some pilot/feasibility studies may not require 
a formal sample size calculation) 
 
Our unit performed 350 VAT lung cancer resections in 2016. We estimate that 50% (175) will be 
eligible from our study criteria, and recruitment to be 60% (105). We envisage that recruitment will 
take at least 12 months with a conservative estimate of 18 months, with final six-month follow-up at 
24 months. From local audit data, we aim to detect a difference of at least 30% in the proportion of 
patient experiencing moderate-to-severe pain of NRS ≥ 3 between the study groups at the 24h time 
point. With a power of 80% and error of 0.05, we calculate that 42 patients per group are necessary. 
To allow for incomplete data, we aim to recruit 50 patients per group. 
 
Participants will be randomised on the day of surgery to the ‘pre-PVB LA’ or ‘pre-PVB saline’ arm, by 
a study investigator, with a 1:1 randomisation ratio using 'Castor' online software. Each subject will 
receive a unique randomization code in an envelope that will only be opened during the preparation 
of the pre-PVB injectate. Authorised staff will be allocated a username and password for the 
randomisation system. Patients may only be randomised into the study by an authorised member of 
staff at the study site, as detailed on the delegation log. The research team member, who is 
responsible for randomisation (not blinded) will perform this in a separate location to the other 
research team members. Patients may only be randomised into the study once. 
14.2  Statistical analysis 
 
Demographic characteristics and other baseline characteristics (e.g. clinical measures taken at 
baseline) will be summarised by appropriate descriptive statistics according to treatment group in 
accordance to CONSORT guidelines (http://www.consort-statement.org. Patient outcomes will be 
analysed according to intention-to-treat. 
 
Primary outcome: 
The proportion of patients with clinically relevant moderate-to-severe pain (Numerical Rating Scale 
[NRS] ≥ 3) related to the surgical site at rest at 24h in treatment (pre-PVB LA) and control (pre-PVB 
saline) arms will be compared using the chi-square test for equality of two proportions 
Secondary outcomes: 
For all secondary outcomes, the distributions of outcome variables will be assessed for normality. To 
compare outcomes between treatment and control arms, we will use Student’s t test to for normally-
distributed continuous outcome variables, the Mann-Whitney test for non-normally distributed 
continuous and ordinal outcome variables, and chi-square tests for binary outcome variables. 
 
There is no plan for interim analysis of the data, and the data collected up to the point of any 
withdrawals will be included in the final analysis. 
14.3  Interim analysis and data monitoring 
14.3.1 Stopping / discontinuation rules and breaking of randomisation code 
 
Completion of the trial is completed after the follow-up period of the 100th participant has been 
completed. There will be no interim analysis. 

 
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The randomisation code will be broken only in the perioperative phase of the study, in the event of a 
serious adverse event (suspected local anaesthetic toxicity with haemodynamic instability) when the 
patient must be treated. All other conditions are identical after the operative theatre phase of the 
study. 
14.3.2 Monitoring, quality control and assurance 
 
This is a single centre trial, and data quality will be checked at the end of the trial.  Good clinical 
practice and research governance guidelines will be adhered to at all times. 
 
15 Ethical Considerations 
The study has Sponsor approval and has been submitted to xxx REC and HRA and received 
appropriate approvals – REC reference x19/XX/xxxx.  Consent will be gained from patients prior to 
their participation. Any patient facing information will be approved by REC. 
Because standardised questionnaires will be used to measure outcomes, non-English speakers will 
be not be included in the study. 
 
 
Patient and public involvement 
Our research question addresses a main concern of patients undergoing surgery for cancer: 
postoperative pain and recovery after surgery. 
1. Cancer Patient Panel Group (South East London Cancer Research Panel) on the 17th July 
2015 
In the design stages of our study, following our first audit, we presented and discussed our 
proposal and received written feedback: 
Efficacy of preoperative paravertebral block analgesia in elective thoracic surgery for lung 
cancer resection 
 
Biomedical Research Centre 
Guy’s & St Thomas’ NHS Foundation Trust and King’s College London  
 
 
Feedback to researcher template 
 
 
1) Using your own words where possible what do you think this research project is 
about? 
 
 

 
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To compare the outcomes for patients in terms of pain control and recovery times of 
having both a pre-operative and post-operative block analgesic injection. 
 
 
 
2) This research project looks like a good idea to me: 
 
 
Strongly 
disagree 
 
 
 
Disagree 
 
 
Neutral 
 
 
 
 
Agree 
 
 
 
Strongly 
agree 
 
 
x 
 
Comments: 
It is a commonly used procedure in other surgeries and appears to work.   There is 
need to check for currently unknown risks or side effects but it would seem that the 
sooner it is standard procedure the better. 
 
3) If I was eligible I would be willing to participate: 
 
 
Strongly 
disagree 
 
 
 
Disagree 
 
 
Neutral 
 
 
 
 
Agree 
 
 
 
Strongly 
agree 
 
 
x 
 
Comments: 
 
 
4) The target group would think this research project was a good idea: 
 
 
Strongly 
disagree 
 
 
 
Disagree 
 
 
Neutral 
 
 
 
 
Agree 
 
 
 
Strongly 
agree 
 
 
x 
 
 
Comments: 
 
 
 
 
 
 
5) The proposal is sensitive to the experiences and feelings of the target group:  
 
 
Strongly 
disagree 
 
 
 
Disagree 
 
 
Neutral 
 
 
 
 
Agree 
 
 
 
Strongly 
disagree 
 
 
x 
 

 
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Comments: 
 
6) There shouldn’t be a problem with recruitment, or the commitment of 
participants:  
 
 
Strongly 
disagree 
 
 
 
Disagree 
 
 
Neutral 
 
 
 
 
Agree 
 
 
 
Strongly 
agree 
 
x 
 
Comments: 
The advantages seem so obvious, I imagine some participants might not want to be 
in the control group.   Though it was stated that should the benefits become 
overwhelming obvious, the trial would be stopped and the procedure changed, this 
would be too late for those in the control group who had already had their surgery. 
 
7) It’s written in a way that would allow most people to understand the words and 
ideas: 
 
 
Strongly 
disagree 
 
 
 
Disagree 
 
 
Neutral 
 
 
 
Agree 
 
 
 
Strongly 
agree 
 
x 
 
 
Comments: 
 
 
 
 
8) It’s the right length: 
 
 
Strongly 
disagree 
 
 
 
 
Disagree 
 
 
Neutral 
 
 
 
 
 
Agree 
 
 
 
Strongly 
agree 
 
x 
 
Comment: 
 
9) Which aspects of the proposal work well? 
 
Comment: 
I think it is a clearly explained proposal.   Couple of suggestions overleaf. 
 
10) What might make it better? 
 

 
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Comment: 
1. It might be helpful for further clarification to add a sentence to the last para 
on page 1.   “This study is to assess whether patients undergoing lung cancer 
resection would benefit for the preoperative paravertebral block treatment” 
2. Under ‘side effects’ on page 2, are these risks that might apply for patients 
having the routine postoperative block – or are they increased if both blocks 
are used? 
3. As suggested in the discussion, clarify the meaning of the first sentence under 
‘Risks’ 
 
11) Any other questions or concerns that haven’t already been addressed above? 
 
Comment: 
 
 
Thank you for your presentation and for answering our questions so fully. 
Good luck with your application and with your work.   You sound like a strong and 
united team.  
 
 
 
The patient group gave us detailed feedback based on their previous hospital experiences, 
and confirmed that this was an important topic to study. They also gave us advice on how to 
improve the patient understanding of the research process, and specify that all patients 
would receive the standard surgical treatment without additional effort.  
We amended the participant leaflet on this advice, and we devised a summary to make 
information more easily understood, and help with recruitment.  
 
2. SELCRP meeting on 26th August 2016  
 
We updated the panel by presenting our changes, and on our application for a research 
grant (RFPB) on the 27th May 2016. We received further feedback on our patient 
information leaflet from the meeting organized by Ambi Williams, Research Manager at the 
King’s Health Partners Cancer Centre:  
 
Two members commented that the patient information summary “was fine and no further 
amendments” were necessary. 
 
One member commented: 
• 
This document is generally extremely clear and the study is well described. 
• 
There are just a couple of areas I think could be explained or amended: 
In the title the surgery is termed “elective” and, seeing this in conjunction with lung 
cancer where there seems very little choice, I realise I don’t know what it means and 
would like a definition.    

 
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• 
In the paragraph “What will happen to me if I take part?” the phrase in line 2 
“………..whether you have PVB or not.” is contradicted by the next phrase “Both 
groups will receive the PVB, after being put to sleep;” 
• 
Is there any additional risk from having an additional PVB? 
• 
“If I were a lung cancer patient in the position of needing this surgery I believe I 
would be happy to be part of the trial.” 
 
We were successful in the first round, but not the second, and the feedback was reviewed 
with the PPI group and Jacintha McGahon from the Clinical Research Network. The feedback 
was that the study was worthwhile and of patient value.  
3. Theatres and Perioperative Medicine (TAP) Research Group 
A research group was set up in our directorate in 2017/2018 which enabled peer review of 
our study with constructive feedback on design and methodology. 
The trial will be presented at the TAP PPI group on 28th May 2019. 
 
16 Financing and Insurance 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If any patients 
are harmed whilst taking part in a clinical trial as a result of negligence on the part of a member of the 
study team this liability cover would apply. 
Non-negligent harm is not covered by the NHS indemnity scheme. Guy’s and St Thomas’ NHS Trust, 
therefore, cannot agree in advance to pay compensation in these circumstances. In exceptional 
circumstances an ex-gratia payment may be offered. However, legislation now requires any GMC 
registered medical professional to hold a valid indemnity cover. 
 
 
17 Reporting and dissemination  
We will present the findings at a national or international conference meeting and aim to publish the 
findings in a peer reviewed journal. 
We have an option with the consent form to be ticked should the participant wish to be informed of 
the results of the study. It will be made clear that this may be up to 3 years following the 
commencement of the study. 
We will inform participants of the key points relating to the primary and secondary outcomes when 
the results become available, accompanied with an explanation in lay terms as to the meaning and 
implications of these results. 
18 Appendices 

 
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Tables, Figures, References 
Appendices 
Including (where relevant): 
Patient information sheet 
Patient consent form 
Data collection forms and validation information 
Ethics form 
 
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11.  
SCTS Thoracic Surgery Audit Group. SCTS (Society for Cardiothoracic Surgery) Thoracic 
Registry Brief Report 2011-12 to 2013-14.  
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NIAA Priorities [Internet]. Available from: https://www.niaa.org.uk/JLA-NIAA-Priority-
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Bayman EO, Brennan TJ. Incidence and severity of chronic pain at 3 and 6 months 
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Vogt  a, Stieger DS, Theurillat C, Curatolo M. Single-injection thoracic paravertebral 
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[Internet]. 2005;95(6):816–21. Available from: 
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Davies RG, Myles PS, Graham JM. A comparison of the analgesic efficacy and side-
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Joshi GP, Bonnet F, Shah R, Wilkinson RC, Camu F, Fischer B, et al. A systematic 
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Katz J, Clarke H, Seltzer Z. Preventive analgesia: Quo vadimus? Vol. 113, Anesthesia 
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Bong CL, Samuel M, Ng JM, Ip-Yam C. Effects of preemptive epidural analgesia on 
post-thoracotomy pain. Journal of Cardiothoracic and Vascular Anesthesia. 2005.  
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Andreae MH, Andreae DA. Regional anaesthesia to prevent chronic pain after 
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Kaya FN, Turker G, Mogol EB, Bayraktar S. Thoracic paravertebral block for video-
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Useful reading/websites 
 
Integrated Research Application System (IRAS) 
https://www.myresearchproject.org.uk/  
 
Health Research Authority (HRA) 
www.hra.nhs.uk  
 
HRA Guidance for Patient Information Sheet and Informed Consent  
http://www.hra.nhs.uk/research-community/before-you-apply/participant-information-sheets-and-
informed-consent/  

 
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CONSORT statement  
A set of recommendations for improving the quality of reports of parallel group randomised trials 
http://www.consort-statement.org/  
 
ICH Harmonised Tripartite Guidelines for Good Clinical Practice (1996) 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guidel
ine.pdf  
 
Martin Bland et al, Statistical guide for research grant applications 
http://www-users.york.ac.uk/~mb55/guide/guide.htm  
Includes detailed information and definitions of many aspects required for a research protocol as well 
as information about randomisation software and services 
 
Martin Bland, Directory of randomisation software and services 
http://www-users.york.ac.uk/~mb55/guide/randsery.htm  
 
Declaration of Helsinki  
(http://www.wma.net/en/30publications/10policies/b3/index.html) 
 
 

 
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Appendix 1 – Information with regards to Safety Reporting in Non-CTIMP Research 
 
Who 
When 
How 
To Whom 
SAE 
Chief 
Investigator 
-Report to Sponsor 
within 24 hours of 
learning of the event 
 
-Report to the MREC 
within 15 days of 
learning of the event 
 
SAE Report form for Non-
CTIMPs, available from NRES 
website. 
Sponsor and MREC 
Urgent Safety 
Measures  
Chief 
Investigator  
Contact the Sponsor and 
MREC Immediately 
 
Within 3 days  
By phone 
 
 
 
 
Substantial amendment 
form giving notice in writing 
setting out the reasons for 
the urgent safety measures 
and the plan for future 
action. 
Main REC and 
Sponsor  
 
 
 
Main REC with a 
copy also sent to 
the sponsor. The 
MREC will 
acknowledge this 
within 30 days of 
receipt.  
Progress 
Reports  
Chief 
Investigator  
Annually (starting 12 
months after the date of 
favourable opinion) 
Annual Progress Report 
Form (non-CTIMPs) available 
from the NRES website 
Main REC 
Declaration of 
the conclusion 
or early 
termination of 
the study 
Chief 
Investigator  
Within 90 days 
(conclusion) 
 
Within 15 days (early 
termination) 
 
The end of study should 
be defined in the protocol 
End of Study Declaration 
form available from the 
NRES website 
Main REC with a 
copy to be sent to 
the sponsor  
Summary of 
final Report  
Chief 
Investigator 
Within one year of 
conclusion of the 
Research 
No Standard Format 
However, the following 
Information should be 
included:- 
Where the study has met its 
objectives, the main findings 
and arrangements for 
publication or dissemination 
including feedback to 
participants 
Main REC with a 
copy to be sent to 
the sponsor