Conditions: Patients Requiring Diagnostic Gastroscopy With Sedation
Keywords: gastroscopy diagnostic entonox
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 62
Healthy volunteers: no

Brief summary:
This study aims to determine whether Entonox (gas and air) is at least as good as intravenous midazolam in providing analgesia and sedation during gastroscopy. Entonox is used as an adjunct in lower gastrointestinal procedures but is not routinely used in gastroscopy, and there is only one similar published study to date, which was performed in children. The main advantage of Entonox over midazolam is the quick recovery time following withdrawal of the agent, which enables patients to return to independent normal life. The investigators would like to be able to offer Entonox to patients as an option for sedation during gastroscopy, this study is being conducted to determine if it is a safe and feasible option.

Detailed description:

Arms:
arm 1: midazolam sedation combined with pharyngeal anaesthesia

Participants randomized to receive midazolam will have an intravenous cannula sited and, following the administration of xylocaine throat spray as above, will be put into the left lateral position. They will then be given up to 5mg midazolam as appropriate to achieve conscious sedation as for standard protocol in endoscopy. arm 2: Entonox combined with pharyngeal anaesthesia.

Pharyngeal anaesthesia, given as 8-16 sprays of xylocaine to the pharynx; 3 minutes will be given to allow the pharynx to become anaesthetized.

Participants randomized to receive Entonox will be given the 50:50 nitrous oxide:oxygen mix via a mouthpiece with a demand valve system, once in position for the procedure. Inhalations will be given for 3-5 minutes (or until the participant feels adequately sedated) measured using a stopwatch. Oxygen will be given at 2 litres per minute via nasal cannulae during the procedure, (standard care for sedated procedures). The endoscopist will then proceed to intubate the cricopharynx and perform the procedure in the standard manner.

Interventions: intervention 1: Entonox intervention 2: Midazolam
Intervention descriptions: intervention 1: Entonox arm intervention 2: up to 5mg midazolam as appropriate

Protocol document:
Prot_SAP_000.pdf: 
Version: 6 Date:  17th May 2019 
 
1 
 
PROTOCOL 
Version: 6 
Date: 17th May 2019 
Sponsor: University Hospitals Dorset NHS Foundation Trust 
 
 
Study Title: 
A single-centre, randomised controlled study of Entonox versus 
midazolam sedation in gastroscopy. 
 
Chief Investigator: Dr. Simon McLaughlin 
 
 
EudraCT:  
2012-002242-20 
 
REC Number:  
12/LO/0886 
 
IRAS ID:  
 
  101675 
 
 
 
 
 
 
 


Version: 6 Date:  17th May 2019 
 
2 
 
CONTENTS  
 
 
 
 
 
Page number 
Team contact   
 
 
 
 
 
 
3 
 
Figure 1: Flow Diagram 
 
 
 
 
 
4 
Summary  
 
 
 
 
 
 
 
5 
Introduction                                                                                      5  
Study aims 
 
 
 
 
 
 
 
6 
Methods: 
 
recruitment/population /sample size 
 
 
6 & 7 
 
inclusion and exclusion criteria 
 
 
 
7 
 
randomisation process  
 
 
 
 
8 
 
informed written consent  
 
 
 
8 
 
study procedure  
 
 
 
 
9 
 
post procedure care 
 
 
 
 
9 
Study drug supply 
 
storage and accountability 
 
 
 
11 
 
dispensing and returns 
 
 
 
 
11 & 12 
Concurrent medication / treatment   
 
 
 
12 
Duration/end of the study  
 
 
 
 
 
12 
Assessment of efficacy  
 
 
 
 
 
13 
Adverse Events 
 
definitions  
 
 
 
 
 
13 
 
common/uncommon/rare  
 
 
 
13 
 
reporting procedure & serious adverse events  
15 & 16 
Participant withdrawal deviations / violations  
 
 
16 
Data recording 
 
 
 
 
 
 
data collection  
 
 
 
 
17 
 
primary & secondary outcome measures 
 
17 & 18 
Source data / documents / confidentiality 
 
 
 
18 
Statistical considerations  
 
 
 
 
 
18 
Ethical considerations  
 
 
 
 
 
19 
Quality control / quality assurance   
 
 
 
19 
End of study  
 
 
 
 
 
 
19 
Publication policy  
 
 
 
 
 
 
20 
Sponsor 
 
 
 
 
 
 
 
20 
Funding 
 
 
 
 
 
 
 
20 
References 
 
 
 
 
 
 
 
21 


Version: 6 Date:  17th May 2019 
 
3 
 
TEAM CONTACTS 
Chief Investigator 
Dr. Simon D McLaughlin, Consultant Gastroenterologist, Royal Bournemouth Hospital 
Co-Investigators 
Dr Charles Gordon (Consultant Gastroenterologist), Dr Abigail Banfield (AMU Consultant), 
Michelle Douel (Nurse Endoscopist), Dr Balint Eross, Charlie Clisby (Nurse Endoscopist), 
Dr. Ghassan El Sayed, Dr. Simon Whiteoak, Dr. Mike Furze 
 
Contact 
 
Dr SD McLaughlin 
Department of Gastroenterology 
The Royal Bournemouth Hospital 
Castle Lane East 
Bournemouth 
BH7 7DW 
Telephone: 01202 704961 
Email: simon.mclaughlin@rbch.nhs.uk 
 
Clinical Queries 
Clinical queries should be directed to Dr Simon McLaughlin in the first instance who will 
direct the query to the appropriate person. 
 
SAE Reporting 
Safety Reporting 
ResearchOffice@rbch.nhs.uk 
01202 962378 
 
 
 
 
 


Version: 6 Date:  17th May 2019 
 
4 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: STUDY PROCESS FLOW DIAGRAM 
72 hours post procedure 
Patients will be contacted via telephone and the discomfort 
score will be repeated  
Invitation letter sent to patient. Follow up phone call 
to see if patients are interested and to explain the 
study. PIS sent to patients interested in the study.  
Patient admitted for procedure and if willing to 
participate, signs informed consent form 
Inclusion/exclusion criteria confirmed 
Relevant study documents completed 
Pharyngeal anaesthesia 
Given as 8-16 sprays of xylocaine to the pharynx 
Randomise 
Relevant study documents completed 
Group 1 
Arm - Entonox 
Inhaled for 3-5 mins 
Group 2 
Arm - Midazolam 
Given over 1-2 mins 

Elective diagnostic gastroscopy 

Adverse event recording 

Post procedural care & advice 

Adverse events followed up  

Patient discharged 

Study information sent to GP if consent given 
60-90 minutes for 
gastroscopy, adverse 
event recording & post 
procedural care & advice 
30 minutes or longer as 
patient requires before 
discharge 
1-2 weeks to decide 
whether to participate, 
discussions with study team 
as required 
3-5 minutes as per 
standard practice 
20-30 minutes 


Version: 6 Date:  17th May 2019 
 
5 
 
SUMMARY 
This study aims to determine whether Entonox (gas and air) is at least as good as 
intravenous midazolam in providing analgesia and sedation during gastroscopy. Entonox is 
used as an adjunct in lower gastrointestinal procedures but is not routinely used in 
gastroscopy, and there is only one similar published study to date, which was performed in 
children. The main advantage of Entonox over midazolam is the quick recovery time 
following withdrawal of the agent, which enables patients to return to independent normal 
life. We would like to be able to offer Entonox to patients as an option for sedation during 
gastroscopy, this study is being conducted to determine if it is a safe and feasible option. 
 
INTRODUCTION 
Gastroscopy is an uncomfortable but usually a short diagnostic procedure.  At present the 
options for patients are to have the procedure with intravenous sedation (with or without 
local-pharyngeal anaesthesia) or local-pharyngeal anaesthesia without any sedation. 
General anaesthetic may be offered in exceptional circumstances. The aims are for 
patients to have a pain-free procedure with minimal side effects, no complications and a 
choice of options to suit individual preference. Conscious sedation using benzodiazepines 
reduces anxiety and promotes amnesia but has some hangover effects, which, according 
to national guidelines, mean patients are deemed unsafe to drive or work for 24 hours after 
the procedure and require both a responsible adult to accompany them home and to stay 
with them for 12 hours1. Local anaesthesia of the pharynx has no anxiolytic effect, is 
acceptable to some patients and has the advantage of lasting for around 1 hour with no 
psychomotor effects. To have an option that combines the advantages of both these 
routinely used modalities would be ideal for many patients. 
Entonox is a 50:50 mix of nitrous oxide and oxygen and has long been used in a variety of 
settings as a short-term analgesic with sedative and amnesic properties. It has an induction 
time of 2-5 minutes with a duration of effect of 3-5 minutes after withdrawal2,3.  Side effects 
are minimal but may include nausea, vomiting, headache, dizziness and paraesthesia2. It is 
without long-lasting psychomotor effects that typically affect the ability to drive3,4,5. Entonox 
is already used in many endoscopy units during lower gastrointestinal endoscopy, often as 
an adjunct to intravenous sedation and analgesia and has been found to be beneficial5,6,7,8. 
The advantages of Entonox over traditional sedation with midazolam are that patients are 
deemed fit to drive 30 minutes after their procedure (British Society of Gastroenterologists 
guidance 2011). In addition, they do not require a responsible adult to accompany them 
home and can return to work the same day. This has obvious benefits especially for those 
who are self-employed.  The benefit to the NHS as a result of this reduced recovery time 
may have a positive impact on departmental throughput.  


Version: 6 Date:  17th May 2019 
 
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In a Cochrane review (2011) of nitrous oxide with conventional intravenous analgesia 
during colonoscopy, nitrous oxide is comparable in efficacy and safer, with a shorter 
recovery period9. Its use in flexible bronchoscopy has also been studied and, in 
combination with local anaesthesia, found to be a good alternative to general 
anaesthesia10,11.  
To the best of our knowledge the use of Entonox during gastroscopy has been examined in 
only one published study to date in paediatric patients. Michaud et al (1998) studied 37 
participants, 30 of whom underwent gastroscopy using Entonox either before or both before 
and during the procedure. The authors found that Entonox provided safe and effective 
analgesia without heavy sedation and allowed adequate patient relaxation and efficient 
endoscopy with quick recovery times of 3-5 minutes2. However this study did not compare 
Entonox to conventional methods of sedation and analgesia.  
To the best of our knowledge there are no published data on the use of Entonox for 
gastroscopy in adults. 
 
AIMS 
Primary Aim 
To establish whether Entonox and pharyngeal anaesthesia could provide levels of patient 
comfort equal to that of midazolam sedation and pharyngeal anaesthesia when performing 
gastroscopy. 
 
Secondary Aim 
To establish whether completion rates of gastroscopy using Entonox and pharyngeal 
anaesthesia are equal to those performed with midazolam when performing gastroscopy.  
 
METHODS 
Population 
Adult participants attending for diagnostic gastroscopy who are suitable for sedation will be 
approached to enroll in this study. We aim to recruit 200 participants.  
 
 


Version: 6 Date:  17th May 2019 
 
7 
 
Inclusion criteria 
 Male/female aged 18 years or over 
 Confirmed clinical requirement to undergo diagnostic gastroscopy 
 Suitable for sedation 
 Able to provide informed consent 
 
Exclusion criteria 
 History of severe chronic respiratory or significant cardiac disease  
 Requirement for longer procedure eg Barrett’s surveillance 
 Previous known adverse reaction to Entonox or Midazolam 
 Patients who are pregnant or breastfeeding 
 Entonox use in the previous 4 days 
 
Any of the following known contra-indications to Entonox (Entonox should not be used 
in any condition where gas is entrapped in a part of the body where its expansion may 
be dangerous, such as air lodged in an artery or artificial traumatic or spontaneous 
pneumothorax), Specifically: 
o Pneumothorax in the past 3 months 
o Air embolism in the past 2 months 
o Sub aqua diving activity within the last 2 weeks 
o Air encephalography in the past 2 weeks 
o Severe bullous emphysema 
o Myringoplasty in the past 2 weeks 
o Gross abdominal distension eg. Pseudobstruction. 
o Severe injuries to the face and jaw in the past 2 months   
o Severe head injuries in the past 2 months   
o Eye surgery requiring injections of gas to be used in the past 2 months  
 
Recruitment 
Patients will be recruited in a number of ways. The method of recruitment will depend on 
the capacity of the research and endoscopy staff. 


Version: 6 Date:  17th May 2019 
 
8 
 
Patients who are awaiting a diagnostic gastroscopy will be sent a letter of invitation asking 
them if they want to take part in the study. The following week, after the invitation letter has 
been sent, the research nurse will telephone the patient and an opportunity will be given to 
the patient to discuss the study in more detail and see if they may be interested in taking 
part. From a practical point of view, at times it may be easier if we group all the research 
participants onto one list. If we plan to do this then patients will be approached prior to them 
receiving a date for their procedure.  
We will also display posters in the waiting room and research staff may approach patients 
in the waiting area. If patients express an interest in the study on the day of their procedure 
we will ensure that they have had sufficient time to read through the information sheet and 
consent form, that the study has been explained to them and that they have had the 
opportunity to ask any questions before signing the consent form.  
 
Randomisation 
Randomisation will be achieved by opening the next numbered sealed envelope stored in 
the study site file in the research office. They are a sequence of opaque envelopes 
containing a group number (either group 1 or group 2) and associated treatment allocation 
(either midazolam sedation combined with pharyngeal anaesthesia or Entonox combined 
with pharyngeal anaesthesia).  
 
Informed Consent 
Patients will be consented on the day that they come in for their procedure. A research 
nurse or GCP trained endoscopist/endoscopy nurse trained in consent who has been 
delegated the task, will explain the procedure to them and go through the information sheet 
and consent form. They will ask the patient if they have any questions and ensure that any 
questions are answered to the patient’s satisfaction prior to signing the informed consent 
form. The patient and then the health care professional gaining consent will sign and date 
the consent form. A copy of the signed consent form will be given to the patient to retain. In 
addition to signing a study consent form, the patient will also sign the hospital endoscopy 
consent form which is the normal procedure run by the endoscopy department.  
 
Eligibility  
Eligibility for the study will be determined by any suitably trained health care professional 
deemed competent by the CI and who has been delegated this task. This could be an 


Version: 6 Date:  17th May 2019 
 
9 
 
endoscopy or research nurse experienced in the use of Entonox for endoscopy, medical or 
nursing endoscopist experienced in the use of Entonox for endoscopy, who holds a current 
GCP certificate. Clinical Trial Assistants cannot assess eligibility for this study.  
 
Study Procedures  
All participants will arrive having fasted for 4 hours before the procedure in order to 
visualize the upper gastrointestinal tract as per the endoscopy unit standard protocol. The 
standard process of admission to the department will take place, including clinical 
observations of pulse rate, blood pressure and oxygen saturation. The consent forms will 
be completed as described above and the patient will then be randomised to either the 
Entonox or Midazolam arm (standard of care).  
Once the participant is in the endoscopy room they will then receive pharyngeal 
anaesthesia, given as 8-16 sprays of xylocaine to the pharynx; 3 minutes will be given to 
allow the pharynx to become anaesthetized.   
Participants randomized to receive Entonox will be given the 50:50 nitrous oxide:oxygen 
mix via a mouthpiece with a demand valve system, once in position for the procedure. 
Inhalations will be given for 3-5 minutes (or until the participant feels adequately sedated) 
measured using a stopwatch. Oxygen will be given at 2 litres per minute via nasal cannulae 
during the procedure, (standard care for sedated procedures). The endoscopist will then 
proceed to intubate the cricopharynx and perform the procedure in the standard manner. 
Participants randomized to receive midazolam will have an intravenous cannula sited and, 
following the administration of xylocaine throat spray as above, will be put into the left 
lateral position. They will then be given up to 5mg midazolam as appropriate to achieve 
conscious sedation as for standard protocol in endoscopy. 
All participants will be monitored throughout the procedure in both study groups, with 
continuous oxygen saturation and pulse rate monitored via finger probe, as per standard 
departmental protocol. 
 
Post- procedure care 
Participants who have received Entonox will be recovered in the seated recovery area or in 
the recovery area of the Endoscopy Unit depending on the time taken to meet discharge 
criteria of full responsiveness, stable vital signs and ability to walk unaided. The Endoscopy 
nursing staff are fully trained in safe discharge of patients. We anticipate that this will only 
require a maximum of 10 minutes, based on our previous experience with its use in lower 


Version: 6 Date:  17th May 2019 
 
10 
 
GI procedures and product literature. Participants are allowed to drive 30 minutes after 
discharge, according to British Society of Gastroenterology guidance. Post-procedure 
safety and contact information will be given on discharge. 
Participants who have received midazolam will be recovered in the recovery area and then 
discharged from the department by the endoscopy nursing staff with standard information 
regarding safe time to eat and drink following the procedure.   
The comfort score as assessed by the nurse, will be completed during the routine 
procedure write up. One attending nurse will use the modified Global Rating Scale scoring 
system (the system used by all endoscopy departments to comply with JAG recommended 
data recording) to assess the patient’s perceived comfort during the procedure. This 
comfort score will be recorded on the endoscopy departments HICCS database and on the 
study proforma and the scoring system is shown below. 
Modified Global Rating Scale Comfort score 
0 – Not Specified/entered. 
1 – Extreme discomfort frequently during procedure. 
2 – Significant discomfort, experienced several times during procedure. 
3 – More than two episodes of discomfort, adequately tolerated. 
4 –One or two episodes of mild discomfort, well tolerated.  
5 – None – resting comfortably throughout. 
 
Following the procedure, when the patient is in the recovery area, all patients will be asked 
to score their discomfort/pain on a scale of 1 to 5 similar to the Global Rating Scale system. 
In addition they will be asked to score their comfort on a 100mm visual analogue scale, 
detailed below. 
Figure 2. Visual analogue scale patients complete after the procedure. 
If there are any concerns about a participant’s fitness for discharge the endoscopist, or 
suitable other clinician, will be asked to review the participant and formulate a plan, as is 
standard practice in the Endoscopy department.  


Version: 6 Date:  17th May 2019 
 
11 
 
All patients will be given contact information for members of the research team and asked 
to contact them immediately if they experience any problems, even if they appear to be 
unrelated to the procedure. 
The research team will review the discharge summary/nursing and medical records from 
endoscopy team to identify any adverse events that could have occurred following 
administration of midazolam or Entonox. 
After 72 hours post procedure the patient will be contacted by the research team by 
telephone to repeat their comfort level score and check if they have experience any 
adverse events from either medication. 
 
STUDY DRUG SUPPLY 
Storage 
Cylinders of Entonox are used and stored in the Endoscopy Unit on a continuous basis, in 
conditions recommended by the manufacturers. A cylinder clearly labeled for ‘clinical trial 
use only’ will be stored in the medical gasses unit at Royal Bournemouth Hospital as per 
the Medical Gases Operational Policy.  
Accountability 
The endoscopy staff and research team will be accountable for the correct storage of 
Entonox cylinders and for recording the drug batch numbers for the Entonox supply which 
is delivered to each patient.  
The supply of midazolam will come from the endoscopy department stock drugs, which 
pharmacy will supply in accordance with standard practice.  
The midazolam and Entonox are both used routinely in the endoscopy department and are 
prescribed within the HICCS system and recorded as administered in the HICCS system 
and in the endoscopy care plan. In order to emulate clinical practice this same process will 
be followed.  
Dispensing 
The Entonox will be dispensed in the endoscopy room where the procedure takes place. 
The batch number of the Entonox cylinder used will be recorded for each participant. As 
Entonox is self-administered the nurse or doctor who has observed the patient 
administering the Entonox will document the time that the Entonox was used for in the 
research notes.  


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The midazolam will be dispensed in the endoscopy room with the endoscopy team present. 
The batch number of the midazolam will be recorded for each participant and the amount of 
midazolam given will be recorded as per standard practice.  
Returns 
Any excess Entonox will be returned to the supplying company, BoC Healthcare and 
recorded on a study specific returns log. Should a problem be found with the Entonox 
supply, the batch will be withdrawn from use and returned to BoC Healthcare. Such an 
event will be documented as an adverse event and the Sponsor will be informed along with 
the ethics committee and regulatory authority if required. 
There will be no midazolam returns as ward stock is being used. 
 
CONCURRENT MEDICATION/TREATMENT 
All participants enrolling in this study will receive pharyngeal throat spray (unless they 
decline).  This and the midazolam will be supplied via the Royal Bournemouth Hospital 
Pharmacy department and managed by the Trust’s Pharmacy department according to 
Trust standard operating procedures for medication management and standard endoscopy 
practice.  
Other medications normally taken by the participant will be recorded on admission as per 
standard protocol on individual case report forms. 
Cautions: 
Entonox has an additive effect on centrally acting drug such as opiates and 
benzodiazepines.  
 
STUDY DURATION 
Recruitment:  
0-8 years 
Data analysis:  
3  months  
Total duration: 
8 years 
End of study:  
Last patient, last visit. 
 
 


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ASSESSMENT OF EFFICACY 
All data collected will be analysed for any evidence that Entonox is not an efficacious form 
of sedation in gastroscopy.  Data will be reviewed by the investigators to ensure participant 
safety is a priority. 
Participants will be asked about any adverse effects experienced. These will be 
documented and reported in accordance with regulatory requirements and Trust policy.   
The sponsor will be informed of all adverse events. 
 
ADVERSE EVENTS 
Definitions  
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study 
subject.   
 
Patients will be closely monitored for adverse events from the point of joining the study 
(consent) until they leave the endoscopy department. Between this point and 72hrs post 
procedure only serious adverse events will be identified and recorded by the research team 
contacting the patient at 72 hours. 
 
As the patient is receiving Midazolam or Entonox for sedation and pain relief then the 
following events are expected and therefore will not be recorded as adverse events: 
 
 Mild sedation 
 Euphoria 
 Dizziness 
 Headache 
 Dry mouth 
 Tiredness 
 Nausea 
 Vomiting 
 Paraesthesia 
 
Over sedation requiring reversal agents ie flumazenil for midazolam should be recorded as 
an AE. 
 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or 
affect that: 
 
 
Results in death 


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14 
 
 
Is life-threatening – refers to an event in which the subject 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 
 
Requires 
hospitalisation, 
or 
prolongation 
of 
existing 
inpatients’ 
hospitalisation 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death 
or hospitalisation but may jeopardise the subject or may require intervention to prevent one 
of the other outcomes listed in the definition above, should also be considered serious. 
Common side effects of Entonox are: 
Euphoria, nausea, headache, dizziness, dry mouth, tiredness and paraesthesia.  
Uncommon side effects of Entonox are: 
Usually due to frequent or prolonged usage and include raised intercranial pressure, bowel 
distension, middle ear damage, rupture of eardrums, respiratory depression, inactivation of 
Vitamin 
B12/folate 
leading 
to 
neurological 
toxicity 
and 
megaloblastic 
anaemia/agranulocytosis. 
Rare side effects of Entonox are: 
High dose oxygen may increase risks of amiodarone induced adult respiratory distress 
syndrome, bleomycin pulmonary toxicity, paraquat pulmonary toxicity. 
Entonox will also diffuse rapidly into air-containing body cavities, which can result in a 
temporary increase in either pressure and/or volume depending upon distensibility. This 
can result in significant morbidity and even death.  
If any serious uncommon or rare adverse events occur the study will be suspended until 
the event is fully assessed by the Chief Investigator, Sponsor, Medicines and Healthcare 
Regulatory Agency (MHRA) and Research Ethics Committee (REC) as per the reporting 
procedure below. 
Causality 
Investigators will be required to record their opinion as to whether the SAE as defined 
above was related to the study medication. It is accepted that a causality assessment is not 
always available at the time of the initial report (see reporting procedure below), however, 
this opinion should be provided as soon as possible to ensure regulatory reporting timelines 
are met. 


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15 
 
Expectedness 
The Sponsor team will assess the SAE for expectedness. A limited number of specifically 
delegated reviewers on behalf of the Sponsor will assess the expectedness of reported 
events. When assessing expectedness, reviewers should refer to the following reference 
safety information documentation: 
Study drug 
Document used as Reference Safety 
Information 
Relevant section 
Entonox 
Current Summary of Product Characteristics (held 
by BOC) 
4.8 
Midazolam 
Current Summary of Product Characteristics (held 
by ADVANZ Pharma) 
4.8 
 
Reporting procedure 
All adverse events should be reported.  Depending on the nature of the event the reporting 
procedures below should be followed.  Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.  All project team members 
will be GCP trained.  
All such events, whether expected or not, should be recorded in the CRF, a member of the 
research team will: 
 
 review all documentation (e.g. hospital notes, laboratory and diagnostic reports) 
relevant to the event 
 record the event and relevant comments in the subject’s medical notes/endoscopy 
report on HICCS (or source data where this is not the medical notes) 
 record the event in detail on a case record form to allow analysis at a later stage. 
The Chief Investigator will keep the Sponsor, REC and Regulatory Authority informed of 
any relevant significant findings. At the conclusion of the study all adverse event/reactions, 
recorded during the study will be reviewed and subsequent conclusions included in the final 
study report. 
If it becomes apparent during monitoring of the study that there are multiple minor adverse 
events relating to the study drug then a discussion with the study team, sponsor and ethics 
committee will be mandatory and the study may have to be stopped prematurely. 
 
 


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16 
 
Serious Adverse Events (SAE) 
Immediately (within a maximum of 24 hours) after a member of the research team 
becoming aware of a serious adverse event the sponsor must be notified, by emailing the 
completed 
SAE/SUSAR 
reporting 
form 
(provided 
by 
the 
Sponsor) 
to 
Research.Office@rbch.nhs.uk. The initial report will include as much information as is available 
at the time.  
After the initial report the Investigator will actively follow up the subject. The Investigator (or 
delegated person) will provide follow-up information when new information is available or 
as requested by the Sponsor team. The Sponsor team, in collaboration with the Chief 
Investigator, are responsible for informing the regulatory bodies as required. SAE’s will be 
followed up until the SAE has resolved or a decision for no further follow up has been taken 
by the Sponsor team. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be reported to the 
MHRA in line with The Medicines for Human Use (Clinical Trials) Regulations 2004. 
The reporting period for SAE’s for this study is 72 hours from dose administration. This 
means that any events that occur within 72 hours of study drug administration, will be 
reporting according to the Sponsor’s standard operating procedures.  
 
PATIENT WITHDRAWAL/VIOLATIONS 
Participants will be advised that they may withdraw their consent to participate in the study 
at any time.  
If it is not possible for the patient to tolerate the procedure with the allocated treatment, 
then alternative sedation, as per standard of care, will be given to the patient by the 
Endoscopist.  If this occurs, it will be recorded as an incomplete procedure and the reason 
documented. All other data points will continue to be collected including the post procedure 
follow up. 
If the patient wishes to withdraw consent from the study then it will be discussed with the 
patient if they are happy for the data to continue to be used. The patient’s wishes will be 
followed and the conversation will be clearly documented in the patient’s medical/research 
notes and in a file note.  
 
 
 


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17 
 
DATA RECORDING 
Data Collection  
Data will be collected on the proforma and entered onto the electronic case report form 
(eCRF). The following will be recorded.  
 Time of the administration of entonox or midazolam  
 Time the procedure was completed  
 Time from procedure end to discharge from the unit  
 Total amount of midazolam given and time it was given. 
 Questions about the patients experience, comfort 
scale and discomfort 
questionnaire.  
 If the procedure could not be completed and the reasons for this 
 Any adverse events experienced 
 Contact patient over the phone within 72 hours post procedure to repeat their 
comfort level score. 
 Concomitant medications related to adverse events 
 
OUTCOME MEASURES 
Primary outcome measure 
The primary endpoint of percentage of patients with a score of 4 or 5 on the 5-point comfort 
scale, as measured by the patient, will be compared between the midazolam and entonox 
groups, per protocol. 
The results will be analysed per-protocol; (defined as the data from any patient who 
received study medication).  
Secondary outcome measures 
 Percentage of patients with a score of 4 or 5 on the 5-point comfort scale, as 
measured by the endoscopy nurse, will be compared between the midazolam and 
Entonox groups, per protocol. 
 Percentage of procedures completed, per protocol. 


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 Comparison of procedure time, defined as start time to end time in the per protocol 
population, between the two groups. 
 Comparison of procedure start time to discharge time in the per protocol population 
between the two groups. 
 Number of patients with adverse events. 
 Comparison of VAS scores between the two groups (per protocol). 
 The number of people who moved from a score of 4/5 on the modified GRS to <3 at 
72 hours post-procedure. 
 
SOURCE DATA/DOCUMENTS/CONFIDENTIALITY 
The participants’ electronic and paper medical records will be used for the purposes of 
recording source data for the procedure. All research related data will be collected through 
a proforma and the standard gastroscopy care plan. The required data will then be 
transcribed into the electronic Case Report Form. Paper copies of the study data will also 
be kept in a file and transferred onto a secure NHS electronic patient record (EVOLVE). 
The Data Protection Act (2018), Caldicott Principles and GDPR (2016) will be adhered to at 
all times. 
 
STATISTICAL CONSIDERATIONS 
This sample size will provide 100 participants allocated to receive Entonox plus anaesthetic 
throat spray, and 100 participants to receive midazolam plus anaesthetic throat spray. This 
will provide the power to detect a 6% difference between the two forms of sedation using 
the Comfort Score Scale. If recruitment is more difficult than anticipated, then 150 patients 
will enable a power detection of 7%. 
This sample size was decided upon based on a published study comparing entonox with 
midazolam and pethidine in colonoscopy which had a sample of 137 patients, and 
acceptable comfort score in 97% of patients who receive midazolam and throat spray in our 
department. The sample size was calculated as a non-inferiority study with power to detect 
a 6% difference between the two methods of sedation. 
The primary endpoint of percentage of patients with a score of 4 or 5 on the 5-point comfort 
scale will be compared between the midazolam and entonox groups using the chi-squared 
test or the Fisher's exact test if the numbers in some categories are small. A 1-sided 95% 
confidence interval for the difference in percentage with scores 4 or 5 between the 
treatment groups will be calculated. The visual analogue scale will be summarised using 
means and standard deviations and a 95% confidence interval for the difference between 


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the treatment groups calculated. The t-test will be used to compare mean scores on the 
visual analogue scale between the treatment groups. If the distributions of the visual 
analogue scale are skewed, medians and interquartile ranges will be used and the 
treatment groups compared using the Mann-Whitney test. 
 
ETHICAL CONSIDERATIONS 
The ethical risks in this study are minimal. The use of pharyngeal anaesthesia and 
midazolam is as for routine care and although Entonox is widely used in various settings 
including as an adjunct in lower GI endoscopy, it may not meet the expectations of 
participants in terms of sedation. Major side effects are not reported.  
The Chief Investigator has obtained approvals from the Research Ethics Committee and 
NHS R&D department. The study will be conducted in accordance with the 
recommendations for physicians involved in research on human subjects adopted by the 
18th World Medical Assembly, Helsinki 1964 and later revisions. 
 
SAFETY MEASURES  
Standards of safety and quality will be monitored using the modified Global Rating Scale as 
for all endoscopic procedures.  The outcome of each participant in this study will be 
reviewed by the CI/co-investigator within 2 working days of recruitment to identify any 
safety concerns. Any complications which arise during or after the procedure will be 
managed according to the clinical judgement of the endoscopist and hospital policy, e.g. if 
a patient’s oxygen saturations drop to less than 92%, then the procedure may be 
abandoned as clinically appropriate. They will be recorded as adverse events and related 
concomitant medications recorded appropriately. 
 
QUALITY ASSURANCE/QUALITY CONTROL 
This study will adhere to the principles outlined in the UK Policy Framework for Health and 
Social Care Research (2017). It will be conducted in compliance with the protocol, the Data 
Protection Act and other regulatory requirements as appropriate.  
The study will be monitored and audited in accordance with ICH GCP requirements by the 
Sponsor.  Compliance with the protocol by investigators and participants will be scrutinized 
and reported. The study will be monitored by the Sponsor at regular intervals throughout. 
 


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END OF STUDY 
At the end of the study the Chief Investigator will submit an end of study report to the 
Sponsor, MHRA and REC. The study will be archived in accordance with Trust policy.  
 
PUBLICATION POLICY 
The Chief Investigator will retain ownership of all data arising from this trial. The intention is 
to publish this research in a specialist peer reviewed scientific journal on completion of the 
study. The results may also be presented at scientific meetings and/or used for other 
academic research purposes. The Investigators will be involved in reviewing drafts of the 
manuscripts, abstracts, press releases and any other publications arising from the study.  
They will retain final editorial control. 
All data collected will be anonymised. 
 
SPONSOR 
University Hospitals Dorset NHS Foundation Trust is the Sponsor for this research study. 
For further information regarding the Sponsorship of this study please contact the R&D 
Office at: 
Rm501, 5th Floor 
Royal London House 
Christchurch Road 
Bournemouth 
BH1 3LT 
01202 962376 
 
FUNDING 
The study will be funded by University Hospitals Dorset NHS Foundation Trust.  The study 
will be managed and conducted by the study team and the Sponsor. 
 
 
 
 


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