Alpha 2 Agonists for Sedation to Produce Better Outcomes From Critical Illness (A2B Trial): A Randomised, Parallel-group, Allocation Concealed, Controlled, Open, Phase 3 Pragmatic Clinical and Cost- Effectiveness Trial With Internal Pilot
Phase: PHASE3
Conditions: Critical Illness
Sponsor: University of Edinburgh

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Study Protocol 
Alpha 2 agonists for sedation to produce better outcomes from 
critical illness (A2B Trial): A randomised, parallel-group, allocation 
concealed, controlled, open, phase 3 pragmatic clinical and cost- 
effectiveness trial with internal pilot  
A2B Trial 
 
 
 
Co-sponsors 
The University of Edinburgh & Lothian Health Board 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Funder 
NIHR Health Technology Assessment 
Funding Reference Number 
HTA 16/93/01 
Chief Investigator 
Professor Timothy Walsh 
Sponsor Reference 
AC18022 
EudraCT Number 
2018-001650-98 
REC Number 
18/SS/0085 
ClinicalTrials.gov 
NCT03653832 
Version Number and Date 
Version7.0, 25th April 2023 
This study is funded by the National Institute for Health Research (NIHR) Health Technology 
Assessment (HTA) Programme (16/93/01). The views expressed are those of the author(s) and not 
necessarily of the NIHR or the Department of Health and Social Care.  

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KEY TRIAL CONTACTS  ( * Protocol Authors) 
 
Chief Investigator 
 
Lead Co-Sponsor Representative 
Name: 
Professor Timothy Walsh* 
 
Name: 
Dr Fiach O’Mahony 
Address: 
Department of Anaesthesia, Critical 
Care & Pain Medicine  
Room S8208, 2nd Floor  
Royal Infirmary of Edinburgh  
51 Little France Crescent  
Edinburgh  
EH16 4SA 
 
Address: 
Research & Governance  
University of Edinburgh 
Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Telephone: +44 (0) 131 242 6395 
 
Telephone: +44 (0)131 242 9418 
Fax: 
 
 
Fax: 
+44 (0) 131 242 9447 
Email: 
timothy.walsh@ed.ac.uk 
 
Email: 
fiach.o’mahony@ed.ac.uk 
Trial Manager  
 
Trial Statistician 
Name: 
Ms Alix Macdonald 
 
Name: 
Professor Chris Weir* 
Address: 
Edinburgh Clinical Trials Unit 
Usher Institute 
The University of Edinburgh 
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh 
EH16 4UX 
 
Address: 
Edinburgh Clinical Trials Unit 
Usher Institute 
The University of Edinburgh 
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh 
EH16 4UX 
Telephone: +44  
(0)131 651 9928 
 
Telephone: +44 (0)131 651 9957 
Fax: 
 
 
Fax: 
 
Email: 
alix.macdonald@ed.ac.uk 
 
Email: 
christopher.weir@ed.ac.uk 
 
 
 
      
 
 

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PROTOCOL APPROVAL SIGNATURE PAGE 
Study Protocol 
Alpha 2 agonists for sedation to produce better outcomes from 
critical illness (A2B Trial): A randomised, parallel-group, allocation 
concealed, controlled, open, phase 3 pragmatic clinical and cost- 
effectiveness trial with internal pilot 
A2B Trial 
EudraCT: 2018-001650-98   
The undersigned accept the content of this protocol in accordance with the appropriate 
regulations and agree to adhere to it throughout the execution of the study. 
 
Professor Timothy Walsh 
 
 
 
Chief Investigator 
 
Signature 
 
Date 
Professor Chris Weir 
 
  
Trial Statistician 
Signature 
 
Date 
Dr Fiach O’Mahony 
 
 
 
Lead Co-Sponsor Representative 
Signature 
 
Date 
 
 
For multi-site trials, the Principal Investigator must sign below to document that the protocol 
has been read and understood.  
 
 
Name 
 
 
 
 
 
Principal Investigator 
Signature 
 
Site 
 
Date 
 
 
 
 
 
Tim Walsh (Jun 16, 2023 12:27 GMT+1)
Jun 16, 2023
Christopher J Weir (Jun 16, 2023 13:27 GMT+1)
Christopher J Weir
Jun 16, 2023
Fiach O'Mahony (Jun 16, 2023 13:28 GMT+1)
Fiach O'Mahony
Jun 16, 2023

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CONTENTS 1. INTRODUCTION ...................................................................... 14 
1.1 
BACKGROUND ............................................................................... 14 
1.1.1 
Relationship between sedation practice and patient outcomes ..... 14 
1.1.2 
Implications for healthcare costs ................................................... 14 
1.1.3 
Delirium ......................................................................................... 14 
1.1.4 
Current sedation practice in the UK ............................................... 15 
1.1.5 
Current evidence relating to dexmedetomidine and clonidine for ICU 
sedation ........................................................................................ 15 
1.2 
RATIONALE FOR STUDY ............................................................... 17 
2. 
STUDY OBJECTIVES .............................................................................. 18 
2.1 
OBJECTIVES .................................................................................. 18 
2.1.1 
Primary Objective .......................................................................... 18 
2.1.2 
Secondary Objectives ................................................................... 19 
2.2 
ENDPOINTS .................................................................................... 19 
2.2.1 
Primary Endpoint .......................................................................... 19 
2.2.2 
Secondary Endpoints .................................................................... 20 
3. 
STUDY DESIGN ....................................................................................... 21 
3.1 
HYPOTHESIS .................................................................................. 21 
3.2 
TYPE OF STUDY ............................................................................ 22 
3.3 
‘PICO’ QUESTION ........................................................................... 22 
3.4 
DESIGN AND ANALYTIC/CONCEPTUAL FRAMEWORK ............... 22 
3.5 
PRE-PLANNED SUB-GROUP ANALYSIS ....................................... 22 
3.6 
BLINDING ........................................................................................ 23 
3.7 
STUDY DETAIL ............................................................................... 23 
3.7.1 
Internal pilot and overall recruitment strategy ................................ 23 
3.7.2 
Centres ......................................................................................... 24 
4. 
STUDY POPULATION ............................................................................. 24 
4.1 
TARGET POPULATION .................................................................. 24 
4.2 
NUMBERS OF PARTICIPANTS ...................................................... 24 
4.3 
INCLUSION CRITERIA .................................................................... 24 
4.4 
EXCLUSION CRITERIA ................................................................... 25 
4.5 
CO-ENROLMENT ............................................................................ 25 
5. 
PARTICIPANT SELECTION AND ENROLMENT .................................... 26 
5.1 
IDENTIFYING PARTICIPANTS ....................................................... 26 
5.2 
CONSENTING PARTICIPANTS ...................................................... 26 
5.3 
SCREENING FOR ELIGIBILITY ...................................................... 29 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS .................... 29 
5.5 
RANDOMISATION ........................................................................... 29 
5.5.1 
Randomisation Procedures ........................................................... 29 
5.5.2 
Treatment Allocation ..................................................................... 29 
5.6 
INTERVENTION GROUPS .............................................................. 29 
5.6.1 
Dexmedetomidine group ............................................................... 30 
5.6.2 
Clonidine group ............................................................................. 30 
5.7 
USUAL CARE GROUP .................................................................... 30 
5.8 
DURATION OF INTERVENTION ..................................................... 30 
5.9 
MANAGEMENT DURING INTERVENTION PERIOD ...................... 31 
5.9.1 
Titration to sedation targets ........................................................... 31 

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5.9.2 
Management of participants with cardiovascular instability ............ 31 
5.9.4 Patients in whom deep sedation is requested by the clinical team ... 32 
5.9.5 Duration of effects following reduction or discontinuation of study 
drug .............................................................................................. 33 
5.9.6 Weaning from mechanical ventilation ............................................... 33 
5.10 
WITHDRAWAL OF STUDY PARTICIPANTS ................................... 33 
5.11 
Stopping Criteria .............................................................................. 34 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT .......................................... 34 
6.1 
ALPHA-2 AGONIST DRUGS ........................................................... 34 
6.1.1 
Dexmedetomidine ......................................................................... 35 
6.1.2 
Clonidine ....................................................................................... 35 
6.2 
PROPOFOL (USUAL CARE) ........................................................... 35 
6.3 
STUDY DRUG IDENTIFICATION .................................................... 36 
6.3.1 
Study Drug Identification ............................................................... 36 
6.3.2 
Study Drug Manufacturer .............................................................. 36 
6.3.3 
Marketing Authorisation Holder ..................................................... 36 
6.3.4 
Labelling and Packaging ............................................................... 37 
6.3.5 
Storage ......................................................................................... 37 
6.4 
DOSING REGIMEN ......................................................................... 37 
6.5 
PARTICIPANT COMPLIANCE ......................................................... 38 
6.6 
OVERDOSE .................................................................................... 38 
6.7 
OTHER MEDICATIONS ................................................................... 38 
6.7.1 
Prohibited Medications .................................................................. 38 
6.7.2 
Medications used with caution and clinical judgement ................... 38 
7. 
STUDY ASSESSMENTS AND DATA COLLECTION .............................. 39 
7.1 
SCREENING DATA ......................................................................... 39 
7.2 
BASELINE DATA ............................................................................. 39 
7.3 
DAILY DATA COLLECTION DURING ICU STAY ............................ 39 
7.3.1 
Data recorded by bedside clinical nurse ........................................ 39 
7.3.2 
Data collected from a visiting relative/partner/friend ...................... 39 
7.3.3 
Data collected by research staff .................................................... 39 
7.4 
ICU DISCHARGE DATA .................................................................. 40 
7.5 
HOSPITAL DISCHARGE DATA ....................................................... 40 
7.6 
POST HOSPITAL DISCHARGE ASSESSMENTS ........................... 40 
7.6.1 
30 days post-randomisation assessments (up to 45 days) ............ 40 
7.6.2 
90 days post-randomisation assessments (up to 105 days) .......... 40 
7.6.3 
180 days post-randomisation assessments (up to 195 days) ........ 40 
7.6.4 
Survival status ............................................................................... 40 
7.7 
DATA MANAGEMENT ..................................................................... 41 
7.7.1 
Personal Data ............................................................................... 41 
7.7.2 
Transfer of Data ............................................................................ 41 
7.7.3 
Data Processor ............................................................................. 42 
7.7.4 
Data Controller .............................................................................. 42 
7.8 
SOURCE DATA DOCUMENTATION ............................................... 42 
7.9 
CASE REPORT FORMS ................................................................. 42 
7.10 
TRIAL DATABASE ........................................................................... 42 
8. 
STATISTICS AND DATA ANALYSIS ...................................................... 42 
8.1 
SAMPLE SIZE CALCULATION ........................................................ 42 
8.1.1 
Modelling primary outcome ........................................................... 42 
8.1.2 
Loss to follow-up ........................................................................... 44 

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8.1.3 
Final sample size .......................................................................... 45 
8.1.4 
Mortality ........................................................................................ 45 
8.2 
PROPOSED ANALYSES ................................................................. 45 
8.2.1 
Estimand ....................................................................................... 45 
8.2.2 
Statistical analysis ......................................................................... 46 
8.2.3 
Analysis populations ..................................................................... 47 
8.2.4 Exploratory analyses........................................................................ 47 
9. 
PROCESS EVALUATION ........................................................................ 47 
9.1 
AIMS AND OBJECTIVES ................................................................ 47 
9.2 
DATA COLLECTION METHODS ..................................................... 48 
9.3 
DATA ANALYSIS ............................................................................. 48 
10. 
HEALTH ECONOMIC EVALUATION ...................................................... 48 
10.1 
OVERVIEW ..................................................................................... 48 
10.2 
WITHIN-TRIAL ANALYSIS .............................................................. 49 
10.3 
LIFETIME ANALYSIS ...................................................................... 50 
11. 
MECHANISTIC SUB-STUDY ................................................................... 50 
12. 
PHARMACOVIGILANCE ......................................................................... 51 
12.1 
DEFINITIONS .................................................................................. 51 
12.2 
IDENTIFYING AEs AND SAEs ........................................................ 52 
12.3 
RECORDING AEs AND SAEs ......................................................... 52 
12.3.1 AEs and SAEs that do not require recording in the CRF ............... 52 
12.3.2 Pre-existing Medical Conditions .................................................... 53 
12.3.3 Worsening of the Underlying Condition during the Trial ................. 53 
12.4 
ASSESSMENT OF AEs AND SAEs ................................................. 53 
12.4.1 Assessment of Seriousness .......................................................... 53 
12.4.2 Assessment of Causality ............................................................... 53 
12.4.3 Assessment of Expectedness ....................................................... 53 
12.4.4 Assessment of Severity ................................................................. 54 
12.5 
REPORTING OF SAEs/SARs/SUSARs ........................................... 54 
12.6 
REGULATORY REPORTING REQUIREMENTS ............................. 54 
12.7 
FOLLOW UP PROCEDURES .......................................................... 55 
12.8 
PREGNANCY .................................................................................. 55 
13. 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS............... 55 
13.1 
TRIAL MANAGEMENT GROUP ...................................................... 55 
13.2 
TRIAL STEERING COMMITTEE ..................................................... 55 
13.3 
DATA MONITORING COMMITTEE ................................................. 55 
13.4 
INSPECTION OF RECORDS .......................................................... 55 
13.5 
RISK ASSESSMENT ....................................................................... 56 
13.6 
STUDY MONITORING AND AUDIT ................................................. 56 
14. 
GOOD CLINICAL PRACTICE .................................................................. 56 
14.1 
ETHICAL CONDUCT ....................................................................... 56 
14.2 
REGULATORY COMPLIANCE ........................................................ 56 
14.3 
INVESTIGATOR RESPONSIBILITIES ............................................. 56 
14.3.1 Study Site Staff ............................................................................. 56 
14.3.2 Data Recording ............................................................................. 56 
14.3.3 Investigator Documentation ........................................................... 57 
14.3.4 GCP Training ................................................................................ 57 
14.3.5 Confidentiality ............................................................................... 57 

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14.3.6 Data Protection ............................................................................. 57 
15. 
STUDY CONDUCT RESPONSIBILITIES ................................................. 57 
15.1 
PROTOCOL AMENDMENTS ........................................................... 57 
15.2 
PROTOCOL NON COMPLIANCE.................................................... 58 
15.2.1 Definitions ..................................................................................... 58 
15.2.2 Protocol Waivers ........................................................................... 58 
15.2.3 Management of Deviations and Violations .................................... 58 
15.3 
URGENT SAFETY MEASURES ...................................................... 58 
15.4 
SERIOUS BREACH REQUIREMENTS ........................................... 58 
15.5 
STUDY RECORD RETENTION ....................................................... 59 
15.6 
END OF STUDY .............................................................................. 59 
15.7 
CONTINUATION OF DRUG FOLLOWING THE END OF STUDY ... 59 
15.8 
INSURANCE AND INDEMNITY ....................................................... 59 
16. 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ...... 60 
16.1 
AUTHORSHIP POLICY ................................................................... 60 
16.2 
PUBLICATION ................................................................................. 60 
16.3 
DATA SHARING .............................................................................. 60 
16.4 
PEER REVIEW ................................................................................ 61 
17. 
REFERENCES ......................................................................................... 62 
18. 
APPENDIX 1: DRUG REGIMENs ............................................................ 67 
18.1 
Clonidine Drug Regimen .................................................................. 67 
18.2 
Dexmedetomidine Drug regimen ...................................................... 68 
19. 
APPENDIX 2: GROUP SEDATION FLOWCHARTS ................................ 69 
19.1 CLONIDINE Flowchart ......................................................................... 70 
19.2 Dexmedetomidine Flowchart ............................................................... 72 
19.3 
USUAL CARE (PROPOFOL) flowchart ............................................ 74 
20. 
APPENDIX 3: CONSENT PROCESS IN THE A2B TRIAL ....................... 76 
 
 
 

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LIST OF ABBREVIATIONS 
 
ACCORD 
Academic and Clinical Central Office for Research & Development - 
Joint office for The University of Edinburgh and Lothian Health Board 
AE 
Adverse Event 
APACHE II 
Acute Physiology and Chronic Health Evaluation 
AR 
Adverse Reaction 
CAM-ICU 
Confusion Agitation Method for delirium in ICU 
CHI 
Community Health Index 
CI 
Chief Investigator 
CONSORT 
Consolidated Standards of Reporting Trials 
COS 
Core Outcomes dataset 
CPAP 
Continuous positive airway pressure 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
ECTU 
Edinburgh Clinical Trials Unit 
EQ-5D-5L 
Euroqual Tool 
EudraCT 
European Clinical Trials Database 
FCI 
Functional Comorbidity Index 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HADS 
Hospital Anxiety and Depression Scale 
HR 
Hazard Ratio 
HRQoL 
Health-related quality of life 
HTA 
Health Technology Assessment Agency 

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IB 
Investigator Brochure 
ICE-Q 
Intensive Care Experience Questionnaire 
ICER 
Incremental cost-effectiveness ratio 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive Care Unit 
IES-R 
Impact of Events Scale (Revised) 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised Controlled Trials Number 
LFT 
Liver Function Tests 
MAR 
Missing At Random 
MCID 
Minimally Clinically Important Difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRC  
Medical Research Council 
MV 
Mechanical Ventilation 
PI 
Principal Investigator 
PRE-DELERIC 
Prediction of Delirium in ICU patients 
NIHR 
National Institute of Healthcare Research 
NIMP 
Non-Investigational Medicinal Product 
NIV 
Non-invasive Mechanical ventilation 
NMB 
Net monetary benefit 
OR 
Odds Ratio 
PE 
Process Evaluation 
PerLR 
Personal legal Representative 
PIS 
Patient Information Sheet 
PPI 
Patient and Public Involvement 
ProLR 
Professional Legal Representative 

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PSS 
Personal Social Services 
QA 
Quality Assurance 
QALY 
Quality-adjusted Life Year 
R&D 
Research And Development 
RASS 
Richmond Agitation Sedation Scale 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
RR 
Risk Ratio 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SmPC/IB 
Summary of Product Characteristics 
SOC 
Systems Organ Class 
SOFA 
Sequential Organ Failure Assessment Score 
SOP 
Standard Operating Procedure 
SQAT 
Sedation Quality Assessment Tool 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TMoCA 
Montreal Cognitive Assessment Tool (Telephone version) 
TSC 
Trial Steering Committee 
VFD 
Ventilation Free Days 

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TRIAL SUMMARY 
 
Trial Title 
Alpha 2 agonists for sedation to produce better outcomes from critical 
illness (A2B Trial): A randomised, parallel-group, allocation concealed, 
controlled, open, phase 3 pragmatic clinical and cost- effectiveness trial 
with internal pilot 
Study Acronym 
A2B Trial 
Clinical Phase 
Phase 3 
Trial Design 
A randomised, parallel-group, allocation concealed, controlled, open, phase 
3 pragmatic clinical and cost- effectiveness trial with internal pilot. Patients 
will be randomised via a web-based system to receive sedation using 
dexmedetomidine or clonidine or to continue on the ‘usual care’ control arm 
in a 1:1:1 ratio. 
Trial Participants 
Adult ICU patients within 48 hours of starting mechanical ventilation (MV), 
expected to require at least 24 hours further MV at randomisation. 
Exclusions include patients with primary brain injury; post-cardiac arrest; 
status epilepticus; and peripheral nervous system disease. 
Planned Number of Participants 
1437 
Planned Number of Sites 
Approximately 40-50 Intensive Care Units 
Countries Anticipated to be 
Involved in Trial 
UK only 
Treatment Duration 
Variable 
Follow up Duration 
6 months with follow up truncated to 1 month from October 2023 
Total Planned Trial Duration 
58 months (recruitment period) 
Primary Objective 
The primary outcome is time to successful extubation (in hours post-
randomisation) using an internationally agreed definition.  
Secondary Objectives 
Secondary outcomes in ICU comprise: delirium, time to optimum sedation, 
average sedation depth, mortality, overall sedation quality, ability to 
communicate with staff, ICU length of stay, pre-defined drug related adverse 
events.  
Secondary outcomes during 6 month follow-up comprise: mortality, patients’ 
recalled experience of ICU stay, anxiety and depression, post-traumatic 
stress, cognitive function, health-related quality of life (HRQoL). 

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Primary Endpoint 
 
For the purpose of the trial, a successful first extubation from mechanical 
ventilation (MV) will be defined as follows: 
 
a) For patients with an Endotracheal tube: 
time of successful extubation will be the time of the first extubation that 
is followed by 48 hours of spontaneous breathing without mechanical 
support (i.e. the start time of the 48 hours of spontaneous breathing)  
b) For patients with a tracheostomy: 
time of successful extubation will be the start time of the patient’s first 
period of 48 hours of spontaneous breathing, where spontaneous 
breathing is defined as receiving support not exceeding 5 cmH2O 
PEEP/CPAP with ≤ 5 cmH2O pressure support above PEEP 
c) For patients who are receiving non-Invasive mechanical ventilation 
(NIV): 
time of successful extubation will be the start time of the patient’s first 
period of 48 hours of spontaneous breathing, where spontaneous 
breathing is defined as receiving support not exceeding 5 cmH2O 
CPAP via mask/hood (NB NIV patients receiving any pressure 
supported breaths will not be considered to be spontaneously 
breathing unassisted) 
NB: The use of high flow nasal oxygen will not be counted as mechanical 
ventilation, so patients on nasal flow oxygen alone will be considered to be 
spontaneously breathing unassisted.   
 
Secondary Endpoints 
 
1) Mortality  
2) Length of ICU stay 
3) Sedation and analgesia quality (RASS) 
4)   Sedation and analgesia quality (SQAT) 
5)   Time to first optimum sedation 
6)   Delirium prior to successful extubation 
7)   Drug-related adverse events 
8)   Health related Quality of Life 
9)   Patient’s ability to communicate pain and ability to cooperate with care 
10)  Patient experience of ICU care 
11)  Relative/Partner/Friend assessment of comfort and communication 
12)  Anxiety and depression 
13)  Post-traumatic stress 
14) Cognitive function 
 
IMP(s) 
Alpha-2 agonists sedation agents 
1) Clonidine 
2) Dexmedetomidine 
3) Propofol 
IMP Route of Administration 
IV Infusion 
NIMP(s) 
N/A 

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Lay Summary of Trial 
Many patients in intensive care (ICU) need help to breathe on a breathing 
machine and need painkillers and sedatives to keep them comfortable and 
pain free. However, keeping patients too deeply sedated can make their 
ICU stay longer, can cause ICU confusion (delirium), and afterwards may 
cause distressing memories. Ideally, we want to keep patients less sedated, 
but it is difficult to get the balance of sedation and comfort right.  
 
For sedation, most ICUs use a drug called 'propofol' that is good at 
reducing anxiety and making people sleepy, but is not a painkiller, so 
additional painkillers are needed. There are two other drugs used less often 
called 'alpha-2 agonists' that have both sedative and pain-killing actions, 
which may make it easier for patients to be more awake and comfortable on 
the ventilator. The two drugs are called clonidine and dexmedetomidine.  
 
We want to know whether starting an alpha2-agonist drug early in ICU, and 
using this instead of propofol as much as possible,  can help keep patients 
more lightly sedated but still comfortable, and whether patients spend less 
time on the ventilator with these drugs. We also want to know how safe they 
are and if they can improve important outcomes during ICU stay (like 
delirium, comfort, and safety) and during recovery (like bad memories, 
anxiety, and depression). We also want to know if they are value for money. 
 
Our trial will include 1437 patients needing to be on a ventilator for at least 
2 days. Patients will be allocated to one of three groups by chance. One 
group will continue to receive propofol; one group will receive 
dexmedetomidine; and one group will receive clonidine. All patients will 
receive extra pain relief if needed, and patients in the dexmedetomidine and 
clonidine groups will continue to receive propofol if they need this in 
addition. Nurses and doctors will alter the doses of sedation drugs to try 
and reduce or stop them, but will always aim to have patients lightly 
sedated and comfortable. We will compare whether patients on 
dexmedetomidine or clonidine come off the ventilator quicker than those 
just on propofol. We will also see if there was a difference between the 
groups in the number of people who experienced delirium in ICU, compare 
how comfortable people were, and measure if participants memories of 
being in the ICU differed.  
 
Patients who were in the trial will be followed up for 180 days afterwards 
because we want to compare if there were differences in the after-effects of 
being ill in ICU between the groups. We will ask patients to complete 
questionnaires that will assess their memories of the ICU experience at 90 
days after entering the trial. At 90 and/or 180 days, we will also ask patients 
to complete questionnaires so that we can detect how they feel about their 
quality of life or if they suffer from anxiety, depression or stress. 
 
Alongside this trial, we will be looking at value for money, which is important 
because clonidine, dexmedetomidine, and propofol costs are quite different. 
Clonidine, in particular, is relatively inexpensive. We will also find out ICU 
nurses’ and doctors’ views on how easy or difficult it was to adjust and use 
the drugs. This will give us valuable practical information that can be shared 
with other ICUs, particularly if alpha2-agonists are found to be better and 
other ICUs want to start using them.  
 
We have a large experienced team of people guiding this study. They 
include doctors, nurses, pharmacists, health economists, statisticians, ex-
patients and others who have expertise in the study methods. Together 
they will ensure that the trial runs smoothly, safely and finishes on time. 
 
 

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1. INTRODUCTION 
1.1 BACKGROUND 
1.1.1 Relationship between sedation practice and patient outcomes   
Around 20 million patients worldwide require intubation and MV in ICUs each year.1 
Almost all require ongoing sedation and analgesia for comfort, to relieve pain and 
anxiety, and to facilitate treatments. International guidelines and professional 
societies recommend that ICU patients who require MV are kept awake or lightly 
sedated whenever possible, and at the earliest opportunity during ICU care.2-4 
Observational studies consistently show an association between deep sedation and 
a range of clinically important adverse short-term outcomes including prolonged 
ventilation and ICU stay, hospital acquired infections, and greater mortality.2 5 Deeper 
sedation is most prevalent during the first 2-3 days of ICU care, when patients 
typically require high levels of organ support and are subject to most invasive 
procedures. Observational studies indicate an association between deeper sedation 
and higher mortality even during early ICU stay.6 7 Several randomised controlled 
trials have compared usual care with protocols designed to decrease the incidence of 
deep sedation. Most used a nurse-led protocol and/or regular interruption of sedation 
drugs followed by reassessment (a sedation ‘hold’ or ‘break’).8 9 Although results are 
inconsistent, most support a clinical benefit from lighter sedation especially for 
reducing duration of MV.  
An unproven concern regarding patient wakefulness and/or discomfort during ICU is 
that it could increase the prevalence of long-term psychological morbidity, such as 
post-traumatic stress, anxiety, and depression all of which are prevalent among 
survivors.10-12 Frightening and delusional memories are common among ICU 
survivors, and these may increase long-term psychological morbidity.13 14 However, it 
is uncertain whether ‘light sedation’ strategies or the choice of sedative agent can 
modify this, either directly or by decreasing delirium.11 13 15 
1.1.2 Implications for healthcare costs 
The main driver for ICU cost is duration of ICU stay, which is largely determined by 
the duration of MV. Other factors such as delirium are also important.16 ICU costs 
dominate both short and long-term healthcare costs for critically ill patients.17 18 
Interventions that decrease MV duration or complications associated with prolonged 
ICU and hospital stay, such as delirium, could be highly cost-effective and relieve 
bed pressures on ICU services.  
1.1.3 Delirium 
 
Delirium is a prevalent complication during critical illness, occurring in >40% of MV 
patients.16 Delirium is associated with higher mortality, longer duration of MV and ICU 
stay, and long-term cognitive decline.16 19 It remains unproven whether this 
association is causative, in part because trials designed to decrease delirium in the 
ICU setting have mostly failed to modify delirium prevalence. The biological 
mechanisms of delirium pathogenesis are uncertain, but sedative use especially with 
benzodiazepines significantly increases delirium risk.2 4 20 Whether the choice of ICU 
sedative modifies delirium prevalence is controversial. Current guidelines 
recommend using opioid drugs for analgesia as first-line therapy, introducing the 
short-acting GABA-agonist propofol for sedation, and avoiding benzodiazepines.2 3 
Alpha-2 agonists are the major alternative sedative class. There is biological 
plausibility that these decrease delirium, but evidence is inconclusive and the 
importance of agent choice unknown. 
 
 

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1.1.4 Current sedation practice in the UK 
We recently showed that only 55-65% of patient time in UK ICUs is optimally 
sedated, defined as the absence of deep sedation, agitation, and pain.21 
Unnecessary deep sedation was present for 20% of MV treatment, primarily during 
early ICU stay (the first 2-3 days). Conversely, agitation was also prevalent and 
occurred during 10% of MV treatment. Propofol was the most widely used sedative, 
and α2-agonist use was infrequent and inconsistent. A recent point prevalence study 
and survey undertaken in the UK included 214 (91 %) of 235 eligible ICUs.22 Propofol 
was the preferred sedative and alfentanil and fentanyl the preferred opioid 
analgesics. Most ICUs (83%) used combinations of sedatives and analgesics. In the 
point prevalence study 72% of patients were receiving propofol, but only 8% 
clonidine and 2% dexmedetomidine. We surveyed UK ICUs in Dec 2016 via the 
NIHR network (159 responses from different units). We found 58% of ICUs reported 
using dexmedetomidine, but in less than 10% of patients. More than 90% used 
clonidine, in up to 25% of patients, but administration route and protocols varied 
widely. Less than 5% of ICUs had clear protocols defining indications or which agent 
to use first. Widespread practice variation was clear. 
From these data, and our clinical experience, we know that current UK practice is 
usually to establish sedation and analgesia following intubation with propofol and an 
opioid and continue this until sedation is no longer clinically indicated (usually at the 
time of extubation or tracheostomy). At present α2-agonists are mostly used in a 
small group of selected patients, for example with established agitation and/or 
delirium, and typically late in ICU stay after usual care has failed to achieve 
comfortable awake sedation. There is wide variation in the choice of α2-agonist and 
dosage regimen between clinicians.  
1.1.5 Current evidence relating to dexmedetomidine and clonidine for ICU 
sedation 
Three systematic reviews summarise current evidence for dexmedetomidine and 
clonidine compared to usual care in critically ill patients.  
A Health Technology Assessment Agency (HTA) review (published 2016) 
underpinning an HTA commission that funded this trial included 18 RCTs (2489 adult 
patients).23 One small low quality trial compared dexmedetomidine with clonidine (N 
= 70), finding that target sedation was achieved in a higher number of 
dexmedetomidine treated patients.23 The remaining 17 trials compared 
dexmedetomidine with propofol or benzodiazepines, but varied considerably in 
relation to population, comparators, dose of sedative agents, and outcome 
measures. Risk of bias was generally high or unclear. Meta-analysis suggested 
dexmedetomidine did not alter mortality [risk ratio (RR) 1.03, 95% confidence interval 
(CI) 0.85 to 1.24], but length of ICU stay (mean difference -1.26 days, 95% CI -1.96 
to -0.55 days) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -
1.09 days) were significantly shorter among patients who received dexmedetomidine. 
Dexmedetomidine increased the risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77). 
There was no clear evidence that dexmedetomidine reduced delirium, but with a 
suggestion of a reduced incidence (RR 0.83, 95% CI 0.65 to 1.06) albeit with 
statistical heterogeneity.  
 
A Cochrane review (last updated January 2015) also summarised the evidence about 
dexmedetomidine and clonidine, but restricted trial populations to long-
term sedation during MV in the ICU (>24 hours).24 This review included seven RCTs 
(1624 adult patients) comparing dexmedetomidine with propofol or benzodiazepines. 
No trials with clonidine were identified. Findings were similar to the HTA review. 
Dexmedetomidine reduced mean duration of MV by 22% (95% CI 10% to 33%), and 
ICU length of stay by 14% (95% CI 1% to 24%). The effect on delirium was similar to 
the HTA review (RR 0.85; 95% CI 0.63 to 1.14), with statistical heterogeneity. 

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Dexmedetomidine did not alter mortality (RR 0.99; 95% CI 0.79 to 1.24). There was a 
doubling of bradycardia risk (RR 2.11; 95% CI 1.39 to 3.20).  
 
A review restricted to clonidine (published 2017) reviewed studies in critically ill 
patients requiring MV.25 Eight studies (642 patients) were included. There was 
important and relevant heterogeneity in multiple areas: four trials were in children; the 
routes of administration varied (6 intravenous and 2 oral); the dosage regimens 
varied widely (especially for intravenous administration; range 0.88 to 3 μg/kg/hour); 
and in 7 of 8 trials clonidine was used for adjunctive rather than stand-alone 
sedation. The only evaluation of clonidine as a single agent was the comparison with 
dexmedetomidine included in the HTA review. There was no difference in the 
duration of MV, ICU mortality, or ICU length of stay but quality and precision of 
estimates were low. In contrast to dexmedetomidine, clonidine was associated with 
increased hypotension (RR 3.11; 95% CI = 1.64 to 5.87), but not bradycardia (RR 
1.34; 95% CI 0.45 to 3.98). 
 
Four additional relevant trials have been published during the past 2 years. Su et al 
did a double blind placebo controlled RCT in patients aged >65 years admitted to the 
ICU after elective non-cardiac surgery.26 Patients received either a short (<24 hours) 
low dose intravenous dexmedetomidine infusion or placebo (350 per group). The 
incidence of the primary outcome of postoperative delirium was significantly lower in 
the dexmedetomidine group (9% versus 23%; odds ratio [OR] 0.35; 95% CI 0.22-
0.54). However, this population had low illness severity, only 55% were MV, and 
sedatives were only used in 51% of patients. The time to extubation among intubated 
patients was also very short (mean 6.9 hours (control) versus 4.6 hours 
(dexmedetomidine). These data support effectiveness in reducing delirium among 
elective low risk post-surgical patients, but the population was not relevant to that 
defined in the HTA brief or proposed in the current proposal.  
Reade and colleagues did a small double blind placebo-controlled RCT in Australian 
ICUs.27 The population was 74 adult patients in whom extubation was considered 
inappropriate because of the severity of agitation and delirium, and most patients had 
been MV for >2-3 days at randomisation. Dexmedetomidine or placebo was titrated 
to achieve physician-prescribed sedation goals for up to 7 days. The primary 
outcome of ventilator-free hours in the 7 days following randomisation was increased 
by dexmedetomidine (median 144.8 vs 127.5 hours; P=0.01)). There was a reduced 
time to extubation (median difference 19.5 hours (95%CI 5.3 to 31.1 hours); 
P<0.001)) and quicker resolution of delirium (median difference 16.0 hours (95%CI 
3.0 to 28.0 hours; P=0.01)). Although a small study, this trial suggests that 
dexmedetomidine may reduce time to extubation in a sub-population of patients with 
difficult agitation after 2-3 days of usual care management.  
Kawazoe et al recently published an open-label, RCT conducted in 8 ICUs in 201 
consecutive adult patients with sepsis requiring MV for at least 24 hours.28 Patients 
were randomized to receive either sedation with dexmedetomidine (n = 100) or usual 
care without dexmedetomidine (n = 101). Other agents used in both groups were 
fentanyl, propofol, and midazolam. The trial hypothesis was based on a post-hoc 
analysis of a trial comparing dexmedetomidine with lorazepam in ICU patients in 
which a mortality benefit was observed in a sub-population with sepsis (84% versus 
59%).29 The authors powered their trial for a large absolute mortality difference (20%) 
with only 80% power (80% versus 60%) and also had co-primary outcomes (mortality 
and ventilator-free days (VFDs; over 28-days)). Mortality was not significantly 
different between the groups (22.8% (dexmedetomidine) vs 30.8% (usual care); 
hazard ratio (HR) 0.69; 95% CI 0.38-1.22; P = 0.20), but the absolute difference (8%) 
could be important if confirmed in an adequately powered RCT. There was also a 
trend to reduction in ventilation time (dexmedetomidine median 20 VFDs; control 
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The SPICE III trial was an open-label randomized trial that enrolled ICU patients who 
had been mechanically ventilated for less than 12 hours and were expected to 
continue to receive ventilatory support for longer than the next calendar day to 
receive dexmedetomidine as the sole or primary sedative or to receive usual care 
(propofol, midazolam, or other sedatives).62 The target range of sedation-scores on 
the RASS was −2 to +1 (lightly sedated to restless). The primary outcome was the 
rate of death from any cause at 90 days. The trial enrolled 4000 patients, and found 
no difference in the primary outcome (29.1% in the dexmedetomidine group versus 
29.1% in the usual-care group (adjusted risk difference, 0.0 percentage points; 95% 
confidence interval, −2.9 to 2.8). Of relevance clinicians indicated a requirement for 
deep sedation for 50-60% of patients on days 1-2, and 20-40% on subsequent days. 
Less than 50% of patients achieved the target light sedation on days 1-2 in ICU, and 
around 60-70% achieved it on subsequent days. To achieve the prescribed level of 
sedation, patients in the dexmedetomidine group received supplemental propofol 
(64% of patients), midazolam (3%), or both (7%) during the first 2 days after 
randomization; in the usual-care group, these drugs were administered as primary 
sedatives in 60%, 12%, and 20% of the patients, respectively. Bradycardia and 
hypotension were more common in the dexmedetomidine group. Among the pre-
defined secondary outcomes in the dexmedetomidine group there was an increase in 
ventilator free days (during 28 days follow-up) of 1.0 days (23.0 days versus 22.0 
days: 95% CI: 0.4 to 1.6 days). The median duration of ventilation was around 3 days 
in both groups. In the dexmedetomidine group there was also an increase in the days 
free of coma and/or delirium during 28 days follow-up (24.0 days versus 23.0 days; 
difference 1.0 days (95% CI: 0.5 to 1.5). There were no differences in deaths at other 
time points, or in cognitinve function or HRQoL during follow-up. Among pre-defined 
subgroup analyses, there were no differences in relation to APACHE II score, 
oxygenation status, the presence of sepsis, or operative/non-operative groups. There 
was an interaction with the median population age of 63.7 years. Patients aged <63.7 
years who received dexmedetomidine experienced more deaths (mean 4.4%; 95% 
CI 0.1% to 8.7% more deaths). Patients aged ≥63.7 years who received 
dexmedetomidine experienced fewer deaths (mean 4.4%; 95% CI 0.8% to 7.9% 
fewer deaths). This finding was explored in a detailed post hoc analysis which 
confirmed the finding using a range of statistical approaches, but without an 
explanation for the effect.30 A cluster analysis suggested that a beneficial 
effect on mortality may be most marked in operative versus non-operative 
patients. 
 
The MENDS trial studied 438 adult patients with sepsis randomised double 
blind to receive either dexmedetomidine or propofol.31 The trial found no 
difference in the primary outcome (delirium/coma free days), ventilation 
outcomes, or mortality between the groups. Only 10% of eligible patients were 
included, many patients had received MV for 1-2 days before enrolment and 
overall mean duration of MV was short. The median dose of dexmedetomidine 
was also low and many patients received midazolam and/or antipsychotics 
(40%). These features may have compromised the fidelity of the planned 
intervention and its external validity. 
 
1.2 RATIONALE FOR STUDY 
 
Our project is in response to an HTA commissioned brief (16/93). This noted the shift 
from benzodiazepine towards propofol-based sedation, but highlighted growing use 
of the α2-agonists clonidine and dexmedetomidine, but without clear evidence for 
effectiveness and cost-effectiveness in the NHS (particularly for clonidine). A key 
recommendation of the systematic review underpinning the brief was that ‘well-

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designed RCTs are needed to assess the use of clonidine in ICUs’. Research 
concurrently comparing dexmedetomidine and clonidine is especially needed 
because: widespread practice variation exists within UK ICUs, clonidine is unlicensed 
for ICU sedation, the pharmacokinetics and dynamics of these agents differ 
considerably which could influence relative risk-to-benefit profiles, and the cost 
differential is substantial.  
 
Dosage regimens based on patient weight are well established for dexmedetomidine. 
We estimate that the average daily dose used in our trial will be around 
0.7μg/kg/hour (1200μg/day), which at current NHS list price will cost around £94 per 
day. In contrast, for clonidine we estimate an equipotent drug cost (1μg/kg/hour 
(1700μg/day)), will cost only around £5-10 per day. If both α2-agonists were superior 
to usual care with equivalent safety and effectiveness, the x10-20 fold lower cost of 
clonidine would represent very substantial cost savings to the NHS. For comparison, 
we estimate daily mean propofol costs are currently around £5-10. 
 
Improving ICU sedation practice and delirium management is also a priority for 
patients. In the James Lind/Intensive Care Foundation patient/professional 
collaboration ‘improving agitation and delirium management’ was a top three, and 
‘enhancing patient comfort during Intensive Care’ a top 10 priority (see: 
www.jla.nihr.ac.uk/priority-setting-partnerships/intensive-care). Our work with PPI 
colleagues has strongly supported the need for this trial. 
 
We searched clinical trial databases for ongoing large trials. We found no trials in 
which dexmedetomidine and clonidine are being concurrently evaluated. For 
clonidine, we found no large trials comparing clonidine to usual care in MV ICU 
patients. The MENDS II trial (NCT01739933) is a US based trial (N = 530) comparing 
dexmedetomidine with propofol in MV septic patients. The primary outcome is 
delirium/coma free days with a range of secondary outcomes. This trial is restricted 
to patients with infection. This trial will provide new data about dexmedetomidine, but 
none for clonidine.  
 
We have designed our trial to directly compare dexmedetomidine with clonidine in 
the context of UK practice and provide both clinical and cost-effectiveness 
comparisons with current practice. The greater UK use of clonidine than 
dexmedetomidine further highlights this need. Our ‘usual care’ group will receive 
propofol, which recent surveys indicate is the most widely used sedative in UK ICUs. 
2. STUDY OBJECTIVES 
2.1 OBJECTIVES 
 
Our overall objective is to determine whether the α2-agonists clonidine or 
dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients 
compared to current usual care. We also aim to determine which agent is most 
clinically effective and offers best value to the NHS given important differences in 
properties and cost between the drugs. 
2.1.1 Primary Objective 
Our primary objective is to determine whether intravenous sedation with the α2-
agonist agents, dexmedetomidine or clonidine, can decrease the time to successful 
extubation from MV among adult critically ill patients.  
 

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2.1.2 Secondary Objectives 
Secondary objectives are to assess the effects of dexmedetomidine and clonidine, 
compared with usual care, on other clinical, patient-centred, and economic 
outcomes in the ICU, hospital, and during up to 6 months follow up post-
randomisation. These will address all outcomes specified in the HTA brief, and some 
additional outcomes suggested by core outcome datasets, biological plausibility for 
clinically important effects, and advice from PPI collaborators co-developing the 
project.   
2.1.2.1 Clinical and Person-centred objectives 
During ICU stay we will compare rates and duration of delirium, time to optimum 
sedation, average sedation depth, the ability of patients to communicate with staff 
and relatives, the quality of sedation, and duration of ICU stay. We will also compare 
safety based on pre-defined adverse events relevant to sedation and α2-agonist 
agents.  
Following discharge from the ICU we will compare patient outcomes for which 
sedation and ICU experience may be on the causal pathway, namely patients’ 
memories of their ICU stay, psychological wellbeing, and cognitive function. We will 
follow up patients for up to 6 months for survival, HRQoL, and healthcare resource 
use.  
2.1.2.2 Economic evaluation 
We will include a detailed cost-effectiveness analysis; we will compare costs and 
cost-effectiveness from an NHS and personal social services (PSS) perspective. 
2.1.2.3 Process evaluation 
The trial, by necessity, is a complex healthcare intervention trial evaluating a novel 
class of sedative agents. We will include a process evaluation, consistent with 
Medical Research Council (MRC) guidance32 33, to understand how α2-agonists were 
used in the trial, how this may explain the results, how best to use the drugs safely in 
a heterogeneous population, and how to implement trial findings into practice.  
2.1.2.4 Mechanistic study 
There is some evidence that in addition to sedative effects, α2-agonists have anti-
inflammatory and immune modulating properties. In a sub-group of patients in whom 
consent is obtained we will collect two blood samples to study whether α2-agonists 
alter inflammation in comparison to current usual care (see section 11). 
2.2 ENDPOINTS 
2.2.1 Primary Endpoint 
 
Time to successful extubation post-randomisation (hours).  
For the purpose of the trial, a successful first extubation from mechanical ventilation 
(MV) will be defined as follows: 
 
a. For patients with an Endotracheal tube: 
a. time of successful extubation will be the time of the first extubation that 
is followed by 48 hours of spontaneous breathing without mechanical 
support (i.e. the start time of the 48 hours of spontaneous breathing)  
b. For patients with a tracheostomy: 
a. time of successful extubation will be the start time of the patient’s first 
period of 48 hours of spontaneous breathing, where spontaneous 

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breathing is defined as receiving support not exceeding 5 cmH2O 
PEEP/CPAP with ≤ 5 cmH2O pressure support above PEEP 
c. For patients who are receiving non-Invasive mechanical ventilation (NIV): 
a. time of successful extubation will be the start time of the patient’s first 
period of 48 hours of spontaneous breathing, where spontaneous 
breathing is defined as receiving support not exceeding 5 cmH2O 
CPAP via mask/hood (NB NIV patients receiving any pressure 
supported breaths will not be considered to be spontaneously breathing 
unassisted) 
NB: The use of high flow nasal oxygen will not be counted as mechanical ventilation, 
so patient on high nasal flow oxygen alone will be considered to be spontaneously 
breathing unassisted.   
 
The 48 hours of successful extubation is included in the definition in order to exclude 
patients with early failed extubations, i.e. those patients requiring reintubation within 
48 hours. If a re-intubation occurs within this time window it is likely to be related to 
the original episode of respiratory failure requiring intubation. In this situation patients 
should continue to be followed for the start time at which a successful extubation 
occurs according to the above definitions  
2.2.2 Secondary Endpoints 
Secondary outcomes are shown in table 1, together with the measurement tool and 
timing. 
 
Table 1: secondary outcomes, measurement tool or method, and timing. 
 
Outcome 
Measurement tool or method 
Timing 
Mortality 
Medical records check 
ICU, hospital, 30, 90 
and 180 days post 
randomisation 
Length of ICU stay 
Days randomisation to ICU discharge 
ICU discharge 
Sedation and analgesia 
quality 
 
Richmond Agitation and Sedation Scale (RASS) 
Plots of lowest and highest RASS score over time 
 
Sedation Quality (based on Sedation Quality 
Assessment Tool (SQAT).34  
Defines four states for sedation quality: 
1. Overall optimum sedation (no agitation; no 
unnecessary deep sedation; no pain behaviour) 
2. Agitation 
3. Unnecessary deep sedation (RASS -4/-5 without 
clinical indication) 
4. Pain (presence of pain behaviour based on limb 
movement and ventilation compliance) 
Four hourly during ICU 
stay until primary 
outcome is reached  
 
Derived from daily 
sedation and analgesia 
quality data during 
intervention period in 
ICU until primary 
outcome is reached 
Time to first Optimum 
sedation 
Hours from randomisation to first RASS score of -2 or 
greater 
Days from randomisation to first day with optimum 
sedation (based on SQAT definition) 
Based on daily sedation 
and pain assessments 
during the intervention 
period 

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Delirium prior to successful 
extubation 
Confusion-Agitation method for ICU (CAM-ICU)35 
Occurrence prior to successful extubation (binary 
outcome) 
Days with delirium or coma prior to successful 
extubation (continuous outcome)  
Twice daily during ICU 
stay until primary 
outcome is reached 
Drug-related adverse events 
Severe bradycardia; cardiac arrhythmias; cardiac 
arrest (defined in protocol) 
Daily during the 
intervention period 
Health-related Quality of Life 
Euroqol tool (EQ-5D-5L)  
 
Recalled HRQoL prior 
to  hospital admission; 
30, 90 and 180 days 
post randomisation 
Patients’ Ability to 
Communicate Pain and 
Ability to Cooperate with 
Care 
Binary assessment for each 12 hours nursing shift 
completed by bedside nurse (based on overall 
assessment of period of care). Answer to the 
following questions: 
1. Was your patient able to communicate pain? 
2. Was your patient able to cooperate with care? 
 
Twice daily until 
primary outcome is 
reached 
Patient experience of ICU 
care 
Intensive Care Experience Questionnaire (ICE-Q)36 
Provides numeric score in four domains: 
1. Awareness of Surroundings 
2. Frightening Experiences 
3. Recall of Experiences 
4. Satisfaction with Care 
90 days post 
randomisation 
Relative/partner/friend 
(PerLR) assessment of 
comfort and communication 
Relative/partner/friends response to the following 
questions (based on their opinion at time of 
assessment): 
1. Does the patient appear awake to the visitor? 
2. Does the patient seem comfortable to the 
visitor? 
3. Does the visitor feel they can communicate with 
the patient? 
Daily at a visit until 
primary outcome is 
reached 
Anxiety and depression* 
Hospital Anxiety and Depression Scale (HADS) 
questionnaire 
180 days post 
randomisation 
Post-traumatic stress* 
Impact of Events Scale-revised (IES-R) 
180 days post 
randomisation 
Cognitive function* 
Montreal Cognitive Assessment Tool (Telephone 
version) (TMoCA) 
180 days post 
randomisation 
 
In addition to these clinical endpoints, a mechanistic sub-study will measure inflammation 
and immune function and compare whether this is different between the three groups (see 
section 11). 
3. STUDY DESIGN 
3.1 HYPOTHESIS 
The primary hypothesis is that sedation with α2-agonists will decrease the time to 
extubation in adult MV ICU patients compared with usual care. 

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3.2 TYPE OF STUDY 
This is a randomised, parallel-group, allocation concealed, controlled, open-label, 
phase 3, pragmatic, clinical and cost-effectiveness trial with an internal pilot.  
 
After intubating and stabilizing patients, we will randomise patients (1: 1: 1) as early 
as possible to receive sedation-analgesia based on clonidine or dexmedetomidine or 
to continue on propofol (usual care) plus opioid analgesia as required.  
 
3.3 ‘PICO’ QUESTION 
Population:   
Adult MV ICU patients within 48 hours of initiation of MV 
Interventions:  
A: Sedation based on clonidine ± opioid analgesic   
 
 
 
B: Sedation based on dexmedetomidine ± opioid analgesic  
Comparator:  
Usual care sedation with propofol ± opioid analgesic 
Outcome (primary): Time from randomisation to successful extubation  
3.4 DESIGN AND ANALYTIC/CONCEPTUAL FRAMEWORK 
 
Our analytic framework has been devised to address all the important questions in 
the HTA brief in a staged hierarchical fashion.37 38 This enables a highly efficient trial 
design that maximises efficiency and restricts the overall Type 1 error rate to at most 
6.5%, with the upper limit being as low as 5% if the Stage 1 test for superiority of 
clonidine to propofol does not show a significant benefit. Importantly, the trial will 
determine whether α2-agonists are superior to current practice but also, if superiority 
is found, which agent is most clinically and cost-effective. We propose three analytic 
stages, where progression to hypothesis testing in sequential stages is dependent on 
preceding results:  
Stage 1 will test whether dexmedetomidine or clonidine (or both) are superior to 
propofol (usual care). If neither test is significant we consider further testing is not 
important because we will have fulfilled our main objective.  
Stage 2 will test whether dexmedetomidine is superior to clonidine or if clonidine is 
non-inferior to dexmedetomidine (if stage 1 testing is significant). This stage is 
important because of the large differences in cost between the drugs.  
Stage 3 will test if clonidine is superior to dexmedetomidine, but only if clonidine has 
been shown to be non-inferior in stage 2. A more detailed description is provided in 
section 11.  
3.5 PRE-PLANNED SUB-GROUP ANALYSIS 
We plan sub-group analyses for patients with:  
1. sepsis (because of possible beneficial anti-inflammatory effects from α2-
agonists, which may be most pronounced in sepsis)29 39  
2. higher delirium risk as defined by the validated PRE-DELIRIC delirium risk 
prediction score, using the version assessing at 24 hours post-admission40 
(because α2-agonists may decrease delirium, which might modify many of the 
other outcomes) 
3. organ dysfunction at randomisation (because this could differentially alter the 
safety profile of the three groups)  
4. age ≥64 years versus age <64 years (this cut-off was found to interact with 
mortality in the SPICE III trial, with younger patients experiencing higher 
mortality at 90 days with dexmedetomidine, and older patients experiencing 

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lower mortality at 90 days with dexmedetomidine; clonidine was not used in 
the SPICE trial)62 
These analyses will be exploratory.  
3.6 BLINDING 
This will be an open-label trial. Issues that were considered justification for an open-
label trial were: 
1. Dynamic adjustment of blinded drugs with different pharmacokinetics and 
dynamics would be extremely challenging to clinical staff (and be potentially 
unsafe) in sick patients.  
2. The cost to supply blinded drugs 24/7 to ICUs was extremely high.  
3. After discussing the pros/cons of blinding with PPI collaborators, they felt a 
more relevant and safe assessment of the drugs was likely if clinicians were 
aware of allocation.  
4. The co-applicants were concerned that blinding might increase enrolment 
bias and slow recruitment, because of safety concerns (this may have 
contributed to low recruitment in a previous trial of clonidine in paediatric 
ICUs41).  
5. Overall, it was thought that an open-label trial would provide a population and 
intervention with greater generalisability, and not compromise internal or 
external validity. 
 
Individuals drafting and updating the trial analysis plan will be blinded from any 
outcome data identifying intervention group until the database is locked. It will not be 
feasible to guarantee blinding for post hospital discharge outcomes, but blinding will 
be achieved where possible. 
 
 
3.7 STUDY DETAIL 
3.7.1 Internal pilot and overall recruitment strategy 
Participants will be recruited from approximately fifty sites and we aim to set these up 
at an average rate of 3 sites per month. The internal pilot study will comprise those 
sites recruiting during the first 9 months of recruitment. Our target recruitment rate is 
around 2 patients per month per centre. This assumes 40-50% recruitment of eligible 
cases, which is similar to recent sedation and delirium trials.21 42 
 
With this approach, during the internal pilot we aim to have 3, 6, 9, 12, 15, and 18 
sites contributing over months 4-9. Assuming, on average, sites are ready to 
contribute by the middle of the month, they will generate 1.5, 4.5, 7.5, 10.5, 13.5 and 
16.5 centre-months (total 54 centre months) during this internal pilot period. At an 
average of 2 recruits per centre per month, the internal pilot should achieve around 
100 randomisations.  
Continuing to add 3 sites per month after the end of the internal pilot the aim is to 
reach 40-50 sites by recruitment month 14 (approximately 239 centre months), and 
steady state of 40-50 sites for the final 16 months of recruitment (approximately 640 
centre months).  
 
The total centre months will be approximately 933 over a total recruitment period of 
30 months. This requires a mean 1.9 recruits per centre per month assuming the 
staged set-up is achieved. 
 
For the internal pilot, we will use a Green-Amber-Red statistical approach. Assuming 
each centre month follows an independent identically distributed Poisson distribution 

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with mean 1.9, the total will be approximately normally distributed with mean 100 and 
SD 10. ‘Green’ will be within 2 standard deviations of 100 i.e. if we have randomised 
80 or more we will continue unchanged. ‘Amber’ will be within 2-4 standard 
deviations i.e. if we have recruited 60-79 we will consider adding new centres and/or 
extending the recruitment window. ‘Red’ will be triggered with <60 randomisations 
and serious consideration, in conjunction with HTA, around stopping the study.  
 
During the internal pilot we will audit screening logs, recruitment, reasons for 
exclusion and protocol compliance. We will also measure the completeness of 
datasets, and the completeness of the primary outcome, which we anticipate should 
be >95% (the only exceptions will be patients transferred to other ICUs before 
reaching the primary outcome or withdrawing). Process evaluation data during this 
phase will be important and will establish protocol fidelity, inform 
clarifications/modifications, and facilitate efficient set-up in other sites. We will also 
optimise the educational materials for use in the wider site recruitment and set-up.  
 
 
 
3.7.2 Centres 
The trial will be undertaken in approximately 40-50 UK ICUs with clinical equipoise 
for using either α2-agonist as per protocol. Participating centres must use sedation 
and weaning practices consistent with the protocol, which represents best practice. 
We will select ICUs from those who have successfully recruited to recent UK 
multicentre critical care trials. Selection will occur through existing trial networks and 
the NIHR critical care network.  
4. STUDY POPULATION 
4.1 TARGET POPULATION 
The target population are critically ill patients requiring MV, recruited as early during 
ICU stay as possible, with an anticipated total requirement for MV of at least two 
days. Patients expected to require short periods of MV are unlikely to experience 
clinically or cost-effective benefits, especially for the primary outcome.  
Patient consent and randomisation is unlikely in most cases to be feasible prior to 
endotracheal intubation, and attempts to obtain it might delay life-saving emergency 
care. Screening will only be undertaken in patients after MV is started in the ICU.  
Alpha2-agonists are not appropriate as single agents for intubation and early 
sedation for most acutely ill patients due to their pharmacokinetic and 
pharmacodynamic properties and cardiovascular side effects. Anaesthesia to 
undertake endotracheal intubation and establish initial ICU sedation-analgesia will 
follow current usual care (almost always intravenous propofol or other anaesthetic 
induction agent, and opioid). It is anticipated that many patients will be established on 
MV prior to ICU admission. 
4.2 NUMBERS OF PARTICIPANTS 
The total number of participants is 1437 (479 per trial group). 
 
4.3 INCLUSION CRITERIA 
1. Patient requiring MV in an ICU 

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2. Aged 18 or over 
3. Within 48 hours of first episode of mechanical ventilation in ICU  
4. Requiring sedation with propofol 
5. Expected to require a total of 48 hours of MV or more in ICU 
6. Expected to require a further 24 hours of MV or more at the time of 
randomisation in the opinion of the responsible clinician 
Note: Criteria 5 and 6 are intended to ensure that all participants require at least 48 hours of 
MV in the ICU and that all patients receive at least 24 hours of the allocated intervention after 
randomisation. 
4.4 EXCLUSION CRITERIA 
The following exclusions will apply 
1. Acute brain injury (traumatic brain injury; intracranial haemorrhage; ischaemic 
brain injury from stroke or hypoperfusion)1  
2. Post-cardiac arrest (where there is clinical concern about hypoxic brain 
injury)1 
3. Status epilepticus1 
4. Continuous therapeutic neuromuscular paralysis at the time of screening or 
randomisation1 
5. Guillain-Barre Syndrome1 
6. Myasthenia gravis1 
7. Home ventilation1, 4  
8. Fulminant hepatic failure2 
9. Patient not expected to survive 24 hours by responsible clinician 
10. Decision to provide only palliative or end-of-life care 
11. Pregnancy 
12. Known allergy to one of the study drugs  
13. Untreated second or third degree heart block3  
14. Transferred from another Intensive Care Unit in which MV occurred for >6 
hours 
15. Prisoners 
16. Enrolled on another CTIMP 
17. Previously enrolled on the A2B Trial 
18. Patient known to have experienced a period with heart rate <50 beats per 
minute for 60 minutes or longer since commencing mechanical ventilation in 
the ICU 
Note: 
1For these conditions the neuromuscular condition will dominate the primary outcome 
unrelated to sedation practice 
2Uncertain pharmacokinetics of α-2 agonist; potential for cerebral oedema mandating deep 
sedation 
3Patients with treated heart block, for example with a pacemaker, are eligible for inclusion 
4Home ventilation does not include patients receiving night-time CPAP and/or BIPAP therapy 
for the treatment of obstructive sleep apnoea syndrome. 
 
4.5 CO-ENROLMENT 
Co-enrolment to other studies will be permitted in cases where the Chief 
Investigators  and/or trial management teams of both studies agree that co-enrolment 
is appropriate. In coming to a decision they must consider the scientific and practical 
implications of co-enrolment, specifically the safety of study participants, the 
interventions involved, participant burden and the potential impact on the study 
endpoints. Relevant UK guidance for critical care trials and/or relevant sponsor and 
local standard operating procedures and policies will be followed (e.g. ACCORD 
POL008).  

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Co-enrolment with other concurrent Clinical Trials of Investigational Medicinal 
products (CTIMPs) will not be permitted.  
Co-enrolment with non-CTIMP intervention studies will be permitted if an agreement 
has been reached between the Chief Investigators and a signed agreement is in 
place between the two studies prior to an individual participant being considered for 
inclusion, and this has been documented in the trial materials and site files and 
authorised by the sponsor.   
Co-enrolment with purely non-interventional research studies (e.g. questionnaire 
studies; observational studies) will be permitted if agreement has been reached 
between the Chief Investigators. A signed co-enrolment agreement is not required, 
but the agreement of the Cis for both studies will be documented. 
5. PARTICIPANT SELECTION AND ENROLMENT 
5.1 IDENTIFYING PARTICIPANTS 
Participants will be identified by clinical ICU teams in collaboration with research 
teams using regular screening of patients on a daily basis, or as often as feasible, 
from the time of ICU admission. 
 
5.2 CONSENTING PARTICIPANTS  
Patients will lack mental capacity at the time of screening and enrolment as a result 
of critical illness and the effects of sedative drugs. The appropriate approaches to 
consent according to UK law will be used, approaching Personal and Professional 
legal representatives. The use of the “emergency provision” will be used in selected 
patients for deferred consent when a legal representative is not available within 2 
hours of meeting eligibility criteria according to procedures agreed with the ethics 
committees.      
 
5.2.1 Informed Consent 
All patients who are potentially eligible for the trial will be critically ill and receiving 
sedative drugs by continuous infusion. They will therefore lack mental capacity. The 
Investigator is responsible for ensuring agreed consent procedures are followed 
before any protocol specific procedures are carried out. These are detailed in the 
flowchart in appendix 3. The process for obtaining informed consent must be 
documented in the patient’s medical records. 
 
5.2.2 Consent process 
In clinical trials that include patients with diminished capacity requiring treatment in a 
critical care environment, a common approach is to seek declaration of agreement 
from a personal consultee or personal legal representative and once the participant 
has regained capacity, to seek retrospective informed consent. For this trial, 
however, any delays in allocation to the treatment group may decrease the potential 
effectiveness of the intervention and would also mean the intervention was not being 
evaluated in the way it would be used in routine care. This issue arises because 
sedation is an early essential intervention following mechanical ventilation, and the 
benefits of alpha2 agonists may be from early use. 
In the majority of participants a legal representative will provide consent prior to 
randomisation. The A2B trial also allows deferred consent for patients in whom a 
legal representative is not present in the ICU or does not attend within 2 hours from 
the time patients become eligible. This model has been developed in conjunction with 
the Patient and Public co-investigators and collaborators.  

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In ICUs, research teams are integrated into clinical teams and/or work closely with 
them. Once the clinical and/or research teams have identified a patient is eligible for 
enrolment in the trial, the aim is to randomise the patient and start the allocated 
intervention as soon as possible. This will maximise the potential benefit from the 
intervention and ensure it is evaluated in the manner it would be used in routine care. 
It is relevant that both intervention drugs are already widely used in UK ICUs, and the 
comparator is current usual care.  
There will be three scenarios through which randomisation may occur: 
 
Patient’s personal legal representative (PerLR) is present at the time eligibility occurs 
or attends within the next 2 hours.  
In this situation the PerLR will be consulted and provided with the Patient Information 
Sheet (PIS) sheet. After the opportunity to ask questions of the research team, 
patients for whom consent is provided will be randomised. This is the default 
approach to be used wherever possible. 
 
Patient’s personal legal representative (PerLR) is not present at the time eligibility 
occurs and does not attend within 2 hours of fulfilling eligibility criteria, but a 
professional legal representative (ProfLR) is identified who is immediately available 
after two hours. 
In this situation the ProfLR will be consulted. If the ProfLR provides consent the 
patient will be randomised.  
 
Patient’s personal legal representative (PerLR) is not present at the time eligibility 
occurs and does not attend within 2 hours of fulfilling eligibility criteria and a 
professional legal representative (ProfLR) is NOT immediately available after two 
hours from meeting eligibility criteria. 
In this situation deferred consent will be used under the ‘emergency provision’ of the  
Medicines for Human Use (Clinical Trials) Regulations. This will enable the patient to 
be randomised to the trial intervention at a time when the intervention is most likely to 
be associated with benefit, and is the time at which the intervention (alpha2-agonist 
based sedation) would be used in routine care.  
 
These situations may arise because relatives are frequently present for a significant 
time around the period of admission and stabilisation in ICU, but frequently then need 
to rest before returning and may have recently left the ICU around the time of 
eligibility. This period is frequently also during night-time hours. A delay in approach 
of more than 2 hours is likely to result in randomisation occurring after at least 6-12 
hours, because the PerLR will require time to be approached and consider consent, 
and then randomisation procedures undertaken and treatment started. This delay is 
important in this trial because early deep sedation, even during the first 24-48 hours, 
has been strongly associated with worse patient outcomes. A key goal of sedation 
with α2-agonists is to reduce early deep sedation (during the first 24-48 hours).  
 
If deferred consent or ProfLR consent is used, the PerLR will be consulted and 
provided with the PIS at the earliest possible time following randomisation, and 
consent requested to continue in the study. If following deferred consent available 
information suggests that the patient does not have a PerLR who will be able to 
attend, then a Professional Legal Representative (ProfLR) opinion will be sought at 
the earliest opportunity and consent requested to continue in the study. 
 
If enrolment and randomisation have occurred under emergency provisions, but the 
PerLR or the ProfLR dos not provide consent when consulted, the patient will be 
withdrawn from the study and continuing care will follow usual care according to the 
direction of the clinical team.  
 

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5.2.3 Obtaining consent from participants who regain capacity 
Once a patient has regained capacity, they will be approached by an authorised 
member of the site research team for informed consent to continue in the trial. This 
will be done as soon as practically possible. A Participant Information Sheet (PIS) will 
be provided to the patient by an authorised staff member. The PIS will provide 
information about the purpose of the study, what participation means for the patient 
(e.g. follow-up questionnaires at 90 and 180 days), confidentiality and data security, 
and the future availability of the trial results. 
Timing of approach for informed consent from the patient: 
 
The majority of enrolled patients will have their invasive mechanical 
ventilation discontinued through removal of the endotracheal tube, prior to 
them having demonstrated capacity and will therefore only be approached for 
informed consent following collection of primary outcome data.  
 
A small proportion of enrolled patients (estimated to be <10%) will have a 
tracheostomy performed as part of their routine clinical care and may be able 
to demonstrate capacity and be approached for informed consent prior to the 
primary outcome endpoint having been reached.  
 
A minority of enrolled patients will have an endotracheal tube in place yet still 
be able to demonstrate capacity and be approached for informed consent 
prior to the primary outcome endpoint having been reached. 
 
In the event that a patient is not able to be approached for consent to remain in the 
trial prior to hospital discharge, the local research team will seek written consent at 
the time of 30 day follow-up by sending a PIS and consent form by post. The patient 
will be asked to return the signed consent form if they wish to remain in the trial, or 
contact the study team if they wish to be withdrawn. If the patient does not return the 
signed consent form but does not ask to be withdrawn from the trial, the ProfLR 
and/or PerLR consent will remain valid and the patient will remain in the trial. In this 
event, a further PIS and consent form will be sent with the 90 days and if necessary 
the 180 days follow-up questionnaires and the patient will be asked to return a signed 
consent. As for 30 days, if the patient does not return the signed consent form but 
does not ask to be withdrawn from the trial, the ProfLR and/or PerLR consent will 
remain valid and the patient will remain in the trial. No further requests to return a 
consent form will be sent after the 180 day follow-up.  
 
 
The Consent Form will indicate that: the information given, orally and in writing, has 
been read and understood; participation is voluntary and can be withdrawn at any 
time without consequence; consent is given for access to medical records for data 
collection. The Consent Form will cover consent for use of data already collected for 
the trial, as well as ongoing data collection and follow-up. 
Patients will be given time to read the PIS and have an opportunity to ask any 
questions they may have about participation in the A2B Trial. After verifying that the 
PIS and Consent Form are understood, the person seeking consent will invite the 
patient to sign the Consent Form and will then add their own name and countersign 
it. A copy will be given to the patient, a copy placed in the patient’s medical notes and 
the original kept in the Investigator Site File. If the patient is unable to physically sign 
the Consent Form (e.g. due to weakness, reduced dexterity), an independent witness 
can sign on their behalf. 
Patients and their representatives will only be approached by authorised staff 
members who have received training in A2B Trial processes and procedures and in 
Good Clinical Practice (GCP). The recruitment process will be done in such a way to 
mitigate any potential undue influence or coercion. No therapeutic promises will be 
made. 
 

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Information about the A2B trial will be displayed on posters in waiting areas. This 
promotes understanding of the study in anticipation of the participants regaining 
capacity and will provide some background for the personal consultees that may 
inform their discussions with the participant when they have regained capacity and 
are considering providing informed deferred consent. 
 
5.3 SCREENING FOR ELIGIBILITY 
All patients admitted to the participating ICUs will be screened for eligibility. 
Screening will start as early as possible post-ICU admission, ideally within 6 hours. 
The maximum benefit from the interventions is likely to occur if patients commence 
treatment as early as possible after starting mechanical ventilation and sedation. 
Specifically, deep sedation during the first 1-2 days in the ICU is associated with 
worse outcomes including higher mortality. The interventions aim to decrease deep 
sedation and enable patients to be awake and comfortable. Screening will continue 
for up to 48 hours following the start of MV in the ICU. Periods of MV prior to ICU 
admission, for example in the operating theatre or the emergency department, will 
not count as part of the 48 hours recruitment window irrespective of their duration. 
Patients can be screened on multiple occasions during the 48 hours if appropriate 
A screening log will be maintained at each site including reasons for non-enrollment 
to enable reporting according to the CONSORT statement.  
5.4 INELIGIBLE AND NON-RECRUITED PARTICIPANTS 
Ineligible patients who are not randomised will continue to receive usual care as 
directed by the clinical care team.  
5.5 RANDOMISATION 
5.5.1 Randomisation Procedures 
Eligible patients will be randomised by staff delegated to undertake this task at the 
earliest opportunity, but within 48 hours from the start of the first episode of MV in the 
ICU. Randomisation should be undertaken immediately after consent is obtained 
from a legal representative, or when deferred consent is used, if this is triggered.  
The individual undertaking randomisation will be responsible for assigning patients to 
the randomisation group and communicating this to clinical teams. The aim is to 
randomise eligible patients as close to the time sedation is used clinically, which in 
routine care is continuously from the time of MV. Participants will be randomised to 
the trial using a remote web-based randomisation system. 
5.5.2 Treatment Allocation 
Randomisation will use a remote web-based randomisation system to allocate 
patients in a 1:1:1 ratio to the three trial groups using permuted blocks (randomly 
arranged sizes of 3, 6, 9, 12) stratified by centre. We will not stratify for any other 
variables to simplify enrolment and decrease time delays. The allocation sequence 
will be stored on a secure server and concealed from all personnel involved in the 
trial, and will be generated by a clinical trials unit member of staff who is not involved 
in clinical care. If the randomisation system is not available then please contact the 
trial office. 
5.6 INTERVENTION GROUPS 
Patients will commence intravenous infusion of open-label study drug according to a 
weight-based dose regimen (see appendix 1) as early as possible post-
randomisation, and within a maximum of two hours.  

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Bedside clinical staff will transition patients to achieve sedation with the allocated α2-
agonist agent as quickly as clinically feasible and safe, to replicate the way these 
drugs would be used in routine practice. Additional opiate will be used for analgesia 
using clinical judgement. Once α2-agonist is established, additional propofol will only 
be used when the maximum α2-agonist dose is reached or because cardiovascular 
or other side-effects limit dose escalation.   
 
5.6.1 Dexmedetomidine group 
For dexmedetomidine, the regimen will follow the manufacturer’s guidance and 
regimens used in previous trials. No loading dose will be administered. The starting 
dose will be 0.7µg.kg-1.hour-1 titrated to a maximum dose 1.4µg.kg-1 hour-1. Lower 
starting doses will be used at clinical discretion for patients with cardiovascular 
instability e.g. for patients on high doses of norepinephrine or those in whom there is 
concern about low baseline heart rate. 
 
5.6.2 Clonidine group 
For clonidine, the regimen is designed to be equipotent with dexmedetomidine based 
on known pharmacokinetics and pharmacodynamics. The chosen regimen is similar 
to that currently used in many UK ICUs as part of routine ‘off label’ practice. No 
loading dose will be administered. The starting dose will be 1.0µg.kg-1.hour-1 titrated 
to a maximum dose of 2µg.kg-1.hour-1. Lower starting doses will be used at clinical 
discretion for patients with cardiovascular instability e.g. for patients on high doses of 
norepinephrine or those in whom there is concern about low baseline heart rate. 
5.7 USUAL CARE GROUP 
Patients will continue to receive intravenous propofol according to current usual care. 
The sedation targets, weaning, and sedation discontinuation procedures will follow 
the same clinical targets as for the clonidine and dexmedetomidine groups. 
5.8 DURATION OF INTERVENTION 
The intervention period will continue until the patient is weaned from MV in the ICU. 
The timing of discontinuation of sedative agents will be at the discretion of the clinical 
team. This may include discontinuation prior to ending MV (for example in patients 
who have undergone tracheostomy), or discontinuation after extubation (for example 
in agitated or delirious patients).  
The intervention period will last for whichever of the following occurs first; 
 
The patient is successfully extubated according to the definition of the primary 
outcome.    
 
The patient dies during MV in the ICU 
 
The patient is transferred to another non-participating ICU prior to achieving 
the primary outcome, or  
 
28 days of MV in ICU have been required following randomisation without 
achieving the primary outcome. 
Once the primary outcome has occurred any further periods of sedation, for example 
after later reintubation or ICU readmission, will follow usual care practice, which may 
include the use of dexmedetomidine or clonidine.    
If the patient is re-intubated before achieving the primary outcome, they should 
continue the group allocated treatment until the primary outcome is successfully 
achieved. 

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If patients are transferred to another ICU that is participating in the trial, the 
intervention and follow up will be continued wherever feasible. If this is not feasible, 
the intervention should stop but follow up should be completed wherever possible. 
5.9 MANAGEMENT DURING INTERVENTION PERIOD 
5.9.1 Titration to sedation targets 
The default sedation target will be the most awake and comfortable state considered 
safe by clinical staff. Bedside clinical nurses will be asked to document, for each 12 
hours nursing shift, whether there is a clinical indication for deep sedation (after 
consultation with medical staff). If there is no requirement for deep sedation, the least 
awake target sedation state will be ‘brief eye contact made in response to voice’. This 
is equivalent to a Richmond Agitation Sedation Scale (RASS) score of -243. Targeting 
a sedation state at this level or more awake throughout ICU care is considered best 
practice, was used in most previous trials, and is generally considered ‘light’ 
sedation.2 3  
 
Bedside ICU nurses will be asked to document RASS score every 4 hours while 
patients are receiving interventions up to the point of achieving the primary outcome. 
A bedside algorithm (Appendix 2) will recommend changes to sedation drug 
(according to group allocation) based on responses to RASS scores. When patients 
do not make brief eye contact to voice and there is no requirement for deep sedation, 
clinical nurses will be asked to decrease propofol dose (if administered in any 
intervention group) or decrease the intervention drug dose if no propofol is being 
administered (according to the dose administration algorithm). 
 
All patients will receive opioid infusions for analgesia as clinically indicated at the 
discretion of clinical teams. Patients that require additional sedation, for example for 
agitation, will receive additional propofol as required, particularly once the maximum 
tolerated dose of intervention drug is reached. 
 
5.9.2 Management of participants with cardiovascular instability 
5.9.2.1 Patients requiring norepinephrine or other vasopressors for treatment of 
shock 
Patients receiving norepinephrine or other vasopressors at the time of eligibility and 
randomisation can be commenced on dexmedetomidine or clonidine according to 
group allocation. The starting dose of allocated sedative is at the discretion of the 
clinical team. However, as guidance, where the dose of norepinephrine is more than 
0.15 micrograms/kg/min it is suggested than a lower starting dose of 
dexmedetomidine or clonidine may be used, at least until the existing propofol 
infusion rate is reduced. 
  
5.9.2.2 Patients who develop severe or worsening hypotension during the 
intervention period 
Any patient who develops hypotension should be managed according to local 
protocols and practice, for example with fluids and vasopressor drugs. All three 
sedative drugs (propofol, dexmedetomidine, and clonidine) can decrease blood 
pressure. If changes to sedation are made the first drug to be decreased should be 
the non-intervention drug according to group allocation, unless this is clinically 
contraindicated. The guidance for adjusting drug doses in relation to sedation state 
provided in appendix 2 applies equally whether or not patients are receiving 
vasopressors. 
If a patient experiences worsening hypotension and/or escalating doses of 
norepinephrine/vasopressors during treatment, the use of sedative drugs should be 

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reviewed especially when deep sedation is required and/or combinations of sedative 
agents are being used. Medical review is recommended. For patients in the 
dexmedetomidine and clonidine groups it is recommended that the rate of the drug 
infusion is reduced or if necessary, stopped  until cardiovascular stability is achieved 
(see appendix 2). It is important to remember that both the sedative and 
cardiovascular effects of dexmedetomidine and clonidine can persist for several 
hours after reducing or stopping the drug dose. Clonidine is likely to take longer than 
dexmedetomidine to wear off, especially in the presence of renal impairment or 
failure (see section 5.9.4 below). The drugs can be re-started and/or up-titrated again 
once the patient is more stable. The research team should encourage re-establishing 
the clonidine or dexmedetomidine, but the decision to do so will be at the discretion 
of the clinical teams. 
 
5.9.2.3 Patients who develop significant bradycardia during the intervention period 
Dexmedetomidine and clonidine both commonly decrease heart rate. If a participant 
in the trial develops severe bradycardia during the intervention, the dose of sedative 
drug can be reduced or if necessary, stopped.  
In the dexmedetomidine or clonidine groups, if the patient’s heart rate decreases to 
less than 50/minute, the dexmedetomidine or clonidine should be temporarily 
stopped until the heart rate increases to greater than 50/minute.  
Advice from the medical team should be obtained when the bedside nurse has 
clinical concerns. Treatment should follow usual local practices for managing 
bradycardia. This may include the use of glycopyrolate, atropine, dobutamine, 
norepinephrine or epinephrine, according to advice from the medical team. 
 
Once the patient is more stable, clonidine or dexmedetomidine can be re-started 
and/or up-titrated again at a dose appropriate to the sedation target, but caution 
should be used when the clinical target is deep sedation . The research team should 
encourage re-establishing the clonidine or dexmedetomidine, but the decision to do 
so will be at the at the discretion of the clinical teams.   
 
5.9.3 Management of participants with other dose limiting side effects. 
If a participant in the trial develops other suspected sedation related side effects, 
medical review is recommended. For patients in the dexmedetomidine and clonidine 
groups it is recommended that the rate of the drug infusion is reduced or if 
necessary, stopped to determine whether symptoms improve.  If symptoms do 
resolve, clonidine or dexmedetomidine can be re-started and/or up-titrated again.  
The research team should encourage re-establishing the clonidine or 
dexmedetomidine, but the decision to do so will be at the at the discretion of the 
clinical teams.   
5.9.4 Patients in whom deep sedation is requested by the clinical team 
Where the clinical team has requested deep sedation this should be recorded on the 
daily nursing shift form. The way deep sedation is maintained is under the guidance 
of the clinical team, but it is suggested that for patients receiving dexmedetomidine or 
clonidine these drugs are titrated up to the maximum tolerated dose according to the 
infusion algorithm. If additional sedative drug is needed to achieve target sedation 
this can be achieved with propofol or benzodiazepine according to the preference of 
the caring clinician. 
Caution should be used in the dexmedetomidine and clonidine groups when deep 
sedation is indicated and the patient develops bradycardia (heart rate <50/minute) 
and/or worsening hypotension or increasing norepinephrine requirements. In these 
situations the clonidine or dexmedetomidine should be reduced or if necessary, 
stopped and medical advice obtained (see sections 5.9.2.2 and 5.9.2.3 above). 

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Sedation may need to be provided using a lower dose of dexmedetomidine or 
clonidine with addition of other sedatives if required. It should be remembered that it 
may take several hours for effects from dexmedetomidine and clonidine to wear off 
(see section 5.9.4 below) 
 
When deep sedation is no longer requested by the caring clinician, Clonidine or 
dexmedetomidine should be re-established as the main IV sedative according the the 
algorithm in Appendix 2.  It is suggested that any propofol or benzodiazepine 
sedation is decreased and stopped prior to reducing the dose of dexmedetomidine or 
clonidine. However, management is at the discretion of the caring clinician. 
 
 
5.9.5 Duration of effects following reduction or discontinuation of study drug 
The ‘elimination half life’ of dexmedetomidine is typically around 2 hours and is not 
altered by renal failure. This means that after a dose change a new steady state of 
clinical sedation effect is expected after around 2-4 hours. After completely stopping 
the drug, the sedation effects would be expected to disappear substantially over the 
next 1-2 hours and be almost completely gone after 4-6 hours. 
 
The ‘elimination half life’ for clonidine is significantly longer than for dexmedetomidine 
and is typically around 13 hours ranging between 10 and 20 hours. In addition, renal 
failure can substantially prolong the elimination of clonidine from the body. More 
variation between individuals is expected for clonidine than for dexmedetomidine. 
This means that after a dose change a new steady state of clinical sedation effect 
could take longer to achieve with clonidine than with dexmedetomidine. Similarly, 
after completely stopping the drug, the sedation effects of clonidine may be slower to 
wear off than dexmedetomidine. This is likely to be more pronounced for patients 
who have received the drug for longer periods at higher doses or who have renal 
impairment. 
5.9.6 Weaning from mechanical ventilation 
All patients should have regular assessments and attempts to wean and discontinue 
mechanical ventilation throughout treatment. The approach used in individual ICUs 
and patients will not be mandated, but should adhere to the following ‘best practice’ 
principles: 
 
Continuous or regular attempts to decrease sedation drug dose to achieve 
the most awake and comfortable state considered safe by clinical staff, with a 
minimum target of ‘brief eye contact made in response to voice’. 
 
Regular sedation interruption or hold if appropriate (regular or protocolised 
sedation interruption is not required unless local practice) 
 
Early attempts to transition patients from mandatory ventilation modes (for 
example Synchronised Intermittent Mandatory Ventilation, Pressure Control 
Ventilation) to spontaneous modes (for example Pressure Support Ventilation 
or Assisted Spontaneous Breathing) 
 
Regular attempts to decrease mechanical support from the ventilator, for 
example by reducing pressure support or undertaking spontaneous breathing 
trials. 
 
Regular assessment of readiness for extubation by clinical teams.  
Advice for weaning participants on each intervention is given in Appendix 2, in the 
bedside advice sheets. 
 
5.10 WITHDRAWAL OF STUDY PARTICIPANTS 
 

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Participants or their representatives, if appropriate, are free to withdraw from the study 
at any point or a participant can be withdrawn by the Investigator. If withdrawal occurs, 
the primary reason for withdrawal will be documented in the participant’s case record 
form, if possible. The participant will have the option of withdrawal from:  
 
(i) Intervention only – follow-up and data linkage permitted  
(ii) Intervention and follow-up only – data linkage permitted  
(iii) All aspects of the trial and follow-up 
 
Patients who are withdrawn during the intervention and participants who do not 
provide consent to remain in the trial after regaining capacity will not be replaced, as 
the sample size allows up to 4.1% loss to follow-up before the primary outcome. 
However, rates of withdrawal will be monitored, especially in relation to withdrawal 
following deferred consent when this approach is used. If withdrawal rates are high a 
strategy to address this will be agreed to ensure study power is maintained. 
5.11 STOPPING CRITERIA 
There are no pre-defined statistical stopping criteria in this trial. The DMC will provide 
oversight of the trial and make their recommendations to the Trial Steering 
Committee. 
6. INVESTIGATIONAL MEDICINAL PRODUCT 
6.1 ALPHA-2 AGONIST DRUGS   
Alpha-2 agonists induce sedation by dose-dependent decrease in activity of 
noradrenergic neurons in the brain stem via post-synaptic receptor-mediated 
inhibition.44 This increases the activity of inhibitory gamma-aminobutyric acid (GABA) 
neurons, resulting in inhibitory neurotransmitter release, especially via GABA 
neurones. This mechanism contrasts with established sedatives, propofol and 
benzodiazepines, which are direct GABA agonists in the central nervous system. 
Unlike GABAergic sedatives, α-2 agonists have analgesic properties, which can 
reduce opioid requirements. Analgesia probably occurs via multiple sites, but 
primarily at the level of the spinal cord.45  
 
Alpha-2 agonists can have biphasic cardiovascular effects especially after loading or 
bolus dosing.45 Initial hypertension can occur due to activation of receptors on 
peripheral vascular smooth muscle. More frequent is hypotension and bradycardia 
due to centrally mediated sympathetic outflow inhibition and vagotonic actions. 
Cardiovascular instability is more likely in shocked and hypovolaemic patients and 
when concurrently administered with other anaesthetic agents. However, α2-agonists 
have minimal negative inotropic effects and may increase coronary blood flow. These 
effects explain why bolus doses or rapid changes to infusion rates are generally 
avoided in critically ill patients, or should be used with caution. The cardiovascular 
effects also explain the relative contraindication in patients with untreated 
second/third degree heart block. Αlpha-2 agonists have minimal effect on respiratory 
function, in contrast to GABAergic agents which can decrease respiratory drive and 
respiratory muscle activity. Other effects include diuresis, dry mouth, constipation, 
and ileus. After prolonged administration, an acute hypertensive withdrawal 
syndrome after rapid discontinuation is described, mainly following long-term 
clonidine treatment for hypertension. 

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6.1.1 Dexmedetomidine  
Dexmedetomidine is a highly selective α2-agonist with a α2:α1 receptor selectivity 
ratio of 1620:1.46 It was developed specifically as a sedative agent and is licensed by 
the US Food and Drug Administration (FDA; initially in 1999) for ICU sedation and 
subsequently procedural sedation in non-intubated patients. In the European Union 
(EU) the license (2011) is for ICU sedation of intubated adult patients requiring light 
to moderate sedation (RASS score 0 to -3). Dexmedetomidine sedation is 
characterized by spontaneous and evoked movements, and by awakening by 
external stimuli. Roused patients are more likely to be cooperative and obey 
instructions. Dexmedetomidine sedation more closely resembles normal 
physiological sleep than seen with GABA-ergic sedatives. Bolus doses and rapid 
infusions of the drug should be used with caution (see above). The drug is >90% 
protein bound; unbound drug freely crosses the blood–brain barrier to exert central 
effects. The distribution half-life is 6 min. Metabolism is by glucuronidation, 
hydroxylation, and N-methylation in the liver to inactive metabolites which are then 
renally excreted. Hepatic impairment will decrease metabolism, but renal impairment 
and renal replacement therapy should not alter activity. The terminal elimination half-
life is around 2 h. A high steady-state volume of distribution (>100 litres in adults) is 
increased in patients with low plasma albumin concentration (common during critical 
illness), prolonging the terminal half-life. 
6.1.2 Clonidine 
Clonidine was the prototype α2-agonist (developed in the 1960s), licensed for 
hypertension (1966), but subsequently used therapeutically for a wide range of 
neuropsychiatric conditions, including attention deficit hyperactivity disorder, anxiety 
disorders, migraine, drug withdrawal syndromes, and in pain medicine.47 The drug is 
available in multiple formulations (including oral; transdermal; and intravenous); 
many clinical uses are unlicensed (including ICU sedation via any route). Clonidine 
has significantly lower α2-receptor selectivity than dexmedetomidine; α2:α1 
selectivity is 220:1 (x8 less than dexmedetomidine). The α1-receptor mediated 
effects may therefore be more frequent than with dexmedetomidine when titrated to 
similar α2-mediated sedation states, which could increase cardiovascular side 
effects. Clonidine is less protein bound than dexmedetomidine (20-40%). It 
undergoes hepatic metabolism through similar mechanisms to dexmedetomidine to 
inactive metabolites that are excreted in the urine, but importantly around 65% is 
excreted unchanged in the urine. The elimination half-life is therefore significantly 
longer (6-23 hours, mean 7 hours), and (unlike dexmedetomidine) is prolonged by 
renal failure (18-41 hours; important in critical illness). Peak effects after a single 
dose occur after 10-60 minutes, but may last 3-7 hours. A single widely agreed 
evidence-based intravenous dosage regimen has not been developed for 
intravenous clonidine.  
6.2 PROPOFOL (USUAL CARE) 
Propofol (2, 6-diisopropylphenol) is a short-acting general anaesthetic agent with a 
rapid onset of action of approximately 30 seconds. Recovery from anaesthesia is 
usually rapid. The mechanism of action, like all general anaesthetics, is poorly 
understood. However, propofol is thought to produce its sedative/anaesthetic effects 
by the positive modulation of the inhibitory function of the neurotransmitter GABA 
through the ligand-gated GABAA receptors. In general, falls in mean arterial blood 
pressure and slight changes in heart rate are observed when propofol is 
administered for induction and maintenance of anaesthesia. However, the 
haemodynamic parameters normally remain relatively stable during maintenance and 

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the incidence of untoward haemodynamic changes is low. Although ventilatory 
depression can occur following administration of propofol, any effects are readily 
manageable in clinical practice. 
Propofol reduces cerebral blood flow, intracranial pressure and cerebral metabolism. 
The reduction in intracranial pressure is greater in patients with an elevated baseline 
intracranial pressure. 
Propofol is extensively distributed and rapidly cleared from the body (total body 
clearance 1.5–2 litres/minute). The decline in propofol concentrations following a 
bolus dose or following the termination of an infusion can be described by a three 
compartment open model with very rapid distribution (half-life 2 –4 minutes), rapid 
elimination (half-life 30 – 60 minutes), and a slower final phase, representative of 
redistribution of propofol from poorly perfused tissue. Clearance occurs by metabolic 
processes, mainly in the liver where it is blood flow dependent, to form inactive 
conjugates of propofol and its corresponding quinol, which are excreted in urine. 
 
6.3 STUDY DRUG IDENTIFICATION  
6.3.1 Study Drug Identification 
The IMP is defined by the active substance only, therefore all authorised brands/ 
concentrations may be used. Several concentrations and brands of these drugs are 
marketed in the UK, examples are given below and in the summaries of product 
characteristics. 
 
Clonidine:  
 
Catapres Ampoules 150 micrograms in 1ml solution for injection 
  
Dexmedetomidine:  
Dexdor 100 micrograms/ml concentrate for solution for infusion 
 
Propofol:  
 
 
Propofol 10mg/ml (1%) emulsion for injection or infusion 
Propofol 20mg/ml (2%) emulsion for injection or infusion 
 
 
6.3.2 Study Drug Manufacturer 
Details of one manufacturer of each of the trial drugs are given below.  Pharmacies 
may provide the brand of each drug that is available to them. Examples of 
manufacturers are given below. 
 
Catapres – Glenwood GmbH, Pharmazeutische Erzeugnisse, Arabellastr. 17, 81925 
Munich, Germany.  
 
Dexdor – Orion Corporation, Orionintie 1, FI-02200 Espoo, Finland  
 
 Propofol– Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business 
Campus, Dublin 24, Ireland  
 
6.3.3 Marketing Authorisation Holder 
Details of one marketing authorisation holder are given below. 
 
Catapres - Glenwood GmbH, Pharmazeutische Erzeugnisse, Arabellastr. 17, 81925 
Munich, Germany under marketing authorisation number PL 22824/0009.   

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Dexdor – Orion Corporation, Orionintie 1, FI-02200 Espoo, Finland under marketing 
authorisation number PLGB 27925/0104  
 
Propofol  – Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business 
Campus, Dublin 24, Ireland under marketing authorisation number PL 39699/0074 
(10mgs/ml) and PL 39699/0076 (20mgs/ml). 
 
6.3.4 Labelling and Packaging 
The trial has been classified as a Type A risk adapted CTIMP as any potential risk is 
no higher than that of standard medical care. Dexmedetomidine and propofol are 
being used as licensed. Clonidine is a licensed drug in the UK but is not licensed for 
ICU sedation. However, the use of clonidine as a sedative for MV patients in ICU is 
common practice in the UK and pre-trial work showed that more than 90% of ICU 
units that responded used clonidine, in up to 25% of patients. Guidelines for use of 
clonidine as a sedative agent are those recommended by the UK Intensive Care 
Society (www.ics.ac.uk/ICS/guidelines-and-standards.aspx) and are detailed in 
appendix 1. 
The IMPs will therefore not require any specific labelling or packaging. 
Detailed prescribing and administration instructions are provided in the protocol. 
6.3.5 Storage 
Drugs will be procured through NHS routes via pharmacy and stocked within ICUs. 
Drugs will be stored unblinded within ICUs under usual clinical conditions, as for 
current routine clinical use. No special monitoring will be performed. 
 
6.4 DOSING REGIMEN 
Both interventional drugs will be used according to a weight based dosing algorithm 
with regular increments or decrements according to sedation state (appendix 1).  
Dexmedetomidine will be diluted with 5% glucose or 0.9% sodium chloride solution to 
a concentration of 8 micrograms per mL in syringes or fluid bags with a total volume 
according to local practice. 
Clonidine will be diluted with 5% glucose or 0.9% sodium chloride solution to a 
concentration of 15 micrograms per mL in syringes or fluid bags with a total volume 
according to local practice. 
Dosing charts will be presented indicating mLs.hour-1 for a range of doses, for a 
range of patient weight estimations from 45kg to 100kg in 5kg increments. Dosing 
concentrations for infusion are those recommended by the UK Intensive Care Society 
(www.ics.ac.uk/ICS/guidelines-and-standards.aspx). Lower starting doses can be 
used at clinical discretion for patients with cardiovascular instability. Patients who 
weigh greater than 100kg will be dosed using the regimen suggested for 100kg 
weight. The trial management team can be contacted for specific advice prior to 
randomisation if required. For patients who weigh less than 45kg, it is suggested that 
advice is sought from the trial management team prior to randomisation.  
For individual patients, it is recommended that the weight-based dose regimen 
closest to the weight on the dosing chart is used. 
Flow charts (Appendix 2) will provide a bedside guide for increasing or decreasing 
dexmedetomidine or clonidine dose according to clinical sedation state and 
cardiovascular status. 

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6.5 PARTICIPANT COMPLIANCE 
Control of drug dose will be by the bedside clinical team. Participant compliance will 
not therefore be relevant. 
Compliance by the clinical teams will be evaluated as part of the process evaluation. 
Training materials to support protocol compliance will be provided to sites, and 
uptake and engagement with these materials will also be examined as part of the 
process evaluation.  
6.6 OVERDOSE 
Patient-initiated overdose will not be relevant because dosing will be controlled by 
clinical staff. Dosing algorithms will provide guidance when to reduce or limit 
dexmedetomidine or clonidine dose according to heart rate and blood pressure. If an 
overdose does occur it will be managed as per standard care. Details of symptoms 
and management of overdose are detailed in the SPC. All patients will be in an 
intensive care unit when receiving the IMP, and closely monitored by staff with 
expertise in managing the IMP use and the common complications that may occur. 
6.7 OTHER MEDICATIONS 
 
6.7.1 Prohibited Medications 
There are no medications that are prohibited in the clonidine or dexmedetomidine 
groups. Clinical staff will be asked to titrate study drug to a clinical sedation target, 
with a default of ‘brief eye contact made in response to voice’, while minimising and 
wherever possible discontinuing propofol. If sedation with clonidine or 
dexmedetomidine at the maximum recommended dose does not control agitation or 
achieve comfort, then propofol can be used to provide additional sedation. In these 
situations, propofol should be the first sedative drug to be decreased if patients 
become deeply sedation or sedation is being decreased for other reasons. 
During the intervention period, clonidine should not be used for first line (post-
randomisation) sedation in patients allocated to the dexmedetomidine group and  
conversely dexmedetomidine should not be used for first line sedation (post-
randomisation) in patients allocated to the clonidine group. 
In the usual care (propofol) group, neither clonidine nor dexmedetomidine should be 
used as first line sedation during the intervention period. Either drug can be used at 
the discretion of the clinical teams for specific indications such as agitation or severe 
delirium or during difficult weaning. In these situations, the use of clonidine or 
dexmedetomidine should be recorded in the CRF.  
 
6.7.2 Medications used with caution and clinical judgement 
Medications that may exacerbate the bradycardic and hypotensive effects of 
clonidine and dexmedetomidine can be used, but caution and clinical judgement 
should be used. For a list of drugs to be used with caution, refer to the summary of 
product characteristics. 
Caution should be used when large doses of propofol are required in addition to 
clonidine or dexmedetomidine to achieve the desired sedation state, because of the 
potential for cardiovascular instability. 
The clonidine, dexmedetomidine and propofol Summary of Product Characteristics 
(SPC) is provided in a separate document with a cover sheet and signature page 
(signed and verified by the CI and Sponsor) and is filed in the TMF. 

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7. STUDY ASSESSMENTS AND DATA COLLECTION 
7.1 SCREENING DATA 
Anonymised screening data will be recorded on screening logs and entered onto the 
database by research teams at site. This data will be used to generate a CONSORT 
diagram at the end of the trial. 
7.2 BASELINE DATA 
The following patient demographic variables will be collected pre-randomisation:  
Date of birth, CHI/hospital number, gender, estimated weight, RASS score, CAM-ICU 
status (unless RASS is -4 or -5, or is -3 but the assessor is unable to assess CAM-
ICU status), final eligibility review 
 
The remaining patient demographic variables will be collected post-randomisation:  
 
Past medical history (including liver co-morbidities), functional comorbidity index 
(FCI), HRQoL prior to hospital admission (assessed by proxy; EQ-5D-5L), APACHE 
II score collected at 24 hours (based on first 24 hours in ICU), Sequential Organ 
failure Score (SOFA) excluding neurologic score, diagnosis at ICU admission, type of 
admission, time from mechanical ventilation in ICU to randomisation, dose of 
sedative and opiate at randomisation, sepsis status, baseline blood results (FBC, 
urea/electrolytes, LFTs, coagulation), arterial blood gas at baseline, baseline delirium 
risk (PRE-DELIRIC score; based on first 24 hours in ICU). 
7.3 DAILY DATA COLLECTION DURING ICU STAY 
The following data will be collected on a daily basis during ICU stay until the 
participant has had the primary outcome confirmed or for up to 28 days after 
randomisation (whichever occurs sooner).  
7.3.1 Data recorded by bedside clinical nurse 
Clinician decision to maintain deep sedation during nursing shift; reason for deep 
sedation (if required); RASS score every 4 hours; behavioural pain assessment (limb 
movement and ventilation compliance elements) every 12 hours; CAM-ICU 
assessment every 12 hours (at end of nursing shift); 12 hourly assessment of 
patient’s ability to communicate pain (binary assessment); 12 hourly assessment of 
patient’s ability to cooperate with care (binary assessment). These data will be used 
to collect the following in the CRF (transcribed by research staff): highest and lowest 
RASS score for each ICU day; ‘least’ and ‘greatest’ pain behaviour for each ICU day; 
CAM-ICU status on each ICU day; whether patient was able to communicate pain on 
each ICU day; and whether patient was able to cooperate with care on each ICU day. 
7.3.2 Data collected from a visiting relative/partner/friend 
This data will be collected until the primary outcome is confirmed (or day 28) from the 
personal legal representative (PerLR) who provided consent for participation on days 
they visit the patient. Relative/ partner/friends response to the following questions 
(based on their opinion at time of assessment): 
Does the patient appear awake to the visitor? 
Does the patient seem comfortable to the visitor? 
Does the visitor feel they can communicate with the patient? 
7.3.3 Data collected by research staff  
MV status, MV mode and settings. Extubation events (time); Use of Non-invasive 
Ventilation (NIV); Reintubation events (time). Tracheostomy events 

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Total dose of propofol during 24 hours; dose of study drug in 24 hours. Use of any 
other drugs for sedation (benzodiazepines; others); use of any other drugs for 
delirium or agitation (haloperidol; other antipsychotic agents). No other drugs need to 
be recorded. 
SOFA score (excluding neurologic score) 
Sedation-related adverse events: unplanned removal of nasogastric tube, central 
line, arterial line or drain; unplanned extubation; peripheral line removal; staff injury; 
or patient injury 
Cardiovascular adverse events: highest vasopressor dose during 24 hours; severe 
bradycardia (HR <50/minute; yes/no); hypotension (lowest systolic blood pressure); 
cardiac arrhythmia (including cardiac arrest; yes/no; type of arrhythmia);  
Other adverse events: ileus (yes/no) 
7.4 ICU DISCHARGE DATA 
Patient status (alive; dead; transfer to other ICU). Date/time of discharge from study 
ICU (and other ICU if applicable), Date/time of final extubation 
7.5 HOSPITAL DISCHARGE DATA 
Date of acute hospital discharge 
7.6 POST HOSPITAL DISCHARGE ASSESSMENTS 
Survival status will be confirmed by the participating sites prior to follow-up. All 
assessments will be done via post or telephone contact, unless the patient is an 
inpatient in the participating hospital at the time of follow up. Follow up at 30 days will 
be undertaken locally by staff at study sites. Follow-up at 90 days and 180 days will 
be undertaken either locally by staff at study sites or centrally, by staff based in 
Edinburgh. We will also send a short study update with the 90 day and 180 day 
follow-up questionnaires (if being completed by post).. 
7.6.1 30 days post-randomisation assessments (up to 45 days) 
Recalled pre-ICU EQ-5D-5L; EQ-5D-5L at 30 days. 
7.6.2 90 days post-randomisation assessments (up to 105 days) 
Patient experience of intensive care (ICE-Q questionnaire); health related quality of 
life (EQ-5D-5L); health resource use questionnaire. (Note: these outcomes will not be 
collected for patients recruited during the final months of the trial recruitment period, 
as agreed with the funder and TSC as a strategy to enable trial completion within 
budget).  
7.6.3 180 days post-randomisation assessments (up to 195 days) 
Anxiety and depression (HADS questionnaire); post-traumatic stress (IES-R 
questionnaire); cognitive function (TMoCA); health related quality of life (EQ-5D-5L); 
health resource use questionnaire. (Note: these outcomes will not be collected for 
patients recruited during the final months of the trial recruitment period, as agreed 
with the funder and TSC as a strategy to enable trial completion within budget). 
7.6.4 Survival status 
Survival will be collected up to 180 days post-randomisation. (Note: this outcome will 
not be collected for patients recruited during the final months of the trial recruitment 
period, as agreed with the funder and TSC as a strategy to enable trial completion 
within budget). 

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Table 2: Table of Assessments. $Note that for patients recruited during the final months of 
trial recruitment, the 90 and 180 days follow will be truncated and not collected. This was 
agreed with the TSC and funder to reduce trial costs and enable trial completion.  
7.7 DATA MANAGEMENT 
The Edinburgh Clinical Trials Unit will be responsible for data management and 
quality. A data management plan will be agreed to cover data entry, coding, security 
and storage, including quality control.  
7.7.1 Personal Data 
The following personal data will be collected as part of the research: 
Participant’s name, address, phone number, date of birth and NHS/Community 
Health Index (CHI) number will be collected as well as the name of the Personal 
Legal representative who gave their consent.  
Personal data will be stored securely by the research team at each recruiting site for 
up to 10 years after the study has finished. 
7.7.2 Transfer of Data 
Data collected or generated by the study may be transferred to external individuals or 
organisations outside of the Sponsoring organisation(s).  It may be provided to 
 
Pre-
Randomis
ation 
Baseline 
Data 
Daily ICU 
Data 
Collection 
 
ICU 
Discharge 
Hospital 
Discharge 
30 
days 
90 
days$ 
180 
days$ 
Screening for eligibility and consent, demographics, 
CHI/hospital number, RASS, CAM-ICU, final eligibility 
check 
X 
 
 
 
 
 
 
 
Baseline data collection - baseline data, FCI, 
APACHE II, SOFA, RASS, CAM-ICU, PRE-DELIRIC 
(collected at 24 hours),  EQ-5D-5L (assessed by 
proxy). 
 
X 
 
 
 
 
 
 
Sepsis substudy only  - 2 blood samples for 
inflammatory markers  
 
Baseline sample (within 12 hours post 
randomisation)  
 
60 hour sample (within 48-72 hours post 
randomisation)  
 
X 
 
 
 
 
 
 
Daily data collection during ICU stay until primary 
outcome confirmed or day 28 – clinical team (4hrly -  
RASS score and pain assessment; 12hrly – CAM-
ICU, SQAT, co-operation and communication 
assessment) 
 
 
X 
 
 
 
 
 
Daily data collection during ICU stay until primary 
outcome confirmed or day 28 – research team (MV 
data collection, IMP and drug usage, SOFA score, 
adverse event data collection) 
 
 
X 
 
 
 
 
 
Assessment of comfort and communication by 
informant until primary outcome confirmed or day 28 
 
 
X 
 
 
 
 
 
Adverse Event data collection until ICU discharge 
 
 
X 
 
 
 
 
 
ICU and hospital discharge data 
 
 
 
X 
X 
 
 
 
Mortality 
 
 
X 
X 
X 
X 
X 
X 
Intensive Care Experience Questionnaire (ICE-Q) 
 
 
 
 
 
 
X 
 
Hospital Anxiety and Depression Scale (HADS) 
questionnaire 
 
 
 
 
 
 
 
X 
Impact of Events Scale – revised (IES-R) 
 
 
 
 
 
 
 
 
X 
Montreal Cognitive Assessment Tool (Telephone 
version - TMoCA) 
 
 
 
 
 
 
 
X 
Euroqol tool (EQ-5D-5L) 
 
 
 
 
 
 
X 
X 
X 
Recalled  Euroqol tool (EQ-5D-5L) 
 
 
 
 
 
 
X 
 
 
Health economic questionnaire (including hospital 
resource use and return to employment) 
 
 
 
 
 
 
X 
X 

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researchers running other research studies outwith NHS Lothian/University of 
Edinburgh. Participant information will only be used by organisations and researchers 
to conduct research in accordance with the UK Policy Framework for Health and 
Social Care Research. Where this information includes identifiable information, it will 
be held securely with strict arrangements about who can access the information. 
We intend to perform data linkage with nationally held databases to find out about the 
participant’s long term health. In order to identify them on these databases we will 
use their NHS/CHI number and other personal details.  
7.7.3 Data Processor 
The data processor is the Edinburgh Clinical Trials Unit, Usher Institute, University of 
Edinburgh. 
7.7.4 Data Controller 
The data controller is the University of Edinburgh and NHS Lothian who are the co-
sponsors of this study. 
 
7.8 SOURCE DATA DOCUMENTATION 
Source data is defined as all information in original records and certified copies of 
original records or clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents. Source documents are original documents, data and 
records where source data are recorded for the first time. 
The source data will be the patient’s medical records, electronic records, data 
collection sheets and completed questionnaires. 
 
7.9 CASE REPORT FORMS  
Study data will be recorded on the electronic CRF by members of the research team 
at site. Follow-up study data collected centrally will also be recorded on the eCRF. 
Paper data collection sheets may be used if required by sites. Case report forms 
must be reviewed and approved by the ACCORD Monitor prior to use (see ACCORD 
SOP CR013 CRF Design and Implementation).  
7.10  TRIAL DATABASE 
A trial database developed by the Clinical Trials Unit in Edinburgh will be used to 
collect all study data. Individuals will be issued log-in details and access will be 
restricted to necessary fields only. The study teams at site and individuals at ECTU 
involved in follow-up data collection or data entry will enter data. Participants contact 
details will be held in an encrypted part of the database. Following data analysis the 
database will be archived by programmers in ECTU. This archived database will be 
stored on University of Edinburgh servers once user access has been disabled. 
Access to the archived database will be controlled by the Chief Investigator. 
 
8. STATISTICS AND DATA ANALYSIS 
8.1 SAMPLE SIZE CALCULATION 
8.1.1 Modelling primary outcome 
Minimum clinically important difference (MCID):  

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Based on clinical consensus, likely economic benefit, and the findings of systematic 
reviews, a MCID of a mean difference of 2 days has been chosen for all superiority 
tests. For non-inferiority of clonidine versus dexmedetomidine, a non-inferiority 
margin of 1 day has been chosen.  
Sample size and power were modelled based on the analytic framework outlined in 
figure 1, which includes a hierarchical approach to hypothesis testing. We used a 
large prospective data set from a recent sedation trial in 8 UK ICUs for modelling 
(N=708).21 Based on this data set, we estimate that 53% of patients in the “usual 
care” group will be extubated and around 14% will have died prior to extubation at 7 
days. 
STAGE ONE:  
If either dexmedetomidine or clonidine are superior to usual care by an overall mean 
difference of 2 days in time to extubation, this translates to an estimated extubation 
rate of 63% in the dexmedetomidine or clonidine arm at 7 days. The death rate of 
14% was assumed to remain the same as for the usual care arm. The minimum 
follow-up period will be 28 days in ICU for all patients. Under these conditions, using 
nQuery version 8 software (log-rank test accounting for competing risks), a sample 
size of 459 per arm (1377 patients in total, 1093 extubation events across the three 
arms) has 99% power to detect hazard ratios of 1.37 indicating superiority of 
clonidine or dexmedetomidine over usual care, assuming a one-sided 2.5% 
significance level.  
STAGE TWO:  
These analyses are only undertaken if one or other or both of the stage one tests are 
significant. For the non-inferiority test of clonidine relative to dexmedetomidine (test 
H3), the non-inferiority margin is fixed on the original scale to be a 1 day absolute 
mean difference in time to extubation. Based on the real dataset from an untreated 
ICU population, a 1 day absolute mean difference translates into an estimated 
survival probability of 63% in the dexmedetomidine arm at 7 days and 57% in the 
clonidine arm at 7 days. This then equates to an estimated non-inferiority margin on 
the hazard ratio scale of 0.83 according to nQuery version 8 software (log-rank test 
accounting for competing risks). As before the death rates in both arms were 
assumed to be 14% at 7 days. The minimum follow-up period is 28 days in ICU for all 
patients. Using this information in nQuery version 8 software (log-rank test 
accounting for competing risks), 459 patients per arm (918 in total, 741 extubation 
events) provides 80% power to conclude non-inferiority of clonidine, using a one-
sided 4% significance level. The power calculation for the superiority comparison of 
dexmedetomidine versus clonidine (test H4) is the same as that for STAGE ONE. 

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Figure 1: Analytic framework which efficiently tests the trial questions using a 
hierarchical analytic structure with serial gatekeeping to preserve study power. 
Hypothesis tests will be performed using a 2.5% one-sided significance level, with 
the exception of the non-inferiority test H3 which will use a 4% one-sided significance 
level. 
 
Simulation work was used to calculate the overall power of test H1 (clonidine 
superiority test versus propofol) and test H3 (clonidine non-inferiority test versus 
dexmedetomidine) being statistically significant using  Fine and Gray proportional 
sub-distribution hazards regression analysis based on 2000 trials simulated from the 
real ICU dataset (mean 7 days on ventilation).21 Assuming that dexmedetomidine 
and clonidine are both superior to usual care by an overall true mean difference of 2 
days, and there is no difference between dexmedetomidine and clonidine, then a 
total sample size of 1377 (459 per group) provides 80% power of concluding non-
inferiority of clonidine over dexmedetomidine (test H3) and concluding clonidine is 
superior to usual care (test H1) based on simulation, using a one-sided 2.5% 
significance level for H1 and a one-sided 4% significance level for H3.  
STAGE THREE: The power calculation for the superiority comparison of clonidine 
versus dexmedetomidine (test H5), which will only be done if stage one 
demonstrates superiority (tests H1 or H2) and clonidine is non-inferior to 
dexmedetomidine (test H3), is the same as that given in STAGE ONE. 
8.1.2 Loss to follow-up 
Withdrawal rates have been <5% in recent NIHR-funded RCTs.48-50 Some other 
patients may be lost if transferred to another ICU before reaching the primary 
endpoint. Experience during the first 950 participants randomised to A2B indicated a 
primary outcome loss to follow-up rate of 4.1%.  Sample size is therefore inflated by 
this amount to allow for drop-out or loss to follow-up (479 per group (1437 in total). 

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8.1.3 Final sample size 
A sample size of 1437 (479 per group) provides a highly efficient trial to address the 
key research questions, namely whether either (or both) α2-agonists are superior to 
usual care and which agent provides best value for money to the NHS. 
8.1.4 Mortality 
For the key outcome of mortality in ICU prior to extubation, a sample size of 459 per 
group provides 76% power to detect a difference in mortality of 7% (equivalent to a 
HR of approximately 1.5) using Cox regression assuming mortality in the usual care 
group is 23% and 16% in the clonidine/dexmedetomidine group, using a 2-sided 5% 
significance level. 
8.2 PROPOSED ANALYSES 
8.2.1 Estimand 
Here we define the estimand for the primary analysis of the primary outcome in the 
trial, in line with the draft addendum to ICH E9 (Statistical Principles for Clinical 
Trials): ICH E9 (R1), Defining the Appropriate Estimand for a Clinical Trial/Sensitivity 
Analyses. 
 
Population 
Adult ICU patients enrolled within 48h of MV starting in ICU and 
expected to require sedation with propofol and MV for at least 48h, at least 24h of 
which would be after randomisation. Long-term home ventilation, terminal illness, 
selected diagnoses, allergy to study medication, pregnancy and expected death 
within 24h are exclusion criteria. 
 
Variable 
Time to successful extubation post-randomisation (hours). 
 
Population-level Summary Cumulative incidence function of time to extubation; 
sub-distribution hazard ratio (HR) 
 
The following Intercurrent Events have been identified which would prevent 
measurement of the primary outcome or change the interpretation of the measured 
primary outcome: 
1. Death before the time point at which randomised treatment is due to start. 
2. (a) Dexmedetomidine allocated in randomisation but not started 
(b) Clonidine allocated in randomisation but not started 
3. Additional propofol being administered when cardiovascular side effects have 
limited the escalation of dexmedetomidine or clonidine. 
4. Additional propofol being administered when non-cardiovascular side effects 
have limited the escalation of dexmedetomidine or clonidine. 
5. Death before successful extubation. 
6. Patient withdrawal from intervention and follow-up (situation where deferred 
consent is not granted is a subset of such events). 
7. Transfer to another ICU before successful extubation. 
8. Use of dexmedetomidine as main sedative in usual care group. 
9. Use of clonidine as main sedative in usual care group. 
10. Use of rescue medication in the presence of agitation or delirium. 
 
Events 1, 2(a), 2(b), 8 and 9 are expected to be rare and no specific actions will be 
taken: analysis of these events will be by intention to treat, except for event 1 which 
will be handled in the same way as event 5. 
 

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Events 3 and 4 will be dealt with using an intention to treat approach.  Non-
cardiovascular side-effects will mostly be sedation-related and therefore will be 
further analysed as secondary outcomes. 
 
Event 5 will be treated as a competing risk for the primary outcome, and will therefore 
be analysed using a hypothetical strategy. 
 
Event 6 will also be handled using a hypothetical strategy, in which the time to 
extubation will be censored at the point of withdrawal and the withdrawals will be 
assumed to lead to missing at random (MAR) data on the primary outcome.  
Complete follow up should still be possible for most participants in whom event 7 
occurs; if not, the hypothetical strategy used for event 6 will also be implemented.   
 
Event 10 is analogous to events 8 and 9 but applies to all treatment arms and 
medications.  An intention to treat approach will be used for this event. 
 
Full details of the methods of dealing with the above intercurrent events will be 
incorporated in the statistical analysis plan.  
 
8.2.2  Statistical analysis 
For the primary analysis, a Fine and Gray proportional sub-distribution hazards 
regression analysis of time from randomisation to successful extubation will be 
performed (this method allows us to directly model the cumulative incidence of 
extubation after taking into account the competing risk of mortality) for each 
hypothesis test permitted under the analytic structure (Figure 1). Results will be 
expressed as sub-distribution HRs with corresponding 95% confidence intervals and 
p-values. 
 
The following supplementary analyses will be performed to provide reassurance 
about the robustness of the main analysis of the primary outcome, for each between-
arm comparison:  
(i) 
A Cox frailty proportional hazards regression model will be fitted to the primary 
outcome, with censoring for deaths or loss to follow-up in ICU while on MV. 
Although death in ICU may be considered a competing risk, this modelling 
approach allows us to estimate the instantaneous risk of experiencing a 
successful extubation event at time t given that the patient is still alive at time t 
(in the literature this is called the “cause-specific hazard” of extubation for 
patients who have not yet died).51-53 Site will be included in the model as a 
random effect.  
(ii) 
A Cox frailty regression analysis of time from randomisation to ICU mortality 
while on ventilation. Patients experiencing successful extubation events or loss 
to follow-up prior to mortality will be censored. This analysis will provide “cause-
specific” HRs for patients on MV to support the primary analysis results. . Site 
will be included in the model as a random effect. 
(iii) 
A Cox frailty regression analysis of time to all-cause mortality, with censoring 
only for patients lost to follow-up during the six months follow-up period. This 
analysis will allow us to compare the risk of overall mortality across trial arms 
for all patients, regardless of whether or not patients are still on MV. Site will be 
included in the model as a random effect. 
(iv) 
For each participant, the proportion of care periods will be recorded in which 
propofol treatment was maintained even though dexmedetomidine or clonidine 
had not been up-titrated to its maximum dose and had no dose-limiting side-

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effects. As an exploratory analysis, the main analysis of the primary outcome 
will be repeated using the adherence analysis set (section 8.2.3) rather than 
the full analysis set. 
 
For the secondary outcomes other than mortality, formal hypothesis testing will not 
be performed but point estimates and 95% confidence intervals for pairwise 
differences between randomised groups will be calculated. A trial analysis plan 
providing full details will be finalised prior to locking the trial database. 
 
8.2.3 Analysis populations 
Unless otherwise stated in the statistical analysis plan, efficacy analysis will be 
performed on the full analysis set: all randomised participants analysed according 
to their allocated treatment group, regardless of the treatment actually received. 
The adherence analysis set will be formed of all randomised participants in the full 
analysis set who, in the dexmedetomidine group received any dexmedetomidine on 
the day of randomisation; in the clonidine group received any clonidine on the day of 
randomisation; or in the usual care group received neither dexmedetomidine nor 
clonidine (except as rescue medication for agitation) on the day of randomisation. 
 
8.2.4 Exploratory analyses 
Exploratory analyses will be undertaken where appropriate to explore whether the 
effects of the interventions on important outcomes were associated with differences 
in the way the intervention protocol was implemented, either at a centre level or a 
patient level. These analyses will be exploratory and will include the use of data from 
the process evaluation if appropriate. Details of a priori defined analyses will be 
included in the Statistical Analysis Plan; any post-hoc analyses will be documented 
separately.  
9. PROCESS EVALUATION  
We have included a process evaluation (PE) in the A2B trial given that ICU sedation 
is a complex healthcare intervention that involves multiple members of the healthcare 
team, assessing and delivering multiple agents using a series of interrelated 
activities. Based on previous evidence, it is highly likely that sedation practices vary 
across site. Therefore, it is essential that we develop a detailed understanding of how 
the study intervention is operationalised in individual sites with a view to developing 
an understanding of the relationship between implementation and trial outcomes. The 
results of the process evaluation, in the context of the trial outcomes, will help us to 
distinguish between intervention failure and implementation failure, which will be 
essential information for interpreting trial results and guiding implementation into 
practice beyond the trial, if appropriate.  
9.1 AIMS AND OBJECTIVES  
The aim of the process evaluation is to explore the processes involved in intervention 
delivery, and identify factors and the mechanisms of their interaction likely impacting 
on trial outcomes. Specific objectives that will guide data collection are: 
1. Establish the extent to which the intervention is delivered as intended (fidelity, 
dose, and reach), over time and across different ICUs;  

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2. Ascertain how clinical staff understand and respond to the intervention, over 
time and across different ICUs;  
3. Explore the importance of context (inter-ICU differences, changes over time) 
and determine factors (including organisational structure and processes) that 
affect intervention implementation and delivery.  
9.2 DATA COLLECTION METHODS 
Pre-trial: information collected from potential sites during the site recruitment process 
regarding usual sedation practices will be used to ensure units with a mix of sedation 
practices are included in the pilot phase so that ability to deliver the intervention in 
various settings is confirmed.  
During internal pilot: At site visits we will interview staff responsible for caring for 
patients in the trial to determine acceptability of the trial protocol and trial drugs, 
including barriers and enablers, organisational processes affecting sedation practice, 
and any other processes that might affect operationalisation of the study. These data 
will inform feasibility and any changes required to maximise recruitment and fidelity to 
the trial protocol.  
During main study: A purposive sample of sites (approximately 10) will selected at 
which staff will be interviewed (either in-person or remotely via tele/video conference)  
to obtain information regarding the implementation process including acceptability of 
the intervention, barriers and facilitators to implementation and delivery, and clinical 
decisions impacting upon fidelity to the protocol.  
Final site visits or consultations: Individual and small group interviews with staff 
involved in trial implementation and/or intervention delivery will be conducted either 
in-person or remotely via tele/video conference. We will employ maximum variation 
sampling to obtain 10 – 15 sites and purposive sampling to obtain a range of 
participants according to grade, profession and role. We will explore reflections on 
use of the trial protocol and trial drugs, including perceived barriers, and enablers, 
and organisational processes affecting sedation practice. 
9.3 DATA ANALYSIS 
We will use a Framework approach to analyse qualitative data. This will allow us to 
use themes identified a priori alongside those that emerge de novo in the 
development of the final analytical framework. To ensure confirmability and 
trustworthiness, a sample of textual data will be double coded and the independent 
analyses shared to identify key difference and similarities in pursuit of an agreed final 
analysis. We will synthesise this evidence with that derived from researcher 
observations of unit context and practice by looking for patterns and exceptions that 
cross-cut the entire body of data. Using this overarching approach, we will generate a 
collective body of evidence on the barriers and facilitators related to trial 
implementation and intervention delivery. 
Routinely collected quantitative trial data will be interpreted using descriptive 
statistics, and examined alongside the qualitative data to understand intervention 
fidelity, dose, and reach. 
10. HEALTH ECONOMIC EVALUATION 
10.1 OVERVIEW 
A detailed health economic evaluation will be included. The significant cost 
differences between dexmedetomidine and both usual care and clonidine make this 
especially relevant. Of importance, the cost of dexmedetomidine has decreased 
substantially during the conduct of the trial, such that the cost-effectiveness of the 

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interventions may be different in the context of pricing in the ‘post trial’ era. Additional 
drug costs associated with α2-agonists should be balanced against potential cost 
savings from reductions in ICU and hospital stay and altered outcomes. We will 
undertake a detailed analysis of the cost and cost-effectiveness of dexmedetomidine, 
clonidine and usual care. Our analysis will conform to accepted economic evaluation 
methods in the UK54. The comparisons made in the economic evaluation will reflect 
those of the staged hypothesis tests for the primary outcome (figure 1). We will 
estimate costs and cost-effectiveness for the ‘within-trial’ period (6 months/short-run 
model) and also over the expected lifetime of the patient (‘lifetime’/long-run model). 
Costs will be assessed from the perspective of the NHS and personal social services 
(PSS). For both the within-trial and lifetime analyses we will undertake cost-utility 
analyses, estimating incremental cost per quality-adjusted life year (QALY) gained54.  
10.2 WITHIN-TRIAL ANALYSIS 
For the within-trial analysis we will calculate detailed cost information on index 
hospitalisation for every patient from ICU admission to hospital discharge and during 
6 months follow-up. Patient-level resource use data will be collected on items 
including: sedative drugs; costs associated with managing adverse events (e.g., 
delirium); length of ICU stay and hospital wards; use of MV; and co-prescribed 
medications. Patient-level resource use data will be collected post-discharge up to 6 
months using questionnaires at 3 and 6 month follow-up: hospital re-admissions; 
A&E and outpatient visits; GP and nurse visits in clinic and at home; medications; 
care home admissions; any other contacts with primary and social care (e.g., 
physiotherapist, occupational therapist, social worker, counsellor). Unit costs will be 
obtained from published sources and inflated where appropriate before being applied 
to the volume of resource use data.55 56 57  
QALYs will be calculated based on the HRQoL and mortality data collected during 
the trial. HRQoL will be measured using the EQ-5D-5L (www.euroqol.org), which we 
will collect at 30 days, 3 and 6 months (see table 1). As patients recruited to the trial 
will be critically ill, completion of the EQ-5D-5L at baseline will not be possible. 
Previous studies have assumed a common baseline value for all patients (e.g., 
zero).58 We will use this approach and two alternatives. First, we will estimate 
baseline utility scores for patients using proxy responses from a person who knows 
the patient. In this case we will use the proxy version of the EQ-5D-5L (by the 
patient’s spouse, parent or (adult) child).59 The type of proxy respondent will be 
controlled for in subsequent analyses. Second, we will ask patients to retrospectively 
record their baseline EQ-5D-5L at the 30 day follow-up point. We will evaluate 
QALYs associated with each strategy using all three approaches; the base case 
approach will use the proxy responses. Patients who die will be assigned a utility 
value of zero at the date of death and all subsequent time periods. Patient-specific 
utility profiles will be constructed assuming a straight line relation between each of 
the patients’ EQ-5D-5L scores at each follow-up point. The QALYs experienced by 
each patient from baseline to 6 months will be calculated as the area underneath this 
profile.  
Multiple imputation by chained equations will be used to deal with missing HRQoL 
and resource use values. Subsequent analyses of imputed data will include variance 
correction factors to account for additional variability introduced into parameter 
values as a result of the imputation process. Cost-effectiveness will be calculated as 
the mean cost difference between groups divided by the mean difference in 
outcomes (QALYs) to give the incremental cost-effectiveness ratio (ICER). We will 
also calculate net monetary benefits (NMBs). We will subject the results to extensive 
deterministic (one-, two- and multi-way) and probabilistic sensitivity analysis. For the 

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latter, non-parametric methods for calculating confidence intervals around the ICERs 
and NMBs based on bootstrapped estimates of the mean cost and QALY differences 
will be used.60 These methods will appropriately account for the multiple imputation of 
the missing data. The bootstrap replications will also be used to construct cost-
effectiveness acceptability curves, which will show the probability that each strategy 
is cost-effective at 6 months for different values willingness to pay for additional 
QALYs by the NHS.  
10.3 LIFETIME ANALYSIS 
In the lifetime model cost-effectiveness will be calculated in terms of the incremental 
cost per QALY gained. A review of the NIHR HTA website 
(www.hta.ac.uk/project/htapubs.asp) and the NHS Economic Evaluation Database 
(NHS-EED, www.crd.york.ac.uk https://www.crd.york.ac.uk/CRDWeb/) (last search 
15/05/2017) reveals there have been no previous analyses to evaluate lifetime cost-
effectiveness of the study strategies61. Given this paucity of evidence, we will develop 
a de novo cost-effectiveness model that will be populated based on available 
evidence, including the data collected during the trial. We will: [1] design a lifetime 
model to characterize health states of ICU survivors; [2] populate the model using 
data identified from the trial and published literature and routine sources; [3] relate 
outcomes from the trial to final outcomes, expressed in terms of QALYs; and [4] 
identify which parameters in the model are most uncertain and are important drivers 
of cost-effectiveness. The model is likely to use a similar structure to a previous 
economic evaluation of long-term cost-effectiveness for ICU patients in the UK62. 
Survival analysis of the RCT data will provide the basis for extrapolating any within-
trial differences in costs and QALYs63. The model will use external data on long-term 
survival of ICU survivors, including from co-applicants expert in this area (Lone, 
Walsh).18 Specific details of the data to be used to populate the model will be 
determined following the development of the structure and the systematic searches 
of the literature to identify existing models. We will undertake deterministic (one-, 
two- and multi-way) and probabilistic sensitivity analysis, the latter assuming 
appropriate distributions and parameter values.63 We will combine data on 
incremental costs with epidemiological data on projected patient numbers and 
undertake a budget impact analysis to evaluate what the total cost impact of each 
strategy would be were it to be scaled up; budget impact will be calculated separately 
for ICU-related costs only, the within-trial period and using a lifetime time horizon, as 
each might be appropriate for different decision-makers. We will also use the 
probabilistic sensitivity analyses combined with the epidemiological information on 
projected patient numbers to undertake a value of information analysis to evaluate 
the potential economic value of future research on this topic.63 
11. MECHANISTIC SUB-STUDY 
In the sub-group of participants with sepsis, consent will be sought to collect blood 
samples. For the sub-group in whom consent is obtained, a 20mL blood sample will 
be collected at two timepoints: 
 
Baseline sample - collect within 12 hours post randomisation 
 
60 hour sample – collect at 60 hours (+/- 12 hours) post randomisation (i.e. 
between 48-72 hours)  
We will analyse blood samples in laboratories in the University of Edinburgh, or 
laboratories in other institutions or organisations if required for particular techniques. 
We will use several methods to explore whether there are differences in inflammation 

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and/or immune function between the trial sub-groups with sepsis at baseline, and 
how these relate to trial outcomes. When consent has been provided, we will also 
explore whether changes in gene expression occur that are modified by alpha2-
agonists, for example using whole blood transcriptomics. Where appropriate, we will 
also measure a panel of circulating pro- and anti-inflammatory mediators in order to 
explore whether alpha2-agonists have anti-inflammatory properties that might 
contribute to or mediate some of their beneficial effects during critical illness.  
12. PHARMACOVIGILANCE 
Local investigators will be responsible for the detection and documentation of events 
meeting the criteria and definitions detailed below. 
Full details of contraindications and side effects that have been reported following 
administration of the IMP can be found in the relevant Summary of Product 
Characteristics. 
The intervention period will continue until the patient is weaned from MV and 
sedation in the ICU. 
The interventions with IMP will continue until the patient is weaned from MV which 
will exclusively occur in the ICU. The protocolised intervention will also end if the 
participant has been on the study for 28 days and has not reached the primary 
outcome or is transferred to an ICU at another non-participating hospital. Clinical and 
research staff will monitor participants for adverse events (AEs) and serious adverse 
events (SAEs) until ICU discharge. Patients will typically spend several additional 
days in the ICU after completing the intervention (with the exception of patients who 
die during the intervention period). The IMP is expected to be completely cleared 
from the participant’s body before ICU discharge, based on their pharmacokinetics. 
All adverse events (AE) that occur in ICU after joining the trial will be documented in 
the medical notes and those that are not considered to be expected in this population 
must be reported in detail in the Case Report Form (CRF).  In the case of an AE, the 
Investigator should initiate the appropriate treatment according to their medical 
judgment.  Participants with AEs must be followed up until resolution of the event or 
hospital discharge, whichever occurs sooner. 
12.1 DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence in a clinical trial 
participant which does not necessarily have a causal relationship with an 
investigational medicinal product (IMP). 
An adverse reaction (AR) is any untoward and unintended response to an IMP 
which is related to any dose administered to that participant.  
A serious adverse event (SAE), serious adverse reaction (SAR). Any AE or AR 
that at any dose: 
 
results in death of the clinical trial participant; 
 
is life threatening*; 
 
requires in-patient hospitalisation^ or prolongation of existing hospitalisation; 
 
results in persistent or significant disability or incapacity; 
 
consists of a congenital anomaly or birth defect; 
 
results in any other significant medical event not meeting the criteria above. 
 
*Life-threatening in the definition of an SAE or SAR refers to an event where the participant 
was at risk of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death if it were more severe. 
 

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^Any hospitalisation that was planned prior to randomisation will not meet SAE criteria. Any 
hospitalisation that is planned post randomisation will meet the SAE criteria. 
 
A suspected unexpected serious adverse reaction (SUSAR) is any AR that is 
classified as serious and is suspected to be caused by the IMP, that it is not 
consistent with the information about the IMP in the Summary of Product 
Characteristics (SPC). 
 
12.2 IDENTIFYING AES AND SAES 
AEs and SAEs will be recorded from the time a participant signs the consent form to 
take part in the study until discharge from the ICU. 
As this study is based in an ICU setting, and involves critically ill patients, it is 
anticipated and expected that many patients will experience events that might be 
considered AEs or SAEs, but are expected features of critical illness requiring ICU 
care. Furthermore, as patients will usually be incapacitated for part or all of the 
intervention period, the identification of AEs and SAEs will largely be the 
responsibility of the clinical team and research teams reviewing patient records. 
Screening and identification of AEs and SAEs will be based on clinical events (from 
daily charts and reviews) and review of laboratory and other investigations 
undertaken as part of routine care. There will be no testing or investigation additional 
to routine care undertaken for the purpose of detection of AEs or SAEs 
12.3 RECORDING AES AND SAES 
When an AE/SAE considered relevant to the trial by clinical or research teams 
occurs, it is the responsibility of the Investigator to review all documentation (e.g. 
hospital notes, laboratory and diagnostic reports) related to the event.  The 
Investigator will then record all relevant information in the CRF and on the SAE form 
(if the AE meets the criteria of serious). 
Information to be collected includes dose and intervention group, type of event, onset 
date, investigator assessment of severity and causality, date of resolution as well as 
treatment required, investigations needed and outcome.   
 
12.3.1 AEs and SAEs that do not require recording in the CRF 
AEs and SAEs that are considered consistent with the patient’s critical illness do not 
require recording or reporting unless the Investigator considers they may relate to 
participation in the trial. These include, but are not limited to:  
 
new or deterioration in organ function 
 
new infections 
 
complications of ICU procedures 
 
requirement for further interventions (e.g. surgery) related to the presenting 
diagnosis 
 
reactions to co-prescribed medications. 
Death during and after ICU discharge is expected to occur in around 20% of 
participants in the trial and is a key secondary outcome. Deaths only need to be 
recorded as AEs/SAEs if the Investigator considers they may relate to participation in 
the trial or if they were not consistent with the patient’s critical illness and/or expected 
worsening of an underlying medical condition 
Sedation related adverse events, and well recognised defined potential side effects 
of alpha-2 agonists (bradycardia, hypotension, ileus), are collected daily during the 
intervention period and are important secondary outcomes in the trial. These events 
do not need to be routinely recorded as AEs or SAEs. 

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12.3.2 Pre-existing Medical Conditions 
Pre-existing medical conditions (i.e. existed prior to informed consent) should be 
recorded as medical history and only recorded as adverse events if medically judged 
to have worsened during the study or if the medical Investigator considers that it may 
be related to trial participation 
12.3.3 Worsening of the Underlying Condition during the Trial 
Medical occurrences or symptoms of deterioration that are expected due to the 
participant’s underlying condition should be recorded in the patient’s medical notes 
and recorded as AEs on the AE log if medically judged to have unexpectedly 
worsened during the study. Events that are consistent with the expected progression 
of the underlying disease should not be recorded as AEs unless the medical 
Investigator considers that they may be related to trial participation.    
12.4 ASSESSMENT OF AES AND SAES 
Seriousness, causality, severity and expectedness will be assessed by the Principal 
Investigator or another Investigator who is a suitably qualified physician, trained in 
recording and reporting AEs, who has been delegated this role.  As this is an 
unblinded trial, Investigators can take group allocation into account when assessing 
AEs and SAEs.  
The Investigator is responsible for assessing each AE.   
The Chief Investigator (CI) may not downgrade an event that has been assessed by 
an Investigator as an SAE or SUSAR, but can upgrade an AE to an SAE, SAR or 
SUSAR if appropriate. 
12.4.1 Assessment of Seriousness 
The Investigator will make an assessment of seriousness as defined in Section 12.1. 
12.4.2 Assessment of Causality 
The Investigator will make an assessment of whether the AE/SAE is likely to be 
related to the IMP according to the definitions below.   
 
Unrelated: where an event is not considered to be related to the IMP. 
 
Possibly Related: The nature of the event, the underlying medical condition, 
concomitant medication or temporal relationship make it possible that the AE 
has a causal relationship to the study drug.   
 
Causality assessment decisions will be made by a medically qualified doctor, using 
medical and scientific judgement as well as knowledge of the subject concerned.  
 
Where non Investigational Medicinal Products (NIMPs) e.g. rescue/escape drugs are 
given:  if the AE is considered to be related to an interaction between the IMP and 
the NIMP, or where the AE might be linked to either the IMP or the NIMP but cannot 
be clearly attributed to either one of these, the event will be considered as an AR. 
Alternative causes such as natural history of the underlying disease, other risk 
factors and the temporal relationship of the event to the treatment should be 
considered and investigated.  
12.4.3 Assessment of Expectedness 
If an event is judged to be an AR, the evaluation of expectedness will be made based 
on knowledge of the reaction and the relevant Reference Safety Information 

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documented in the SPC (usually section 4.8, although Investigators should consider 
any safety information presented in other SPC sections also). 
The event may be classed as either: 
Expected: the AR is consistent with the toxicity of the IMP listed in the SPC. 
Unexpected: the AR is not consistent with the toxicity in the SPC. 
12.4.4 Assessment of Severity 
The Investigator will make an assessment of severity for each AE/SAE and record 
this on the CRF or SAE form according to one of the following categories: 
Mild: an event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with every day activities. 
Moderate: an event that is sufficiently discomforting to interfere with normal everyday 
activities. 
Severe: an event that prevents normal everyday activities. 
Note: the term ‘severe’, used to describe the intensity, should not be confused with 
‘serious’ which is a regulatory definition based on participant/event outcome or action 
criteria.  For example, a headache may be severe but not serious, while a minor 
stroke is serious but may not be severe. 
 
12.5 REPORTING OF SAES/SARS/SUSARS 
Once the Investigator becomes aware that an SAE has occurred involving a study 
participant, the information will be reported to the ACCORD Research Governance & 
QA Office immediately or within 24 hours. If the Investigator does not have all 
information regarding an SAE, they should not wait for this additional information 
before notifying ACCORD.  The SAE report form can be updated when the additional 
information is received. 
The SAE report will provide an assessment of causality and expectedness at the time 
of the initial report to ACCORD according to Sections 12.4.2, Assessment of 
Causality and 12.4.3, Assessment of Expectedness. 
The SAE form will be transmitted by fax to ACCORD on +44 (0)131 242 9447 or may 
be transmitted by hand to the office or submitted via email to Safety@accord.scot. 
Only forms in a pdf format will be accepted by ACCORD via email. 
Where missing information has not been sent to ACCORD after an initial report, 
ACCORD will contact the investigator and request the missing information.  
All reports faxed to ACCORD and any follow up information will be retained by the 
Investigator in the Investigator Site File (ISF). 
12.6 REGULATORY REPORTING REQUIREMENTS 
The ACCORD Research Governance & QA Office is responsible for 
pharmacovigilance reporting on behalf of the co-sponsors (Edinburgh University and 
NHS Lothian). 
The ACCORD Research Governance & QA Office has a legal responsibility to notify 
the regulatory competent authority and relevant ethics committee (Research Ethics 
Committee (REC) that approved the trial).  Fatal or life threatening SUSARs will be 
reported no later than 7 calendar days and all other SUSARs will be reported no later 
than 15 calendar days after ACCORD is first aware of the reaction.   
ACCORD or delegate will inform Investigators at participating sites of all SUSARs 
and any other arising safety information. 

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ACCORD will be responsible for providing safety line listings and assistance; 
however, it is the responsibility of the Investigator to prepare the Development Safety 
Update Report. This annual report lists all SARs and SUSARs reported during that 
time period. The responsibility of submitting the Development Safety Update Report 
to the regulatory authority and RECs, lies with ACCORD.  
12.7 FOLLOW UP PROCEDURES 
After initially recording an AE or recording and reporting an SAE, the Investigator will 
follow each participant until resolution or death of the participant, or until hospital 
discharge (whichever occurs sooner).  Follow up information on an SAE will be 
reported to the ACCORD office. 
AEs still present in participants at the last study visit will be monitored until resolution 
of the event or until no longer medically indicated. 
12.8 PREGNANCY 
Pregnancy is an exclusion criteria for the trial, and is extremely unlikely to occur 
during hospitalisation for critical illness. Data concerning pregnancy post hospital 
discharge will not be collected. 
13. TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS 
13.1 TRIAL MANAGEMENT GROUP 
The trial will be coordinated by a Project Management Group, consisting of the grant 
holders (Chief Investigator and Principal Investigator in Edinburgh), A Trial Manager 
and coordinating nurse. 
The Trial Manager will oversee the study and will be accountable to the Chief 
Investigator.  The Trial Manager will be responsible for checking the CRFs for 
completeness, plausibility and consistency.  Any queries will be resolved by the 
Investigator or delegated member of the trial team.  
A Delegation Log will be prepared for each site, detailing the responsibilities of each 
member of staff working on the trial.   
13.2 TRIAL STEERING COMMITTEE 
A Trial Steering Committee (TSC) will be established to oversee the conduct and 
progress of the trial.  The terms of reference of the Trial Steering Committee, the 
draft template for reporting and the names and contact details are detailed in CR015 
DMC & TSC Charters. 
13.3 DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (DMC) will be established to oversee the 
safety of participants in the trial.  The terms of reference of the Data Monitoring 
Committee and the names and contact details are detailed in CR0015 DMC & TSC 
Charters. 
The DMC Charter will be signed by the appropriate individuals prior to the trial 
commencing.   
13.4 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit trial related monitoring 
and audits on behalf of the sponsor, REC review, and regulatory inspection(s).  In the 
event of an audit or monitoring, the Investigator agrees to allow the representatives 
of the sponsor direct access to all study records and source documentation. In the 

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event of regulatory inspection, the Investigator agrees to allow inspectors direct 
access to all study records and source documentation. 
13.5 RISK ASSESSMENT 
A study specific risk assessment will be performed by representatives of the co-
sponsors, ACCORD monitors and the QA group, in accordance with ACCORD 
governance and sponsorship SOPs. Input will be sought from the Chief Investigator 
or designee. The outcomes of the risk assessment will form the basis of the 
monitoring plans and audit plans. The risk assessment outcomes will also indicate 
which risk adaptions could be incorporated into to trial design. 
13.6 STUDY MONITORING AND AUDIT 
ACCORD clinical trial monitors, or designees, will perform monitoring activities in 
accordance with the study monitoring plan. This will involve on-site visits and remote 
monitoring activities as necessary. ACCORD QA personnel, or designees, will 
perform study audits in accordance with the study audit plan. This will involve 
investigator site audits, study management audits and facility (including 3rd parties) 
audits as necessary. 
14. GOOD CLINICAL PRACTICE 
14.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of the International 
Conference on Harmonisation Tripartite Guideline for Good Clinical Practice (ICH 
GCP). 
Before the study can commence, all required approvals will be obtained and any 
conditions of approvals will be met.  
14.2 REGULATORY COMPLIANCE 
The study will not commence until a Clinical Trial Authorisation (CTA) is obtained 
from the appropriate Regulatory Authority. The protocol and study conduct will 
comply with the Medicines for Human Use (Clinical Trials) Regulations 2004, as 
amended. 
14.3 INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for the overall conduct of the study at the site and 
compliance with the protocol and any protocol amendments.  In accordance with the 
principles of ICH GCP, the following areas listed in this section are also the 
responsibility of the Investigator.  Responsibilities may be delegated to an 
appropriate member of study site staff. 
Delegated tasks must be documented on a Delegation Log and signed by all those 
named on the list prior to undertaking applicable study-related procedures.    
14.3.1 Study Site Staff 
The Investigator must be familiar with the IMP, protocol and the study requirements.  
It is the Investigator’s responsibility to ensure that all staff assisting with the study are 
adequately informed about the IMP, protocol and their trial related duties. 
 
14.3.2 Data Recording 

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The Principal Investigator is responsible for the quality of the data recorded in the 
CRF at each Investigator Site.  
14.3.3  Investigator Documentation 
Prior to beginning the study, each Investigator will be asked to provide particular 
essential documents to the ACCORD Research Governance & QA Office, including 
but not limited to: 
 
An original signed Investigator’s Declaration (as part of the Clinical Trial 
Agreement documents); 
 
Curriculum vitae (CV) signed and dated by the Investigator indicating that it 
is accurate and current. 
 
ACCORD will ensure all other documents required by ICH GCP are retained 
in a Trial Master File (TMF) or Sponsor File, where required.  The Principal 
Investigator will ensure that the required documentation is available in local 
Investigator Site files ISFs. Under certain circumstances the TMF 
responsibilities may be delegated to the research team by ACCORD. 
14.3.4 GCP Training 
All study staff must hold evidence of appropriate GCP training.  
14.3.5 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records must be 
identified in a manner designed to maintain participant confidentiality.  All records 
must be kept in a secure storage area with limited access.  Clinical information will 
not be released without the written permission of the participant.  The Investigator 
and study site staff involved with this study may not disclose or use for any purpose 
other than performance of the study, any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study.  
Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties.  
14.3.6 Data Protection 
All Investigators and study site staff involved with this study must comply with the 
requirements of the appropriate data protection legislation (including the General 
Data Protection Regulation and Data Protection Act) with regard to the collection, 
storage, processing and disclosure of personal information and will uphold the Act’s 
core principles. Access to collated identifiable participant data will be restricted to 
individuals from the research team treating the participants, representatives of the 
sponsor(s) and representatives of regulatory authorities. 
Computers used to collate the data will have limited access measures via user 
names and passwords. 
Published results will not contain any personal data that could allow identification of 
individual participants. 
15.  STUDY CONDUCT RESPONSIBILITIES 
15.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, 
immediate hazard to the participant in the case of an urgent safety measure, must be 
reviewed and approved by the Chief Investigator.   

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Proposed amendments will be submitted to the Sponsor for classification and 
authorisation.  
Amendments to the protocol must be submitted in writing to the appropriate REC, 
Regulatory Authority and local R&D for approval prior to implementation. 
15.2 PROTOCOL NON COMPLIANCE 
15.2.1 Definitions 
Deviation - Any change, divergence, or departure from the study design, procedures 
defined in the protocol or GCP that does not significantly affect a subjects rights, 
safety, or well-being, or study outcomes. 
Violation - A deviation that may potentially significantly impact the completeness, 
accuracy, and/or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being 
15.2.2 Protocol Waivers 
Prospective protocol deviations, i.e. protocol waivers, will not be approved by the 
sponsors and therefore will not be implemented, except where necessary to eliminate 
an immediate hazard to study participants. If this necessitates a subsequent protocol 
amendment, this should be submitted to the REC, Regulatory Authority and local 
R&D for review and approval if appropriate. 
15.2.3 Management of Deviations and Violations 
Protocol deviations will be recorded in a protocol deviation log and logs will be 
submitted to the sponsors every 3 months. Each protocol violation will be reported to 
the sponsor within 3 days of becoming aware of the violation. Deviation logs / 
violation forms will be transmitted via email to QA@accord.scot Only forms in a pdf 
format will be accepted by ACCORD via email. Forms may also be sent by fax to 
ACCORD on +44 (0)131 242 9447 or may be submitted by hand to the office. Where 
missing information has not been sent to ACCORD after an initial report, ACCORD 
will contact the Investigator and request the missing information. The Investigator 
must respond to these requests in a timely manner.   
15.3 URGENT SAFETY MEASURES 
The Investigator may implement a deviation from or change to the protocol to 
eliminate an immediate hazard to trial participants without prior approval from the 
REC and the MHRA. This is defined as an urgent safety measure and the 
investigator must contact the Clinical Trial Unit at the MHRA and discuss the issue 
with a medical assessor immediately (+44 (0) 20 3080 6456).  
The Investigator will then notify the MHRA (clintrialhelpline@mhra.gsi.gov.uk), the 
REC and ACCORD, in writing of the measures taken and the reason for the 
measures within 3 days by submitting a substantial amendment. 
15.4 SERIOUS BREACH REQUIREMENTS 
A serious breach is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
If a potential serious breach is identified by the Chief investigator, Principal 
Investigator or delegates, the co-sponsors (QA@accord.scot) must be notified within 
24 hours.  It is the responsibility of the co-sponsors to assess the impact of the 
breach on the scientific value of the trial, to determine whether the incident 

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constitutes a serious breach and report to regulatory authorities and research ethics 
committees as necessary.  
15.5 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 5 years from the protocol 
defined end of study point. When the minimum retention period has elapsed, study 
documentation will not be destroyed without permission from the sponsor. 
15.6 END OF STUDY 
The end of study is defined as the last participant’s final follow-up. 
The Investigators and/or the trial steering committee and/or the co-sponsor(s) have 
the right at any time to terminate the study for clinical or administrative reasons.  
The end of the study will be reported to the REC, Regulatory Authority, R&D Office(s) 
and co-sponsors within 90 days, or 15 days if the study is terminated prematurely. 
The Investigators will inform participants of the premature study closure and ensure 
that the appropriate follow up is arranged for all participants involved. End of study 
notification will be reported to the co-sponsors via email to resgov@ed.ac.uk. 
In accordance with ACCORD SOP CR011, a Clinical Study Report (CSR) will be 
provided to the Sponsor (QA@accord.scot) and REC within 1 year of the end of the 
study. 
Upon completion of the study, the Investigator will upload clinical trial results onto the 
EudraCT database on behalf of the Sponsor.  
The Investigator will submit a short confirmatory e-mail to the MHRA 
(CT.Submission@mhra.gsi.gov.uk) once the result-related information has been 
uploaded to EudraCT, with ‘End of trial: result-related information: ‘EudraCT 2018-
001650-98’ as the subject line. The Sponsor(s) will be copied in this e-mail 
(QA@accord.scot).  It should be noted that you will not get an acknowledgment e-
mail or letter from the MHRA. 
15.7 CONTINUATION OF DRUG FOLLOWING THE END OF STUDY 
Trial drug will not be continued following the end of the study as participants will only 
receive trial drug in the acute phase of their illness.  
15.8 INSURANCE AND INDEMNITY 
The co-sponsors are responsible for ensuring proper provision has been made for 
insurance or indemnity to cover their liability and the liability of the Chief Investigator 
and staff. 
The following arrangements are in place to fulfil the co-sponsors' responsibilities: 
 
The Protocol has been authored by the Chief Investigator and researchers 
employed by the University and collaborators.  The University has insurance 
in place (which includes no-fault compensation) for negligent harm caused 
by poor protocol design by the Chief Investigator and researchers employed 
by the University. 
 
Sites participating in the study will be liable for clinical negligence and other 
negligent harm to individuals taking part in the study and covered by the 
duty of care owed to them by the sites concerned.  The co-sponsors require 
individual sites participating in the study to arrange for their own insurance 
or indemnity in respect of these liabilities. Sites which are part of the United 
Kingdom's National Health Service have the benefit of NHS Indemnity. 

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 
Sites out with the United Kingdom will be responsible for arranging their own 
indemnity or insurance for their participation in the study, as well as for 
compliance with local law applicable to their participation in the study. 
 
The manufacturer supplying IMP has accepted limited liability related to the 
manufacturing and original packaging of the study drug and to the losses, 
damages, claims or liabilities incurred by study participants based on known 
or unknown Adverse Events which arise out of the manufacturing and 
original packaging of the study drug, but not where there is any modification 
to the study drug (including without limitation re-packaging and blinding). 
16. REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
16.1 AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team.  On 
completion of the study, the study data will be analysed and tabulated, and a clinical 
study report will be prepared in accordance with ICH guidelines.  
An authorship policy will be agreed prior to completion of recruitment. Authorship of 
manuscripts and other outputs resulting from the trial will be decided according to the 
guidelines from the International Committee of Medical Journal Editors (ICMJEs). 
Authors must demonstrate at least one of the following: substantial contributions to 
the conception or design of the work; or the acquisition, analysis, or interpretation of 
data for the work; AND drafting the work or revising it critically for important 
intellectual content; AND final approval of the version to be published; AND 
agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
16.2 PUBLICATION 
The Clinical Study Report (CSR) will be submitted to the Sponsor and REC within 1 
year of the end of the study. Where acceptable, a published journal article may be 
submitted as the CSR. The Chief Investigator will provide the CSR to ACCORD, for 
review, prior to finalization. The clinical study report may be used for publication and 
presentation at scientific meetings. Investigators have the right to publish orally or in 
writing the results of the study. The results of the study, together with other mandated 
information, will be uploaded to the European clinical trials database within 1 year of 
the end of the study. 
Summaries of results will also be made available to Investigators for dissemination 
within their clinics (where appropriate and according to their discretion). 
The publication plan will be consistent with the policy of the funder. 
16.3 DATA SHARING 
The final trial dataset will be held by the University of Edinburgh on a secure 
password protected drive. A file, or set of files, containing an anonymised version of 
the final analysis data set will be prepared, along with a data dictionary.  These will 
be made available to the Chief Investigator at the end of the analysis phase. Co-
investigators will have the right to access the final data set for the purpose of 
additional analyses that are consistent with the consent provided by participants. 
Similarly, any external party can approach the co-investigators to request access to 
the trial data. In all cases, access to the trial dataset will follow locally approved 
governance proesses. 

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16.4 PEER REVIEW 
This study was commissioned by the HTA in response to a detailed commissioned 
Systematic Review, and prioritization exercise. The study underwent external peer 
review during the application for funding from the HTA. The study was also presented 
to the UK Critical Care Research Group (June 2017)) and received support. The 
study was reviewed on multiple occasions by PPI collaborators during the grants 
application and protocol development process. 
 
 

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36. Rattray J, Johnston M, Wildsmith JA. The intensive care experience: development 
of the ICE questionnaire. Journal of advanced nursing 2004;47(1):64-73. doi: 
10.1111/j.1365-2648.2004.03066.x [published Online First: 2004/06/10] 
37. Alosh M, Bretz F, Huque M. Advanced multiplicity adjustment methods in clinical 
trials. Statistics in medicine 2014;33(4):693-713. doi: 10.1002/sim.5974 
[published Online First: 2013/10/10] 
38. Dmitrienko A, Tamhane, A. C., & Bretz, F. (Eds.). (2009).  Chapman and Hall/CRC. 
Multiple testing problems in pharmaceutical statistics.: Chapman and Hall/CRC 
2009. 
39. Sanders RD, Hussell T, Maze M. Sedation & immunomodulation. Anesthesiology 
clinics 2011;29(4):687-706. doi: 10.1016/j.anclin.2011.09.008 [published 
Online First: 2011/11/15] 
40. van den Boogaard M, Pickkers P, Slooter AJ, et al. Development and validation of 
PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction 
model for intensive care patients: observational multicentre study. BMJ (Clinical 
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sedative agents in critically ill children: the SLEEPS (Safety profiLe, Efficacy 
and Equivalence in Paediatric intensive care Sedation) study. Health 
technology assessment (Winchester, England) 2014;18(71):1-212. doi: 
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42. Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration 
of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-
blind, placebo-controlled trial. The Lancet Respiratory medicine 2013;1(7):515-
23. doi: 10.1016/s2213-2600(13)70166-8 [published Online First: 2014/01/28] 
43. Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU 
patients: reliability and validity of the Richmond Agitation-Sedation Scale 

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(RASS). 
Jama 
2003;289(22):2983-91. 
doi: 
10.1001/jama.289.22.2983 
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agent. 
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(Baylor 
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of 
dexmedetomidine. 
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10.1080/03639045.2016.1232727 
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care unit. Journal of anaesthesiology, clinical pharmacology 2010;26(4):439-
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48. Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory 
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50. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed 
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possibilities and pitfalls. International journal of epidemiology 2012;41(3):861-
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52. Noordzij M, Leffondre K, van Stralen KJ, et al. When do we need competing risks 
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53. Varadhan R, Weiss CO, Segal JB, et al. Evaluating health outcomes in the 
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treating severely bleeding major trauma patients: a national study for England. 
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[published Online First: 2015/07/08] 
56. Curtis L BA. Unit Costs of Health and Social Care. In: Unit PSSR, ed. Kent, 2015. 
57. Health. Do. National Schedule of Reference Costs. In: Health Do, ed. London, 
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61. Dexmedetomidine for Sedation in the ICU or PICU: A Review of Cost-Effectiveness 
and Guidelines: Canadian Agency for Drugs and Technologies in Health; 2014 
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2015/RC0617_Dexmedetomidine%20final.pdf accessed May 1st 2017. 
62. Ridley S, Morris S. Cost effectiveness of adult intensive care in the UK. 
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Evaluation: Oxford University press, 2006. 
 
 
 
 
 

 
Page 67 of 76 
 
18.  APPENDIX 1: DRUG REGIMENS 
18.1 CLONIDINE DRUG REGIMEN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For patients who weigh less than 45kg, please contact the trial management team for specific advice prior to randomisation. 
Patients who weigh greater than 100kg will be dosed using the regimen suggested for 100kg weight. Please contact the trial management team for 
advice if required prior to randomisation. 
 

 
Page 68 of 76 
 
18.2 DEXMEDETOMIDINE DRUG REGIMEN 
 
For patients who weigh less than 45kg, please contact the trial management team for specific advice prior to randomisation. 
Patients who weigh greater than 100kg will be dosed using the regimen suggested for 100kg weight. Please contact the trial management team for 
advice if required prior to randomisation. 

 
Page 69 of 76 
 
19. APPENDIX 2: GROUP SEDATION FLOWCHARTS 
These flowcharts are intended as guidance for clinical teams, especially bedside 
nurses managing the patients. Decisions about sedation management that divert 
from this guidance can be made at the discretion of the clinical team, and do not 
necessarily need to be reported as protocol deviations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 70 of 76 
 
19.1 CLONIDINE FLOWCHART  
 
 
 
 

 
Page 71 of 76 
 
CLONIDINE FLOWCHART – REVERSE 
 
 
 
 
Clonidine Group Sedation 
TARGET: most awake and comfortable state considered safe (the least awake target will be “briefly wakens with eye contact to voice”)  
 
Primary sedative agent is CLONIDINE (diluted with 5% glucose or 0.9% NaCl solution to a concentration of 15 micrograms per ml) 
 
Aim to reduce/stop propofol infusion.   
 
All patients should receive opioid infusions for analgesia as clinically indicated at the discretion of clinical teams.  
 
NB Clonidine has analgesic properties, so it may be possible to reduce opioids if pain is well controlled.   
Drugs you should not give: 
 
Dexmedetomidine should not be used as first line sedation during the intervention period.   
How to manage agitation (RASS +2 TO +4) 
 
Maintain patient/staff safety by bolusing propofol if needed.   
 
Once agitation is under control, try to identify and manage the cause, using local unit policy for the management of 
pain/delirium/anxiety/withdrawal etc. 
 
Anticipate and avoid agitation; use opioid analgesia in advance of uncomfortable or painful interventions or procedures. 
What to do if my patient develops severe bradycardia 
 
If your patient’s heart rate decreases to less than 50 beats per minute, clonidine should be temporarily stopped.   
 
Clonidine commonly decreases heart rate. If a participant in the trial develops significant bradycardia during the intervention, the clonidine rate 
can be reduced (or temporarily stopped, if HR<50).      
 
NB Clonidine’s effect on heart rate can take several hours to resolve, so stopping the clonidine infusion may not immediately resolve 
bradycardia.   
 
Seek advice from medical staff who can review and prescribe glycopyrronium, atropine, dobutamine, adrenaline or other agents, as per your ICU 
policy.  
 
Once the patient is more stable, clonidine can be re-started and/or up-titrated again at a dose appropriate to the sedation target, but caution 
should be used when the clinical target is deep sedation (see below).   
What to do if my patient becomes hypotensive 
 
Hypotension should be treated as per local unit policy. Continuous fluid infusions, fluid challenges and vasopressor infusions are all permitted 
for patients in the A2B Trial.   
 
If changes to sedation are required as a result of hypotension, propofol should be decreased before clonidine, unless clinically contraindicated 
e.g. if patient requires propofol for neuromuscular blockade (see below).   
 
Continue clonidine infusion unless causing haemodynamic compromise, such that target MAP cannot be maintained with 0.15 
micrograms/kg/min of noradrenaline.  If haemodynamically compromised, consider halving the rate of the clonidine infusion, then halving again, 
or stopping, as needed.   
 
NB Clonidine’s effect on heart rate can take several hours to resolve, so stopping the clonidine infusion may not immediately resolve 
hypotension.    
 
Once the patient is more stable, clonidine can be restarted and/or up-titrated again, at a dose appropriate to the sedation target, but caution 
should be used when the clinical target is deep sedation (see below).   
What if my patient requires deep sedation (RASS -3 TO -5) e.g. for neuromuscular blockade (muscle relaxant)? 
 
If medical staff have asked to keep your patient deeply sedated, please record the reason deep sedation was requested on the A2B Shift Form.   
 
Patients who require neuromuscular blockade after randomisation must receive adequate sedation as per standard care, at the discretion of 
the treating clinician, to prevent awareness during paralysis.  Clonidine alone may not provide adequate sedation to prevent awareness.   
 
It is suggested that clonidine is titrated up to the maximum tolerated dose, but if additional sedative drugs are needed to achieve target deep 
sedation this can be achieved with propofol or benzodiazepine.  
 
When deep sedation is no longer requested by the caring clinician, aim to use clonidine as main sedative agent as per flowchart over page.  It is 
suggested that any propofol or benzodiazepine sedation is decreased and stopped prior to reducing the dose of clonidine.    
What if my patient needs an operative procedure/CT scan/MRI etc.? 
 
Increase sedation for transfer if needed, using clonidine and/or propofol.   
 
If required, anaesthesia should be administered as per local perioperative guidelines.   
 
Continue clonidine infusion unless haemodynamically compromised, in which case consider halving infusion rate and halving again or stopping, 
as needed.   
 
Following the procedure, again aim to reduce propofol and use clonidine as main sedative agent as per flowchart over page.   
Weaning and discontinuing Clonidine 
 
Clonidine can be abruptly discontinued, but slower weaning should be used if withdrawal reactions occur (rebound hypertension or 
tachycardia, agitation, sweating etc.).  However, this should not delay weaning from ventilation, as clonidine is relatively free from 
respiratory depressive effects, so can be safely continued post-extubation.   
PTO for Clonidine Group Sedation Flowchart on reverse of this page 

 
Page 72 of 76 
 
19.2 DEXMEDETOMIDINE FLOWCHART  
 
 
 

 
Page 73 of 76 
 
DEXMEDETOMIDINE FLOWCHART – REVERSE 
 
 
 
Dexmedetomidine (Dex) Group Sedation 
 
 
TARGET: most awake and comfortable state considered safe (the least awake target will be “briefly wakens with eye contact to voice”)  
 
Primary sedative agent is DEXMEDETOMIDINE (diluted with 5% glucose or 0.9% NaCl solution to a concentration of 8 micrograms per ml) 
 
Aim to reduce/stop propofol infusion.   
 
All patients should receive opioid infusions for analgesia as clinically indicated at the discretion of clinical teams.  
 
NB Dexmedetomidine has analgesic properties, so it may be possible to reduce opioids if pain is well controlled.   
Drugs you should not give: 
 
Clonidine should not be used as first line sedation during the intervention period.   
How to manage agitation (RASS +2 TO +4) 
 
Maintain patient/staff safety by bolusing propofol if needed.   
 
Once agitation is under control, try to identify and manage the cause, using local unit policy for the management of 
pain/delirium/anxiety/withdrawal etc. 
 
Anticipate and avoid agitation; use opioid analgesia in advance of uncomfortable or painful interventions or procedures. 
What to do if my patient develops severe bradycardia 
 
If your patient’s heart rate decreases to less than 50 beats per minute, dexmedetomidine should be temporarily stopped.   
 
Dexmedetomidine commonly decreases heart rate. If a participant in the trial develops significant bradycardia during the intervention, the 
dexmedetomidine rate can be reduced (or temporarily stopped, if HR<50).      
 
NB Dexmedetomidine’s effect on heart rate can take several hours to resolve, so stopping the dexmedetomidine infusion may not immediately 
resolve bradycardia.   
 
Seek advice from medical staff who can review and prescribe glycopyrronium, atropine, dobutamine, adrenaline or other agents, as per your ICU 
policy.  
 
Once the patient is more stable, dexmedetomidine can be re-started and/or up-titrated again at a dose appropriate to the sedation target, 
but caution should be used when the clinical target is deep sedation (see below).   
What to do if my patient becomes hypotensive 
 
Hypotension should be treated as per local unit policy. Continuous fluid infusions, fluid challenges and vasopressor infusions are all permitted 
for patients in the A2B Trial.   
 
If changes to sedation are required as a result of hypotension, propofol should be decreased before dexmedetomidine, unless clinically 
contraindicated e.g. if patient requires propofol for neuromuscular blockade (see below).   
 
Continue dexmedetomidine infusion unless causing haemodynamic compromise, such that target MAP cannot be maintained with 0.15 
micrograms/kg/min of noradrenaline.  If haemodynamically compromised, consider halving the rate of the dexmedetomidine infusion, then 
halving again, or stopping, as needed.   
 
NB Dexmedetomidine’s effect on blood pressure can take several hours to resolve, so stopping the dexmedetomidine infusion may not 
immediately resolve hypotension.    
 
Once the patient is more stable, dexmedetomidine can be restarted and/or up-titrated again, at a dose appropriate to the sedation target, 
but caution should be used when the clinical target is deep sedation (see below).   
What if my patient requires deep sedation (RASS -3 TO -5) e.g. for neuromuscular blockade (muscle relaxant)? 
 
If medical staff have asked to keep your patient deeply sedated, please record the reason deep sedation was requested on the A2B Shift Form.   
 
Patients who require neuromuscular blockade after randomisation must receive adequate sedation as per standard care at the discretion of 
the treating clinician, to prevent awareness during paralysis.  Dexmedetomidine alone may not provide adequate sedation to prevent 
awareness.   
 
It is suggested that dexmedetomidine is titrated up to the maximum tolerated dose, but if additional sedative drugs are needed to achieve target 
deep sedation this can be achieved with propofol or benzodiazepine.  
 
When deep sedation is no longer requested by the caring clinician, aim to use dexmedetomidine as main sedative agent as per flowchart over 
page.  It is suggested that any propofol or benzodiazepine sedation is decreased and stopped prior to reducing the dose of dexmedetomidine.   
What if my patient needs an operative procedure/CT scan/MRI etc.? 
 
Increase sedation for transfer if needed, using dexmedetomidine and/or propofol.   
 
If required, anaesthesia should be administered as per local perioperative guidelines.   
 
Continue dexmedetomidine infusion unless haemodynamically compromised, in which case consider halving infusion rate and halving again or 
stopping, as needed.   
 
Following the procedure, again aim to reduce propofol and use dexmedetomidine as main sedative agent as per flowchart over page.   
Weaning and discontinuing Dexmedetomidine 
 
Dexmedetomidine can be abruptly discontinued, but slower weaning should be used if withdrawal reactions occur (rebound hypertension or 
tachycardia, agitation, sweating etc.).  However, this should not delay weaning from ventilation, as dexmedetomidine is relatively free from 
respiratory depressive effects, so can be safely continued post-extubation.   
PTO for Dexmedetomidine Group Sedation Flowchart on reverse of this page 

 
Page 74 of 76 
 
19.3 USUAL CARE (PROPOFOL) FLOWCHART 
 
 
 

 
Page 75 of 76 
 
USUAL CARE (PROPOFOL) FLOWCHART - REVERSE 
 
 
 
 

 
Page 76 of 76 
 
20. APPENDIX 3: CONSENT PROCESS IN THE A2B TRIAL  
 
 

A2B Protocol V7.0 CLEAN 25042023 Final
Final Audit Report
2023-06-16
Created:
2023-06-14
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