Low-dose KETamine as an Adjunct to MOrphine for Acute Pain in the ED: a Randomized, Double-blinded Clinical Trial
Phase: PHASE4
Conditions: Acute Pain, Opioid Use
Sponsor: University of Aarhus

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 Low-dose KETamine as an adjunct to MOrphine for acute pain in the ED: a randomized, 
double-blinded, trial   
Acronym: KeTMo 
 
TRIAL PROTOCOL 
 
Version 3.2 
Date: 26/05-2023 
 
EudraCT number: 2021-005116-64 
 
 
Sponsor 
Lone Nikolajsen 
Clinical Professor and Chair 
Anesthesiology 
Aarhus University Hospital 
Palle Juul-Jensens Boulevard 99, Building C, Plan 3 
Email: lone.nikolajsen@clin.au.dk 
 
Principal investigator  
Stine Fjendbo Galili, M.D., PhD student 
Research Center for Emergency Medicine 
 Aarhus University Hospital 
Palle Juul-Jensens Boulevard 99, Building J, Plan 1 
8200 Aarhus N, Denmark 
Phone: +4520222240 
Email: s.galili@clin.au.dk 
 

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Contents 
Preface ....................................................................................................................................................................... 5 
LIST OF ABBREVIATIONS ............................................................................................................................................ 6 
Overview .................................................................................................................................................................... 7 
Trial flowchart ........................................................................................................................................................... 9 
Project group ........................................................................................................................................................... 10 
Amendments ........................................................................................................................................................... 11 
BACKGROUND ......................................................................................................................................................... 13 
1.1 Pain in the ED – the participant population .................................................................................................. 13 
1.1.1 Incidence and mortality .......................................................................................................................... 13 
1.1.2 Treatment of pain ................................................................................................................................... 14 
1.2 Low-dose ketamine – the trial intervention .................................................................................................. 14 
1.2.1 The NMDA receptor ............................................................................................................................... 14 
1.2.2 Use in pain treatment ............................................................................................................................. 14 
1.2.3 Use in the ED .......................................................................................................................................... 14 
1.2.4 Ketamine................................................................................................................................................. 15 
1.2.5 Side effects reported following anesthetic doses .................................................................................. 16 
2. TRIAL DESIGN, OBJECTIVES AND HYPOTHESES ................................................................................................... 17 
2.1 Overview ........................................................................................................................................................ 17 
2.1.1 Design ..................................................................................................................................................... 17 
2.1.2 Hypotheses ............................................................................................................................................. 17 
2.1.3 Location .................................................................................................................................................. 18 
2.1.4 Participants ............................................................................................................................................. 18 
2.1.5 Objective ................................................................................................................................................. 18 
2.2 ALLOCATION .................................................................................................................................................. 18 
2.3.1 Intervention groups ................................................................................................................................ 19 
2.3.2 Concomitant interventions ..................................................................................................................... 20 
2.3.3 Criteria for modification of interventions for a given trial participant and protocol violations ............ 20 
2.3.4 Assessment of participant compliance ................................................................................................... 20 
2.4 BLINDING ....................................................................................................................................................... 20 
2.5 TRIAL PROCEDURES ....................................................................................................................................... 22 
2.5.1 Patients ................................................................................................................................................... 22 
2.5.2 Clinical personnel ................................................................................................................................... 24 

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3. SETTING AND PATIENT POPULATION .................................................................................................................. 24 
3.1 Setting ............................................................................................................................................................ 24 
3.2 Inclusion criteria ............................................................................................................................................ 24 
3.3 Exclusion criteria ............................................................................................................................................ 25 
3.4 Withdrawal .................................................................................................................................................... 25 
3.5 Co-enrollment ................................................................................................................................................ 26 
4. OUTCOMES .......................................................................................................................................................... 26 
4.1 Primary outcome ........................................................................................................................................... 26 
4.1.1 Definition ................................................................................................................................................ 26 
4.1.2 Rationale ................................................................................................................................................. 26 
4.2 Secondary outcomes ..................................................................................................................................... 26 
4.2.1 Definitions .............................................................................................................................................. 26 
4.2.2 Rationale ................................................................................................................................................. 27 
4.3 Safety and harm ............................................................................................................................................ 27 
4.3.1 General consideration ............................................................................................................................ 27 
4.3.2 Definitions for adverse events and reactions ......................................................................................... 28 
4.3.3 Reporting ................................................................................................................................................ 29 
5. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN ......................................................................... 29 
5.1 Sample size calculation .................................................................................................................................. 29 
    5.2 General considerations .................................................................................................................................. 30 
6. DATA COLLECTION AND DATAMANAGEMENT .................................................................................................... 30 
6.1 Data collection process .................................................................................................................................. 30 
6.2. Variables ....................................................................................................................................................... 31 
6.2.1 Overview ................................................................................................................................................. 31 
6.2.2 Baseline characteristics .......................................................................................................................... 31 
6.3 Data quality and validity ................................................................................................................................ 33 
6.4 Data storage and security .............................................................................................................................. 33 
6.5 Data access .................................................................................................................................................... 33 
6.6 Data obtained from patient records .............................................................................................................. 34 
6.6.1 Data that will be obtained before informed consent and inclusion ...................................................... 34 
6.6.2 Data that will be obtained after informed consent and inclusion ......................................................... 34 
7. CLINICAL TREATMENT ......................................................................................................................................... 35 
7.1 Screening, information and enrollment ........................................................................................................ 35 

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8. ETHICAL CONSIDERATIONS .................................................................................................................................. 36 
8.1 General considerations .............................................................................................................................. 36 
8.2 Procedures ..................................................................................................................................................... 36 
8.2.1 Ethical review committee ....................................................................................................................... 36 
8.3.1 Insurance ................................................................................................................................................ 36 
9. MONITORING ....................................................................................................................................................... 36 
9.1 Good Clinical Practice monitoring ................................................................................................................. 36 
10. TIMELINE AND ENROLLMENT ............................................................................................................................ 36 
10.1 Timeline ....................................................................................................................................................... 36 
10.2 Feasibility ..................................................................................................................................................... 37 
10.3 Enrollment ................................................................................................................................................... 38 
12. PUBLICATION PLAN ........................................................................................................................................... 38 
13. DATA SHARING .................................................................................................................................................. 38 
14. FUNDING ........................................................................................................................................................... 39 
15. TASKS AND RESPONSIBILITIES ........................................................................................................................... 39 
Appendix 1, Conflict of interest disclosures for project group ............................................................................... 39 
Appendix 2, Richmond Agitation and Sedation Scale ............................................................................................. 40 
References ............................................................................................................................................................... 43 
 
 
 
 
 
 
 
 
 
 
 
 

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Preface 
Low-dose-ketamine for acute pain in the ED, a randomized, double-blinded, trial will be conducted 
according to this protocol. The trial will be conducted in accordance with all applicable national and 
international laws, regulations, and guidelines including the revised version of the Declaration of 
Helsinki1, European regulations2, and the international Good Clinical Practice guidelines3. The trial and 
this protocol is developed in accordance with the International Conference on Harmonization (ICH) 
guidelines4 and the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 
statement5. The principal investigator wrote the protocol with input from the project group. Any 
substantial changes or amendments to the protocol will be clearly documented and communicated to 
all relevant parties.  
 
Aarhus 4/10-2021 
Lone Nikolajsen, Clinical Professor and Chair 
 
 
Aarhus 4/10-2021 
Stine Fjendbo Galili, M.D, PhD student 
 
 
 

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LIST OF ABBREVIATIONS 
 
AE:                    Adverse event 
AR:                    Adverse reaction 
AUH:                 Aarhus University Hospital 
ED: 
 
Emergency Department 
eCRF:  
Electronic case report form  
GCP: 
 
Good Clinical Practice  
IV: 
 
Intravenous 
LDK:                   Low-dose-ketamine 
NRS:                  Numeric Rating Scale 
RCT:                  Randomized Controlled Trial 
SAE:   
Serious adverse event 
SAR:   
Serious adverse reaction 
SPIRIT:  
Standard Protocol Items: Recommendations for Interventional Trials 
SUSAR:             Suspected unexpected serious adverse reaction 
 
 
 
 
 

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Overview 
 
Registry and trial number 
EudraCT number: 2021-005116-64  
Date of registration 
EudraCT: 16/09-2021 
Sources of monetary or 
material support 
 
Health Research Foundation of Central Denmark Region  
Sponsor 
Lone Nikolajsen, Aarhus University Hospital 
Contact 
Lone.nikolajsen@clin.au.dk 
Primary investigator 
Stine Fjendbo Galili, Aarhus University Hospital 
Contact 
S.galili@clin.au.dk 
Title 
Low-dose-ketamine for acute pain in the ED, a randomized, 
controlled, double-blinded, trial   
Country of recruitment 
Denmark 
Condition studied 
Acute pain in the ED 
Intervention 
LDK 0.1 mg/kg as an adjunct to morphine  
Comparator 
Morphine and placebo 
Inclusion criteria 
1) Emergency Department admission 
2) Age ≥ 18 years 
3) NRS ≥ 5 
4) Stable vital signs defined as systolic blood pressure ≥ 90 
mmHg, heart rate between 50 and 160 per minute, respiratory 
rate between 8 and 30 per minute, oxygen saturation greater 
than or equal to 92% 
Exclusion criteria 
1) Initial management by trauma-team 
2) Systolic blood pressure ≥ 180mmHg, severe untreated 
arrhythmia, unstable angina, recent myocardial infarction (< 30 
days), severe heart-failure (Ejection fraction < 40 %) 

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3) Symptoms of untreated hyperthyroidism 
4) Cirrhosis with ascites 
5) Known/suspected pregnancy or breastfeeding 
6) Patients for whom consent is not obtainable or psychiatric 
forced treatment. 
7) Previously enrolled in the trial 
8) Psychiatric illness prior to admission defined as prior 
psychosis/schizophrenia  
9) Untreated diagnosed glaucoma 
10) Known hypersensitivity to ketamine or to any excipient or 
prior use of ketamine with a negative experience (i.e. 
hallucinations) 
11) Patient clearly influenced by drugs or alcohol  
Study type 
Interventional  
Intervention model: Parallel 
group 
Allocation Randomized (1:1) 
Masking: Double blinded 
Date of first screening 
15-05-2022  
Target sample size 
160  
Recruitment status 
 Recruiting 
Primary outcomes 
The primary outcome measurement is pain reduction after 10 
min assessed on NRS. 
 
 
 
 
 
 
 
 

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Trial flowchart 

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Project group 
 
Stine Fjendbo Galili, MD,  
PhD student / Primary investigator 
Research Center for Emergency Medicine  
Department of Clinical Medicine 
Aarhus University and Aarhus University 
Hospital 
Lone Nikolajsen, MD, PhD, DMSc 
Professor, Chair, Sponsor,  
Department of Anesthesiology 
Department of Clinical Medicine 
Aarhus University and Aarhus University 
Hospital 
 
 
 
 
 
 
Jette Ahrensberg, MD, PhD,  
Research Center for Emergency Medicine  
Department of Clinical Medicine 
Aarhus University and Aarhus University 
Hospital 
 
Bodil Hammer Bech, MD, PhD, DMSc 
Associate professor,  
Research Unit for Epidemiology 
Department of Public Health  
Aarhus University 
 
Hans Kirkegaard, MD, PhD, DMSc 
Director, Professor  
Research Center for Emergency Medicine  
Department of Clinical Medicine 
Aarhus University and Aarhus University 
Hospital
 
 

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Conflicts of interest 
The members of the project group have no conflicts of interest related to the current trial. A list of all conflict of 
interests is provided in Appendix 1. Trial site  
 
Aarhus University Hospital, Skejby  
Palle Juul-Jensens Boulevard 99 
8200 Aarhus N 
Denmark  
Site investigator: Stine Fjendbo Galili
GCP monitor: 
Lene Brandsborg 
Olof Palmes Allé 15 
8200 Aarhus N 
Phone: +45 7841 3950 
E-mail: gcp@clin.au.dk 
Pharmacy  
Hospitalsapoteket Region Midtjylland 
Universitetsbyen 25 
8000 Aarhus C 
Contact: Lisbet Emmery Jørgensen 
E-mail: lisjoe@auh.rm.dk
 
Amendments 
 
Version 3.2 
Version 3.1 (Apr. 19, 2023) to 3.2  (May 26, 2023) 
• 
Clarifications in the screening process p 35 
 
Version 3.0 (Apr. 19, 2022) to 3.1 Apr. 19, 2023)  
• 
Corrections of minor typos and grammatical issues as well as minor clarifications and updated flowchart 

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• 
Precision on timepoint for registration of vital parameters (p 24) 
• 
Precision of doses for patients with a daily use of opioids (last version 10% of daily dose, this version 
15% of daily dose, AND a minimum of 0.05-0.1 
• 
Precision of opioid doses for patients without a daily use of opioids (last version 0.1 mg/kg, this version 
0.05-0.1 mg/kg)  
• 
Stable pulse changed from 60-150 to 50-160 
• 
Respiratory frequency changed from 8-24 to 8-30  
Version 2.0 (Nov. 22, 2021) to 3.0 (Apr. 19, 2022) 
• 
Corrections of minor typos and grammatical issues as well as minor clarifications 
• 
Addition of EudraCT 
• 
Addition of Study Kits 
• 
Addition on blinding details 
• 
Addition of Hospital Pharmacy 
• 
Clarification that that the unblinded pharmacy staff and nurse will not be involved in outcome 
evaluation, section 2.4 
• 
Change in timepoints (not primary outcome time point) 
 
Version 1.0 (Oct. 4, 2021) to 2.0 (Nov. 22, 2021) 
• IDMC is deleted from the protocol 
• Criteria for patient withdrawel is described 
• Exlusion criteria add 
• Corrections in section 4.3.1 , Safety and Harm, general considerations 
• Corrections conserving Sponsors evaluation of SAR/SUSAR 
• Labels added 
 
 
 
 
 

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BACKGROUND 
1.1 Pain in the ED – the participant population  
1.1.1 Incidence and mortality 
The Danish ED’s have 1.8 million contacts each year6 and several studies find that 70-80% of these 
arrives from patients in pain7,8,9,10. 
This makes pain management an essential component of emergency medicine, but also a challenge in 
many cases and ineffective and/or delayed analgesia for patients attending the ED is a common 
feature11,12,13.  
Many variables contribute to this finding, including limited resources, lack of diligence for assessing 
and treating pain, side effect barriers, inadequate education of providers, and misconceptions on 
behalf of both patients and staff 14. 
This is very unfortunate since the insufficient treatment of acute pain can lead to a number of 
complications, extended hospital stays, chronic pain, and prolonged course of illness15,16. 
A frequent and increasing challenge in the ED is the opioid-tolerant patients requiring acute pain 
management17. They are a group of patients who seek medical help much more often than their opioid 
naïve counterparts18,19, i.e. in the EDs. Since Denmark has one of the highest rates of opioid 
consumption in the world with 3-5% of the population using opioids daily or regularly 20, these patients 
have a strong presence in the ED. 
Besides the above mentioned risks of complications, these patients are in risk of withdrawal symptoms 
and stigmatization because of the need for much larger doses of opioids to achieve pain relief than 
others. The staff in the ED can be reluctant to deviate from standard treatment and the patient can be 
perceived as pleading for opioids. These barriers may be the reason that opioid-tolerant patients often 
do not receive the doses of opioids required to relief their pain21.  

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1.1.2 Treatment of pain 
The primary basis for acute pain relief is the administration of systemic analgesic agents such as 
paracetamol (1 g x 4/24h)22, nonsteroidal anti-inflammatory drugs (NSAIDs) (400 mg x 3/24h)23 (if no 
contraindications), and opioids i.e. morphine 0.05- 0.1 mg/kg or fentanyl 0.5-1 µg/kg24,25.  
Single opioid doses less than 0.1 mg/kg of intravenous morphine or 1 μg/kg of intravenous fentanyl are 
likely to be inadequate for severe, acute pain and the need for additional doses should be 
anticipated13. 
1.2 Low-dose ketamine – the trial intervention  
1.2.1 The NMDA receptor 
Ketamine functions primarily as an antagonist of the N-methyl-D-aspartate receptor (NMDA), thus   
counteracting signals and impulses, which lead to hyperalgesia, central sensitization and opioid 
tolerance, besides reducing the wind-up phenomenon, and activating descending inhibitory 
monoaminergic pain pathways via  interaction with opioid receptors26 27 28.  
1.2.2 Use in pain treatment 
Low-dose ketamine (LDK) has been used for decades and has been shown to be safe and effective in 
the reduction of acute postoperative pain and to reduce analgesic consumption in a variety of surgical 
interventions28,29,30,31,32,33,34. Furthermore, LDK has been shown to prevent hyperalgesia and acute 
opioid tolerance due to the use of morphine and/or fentanyl10,28. 
LDK has been studied as analgesic in a variety of contexts, including as a stand-alone treatment, as an 
adjunct to opioids, and, to a lesser extent, as an intranasal formulation 26,35,30,36.   
1.2.3 Use in the ED 
Regarding management of acute pain in the ED, finding alternatives to opioids has become increasingly 
interesting and LDK is studied both as a single agent 37,38,39,40,41,42 and as an adjunct to 
morphine43,44,45,46,47. These studies overall found that both LDK and LDK + morphine had analgesic 
effects within the 60 minutes of administration, was opioid sparing, and had comparable safety profiles 
with placebo.  

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These studies conducted in the ED did not mention/or excluded patients with chronic pain and patients 
with prior opioid consumption. Therefore, these above mentioned RCTs provide no information 
regarding the management of patients with chronic pain and/or opioid tolerance. 
Studies evaluating the benefits of LDK in the opioid tolerant patients have exclusively been conducted 
in the peri- and postoperative setting, and have been found to reduce postoperative pain48 and opioid 
requirements29,31. Other (smaller) studies in the opioid tolerant population have found less or no 
benefit49,50,51. Taken together, these studies suggest at least a mild benefit for ketamine in the opioid-
tolerant population in the postoperative period.   
We believe that patients with chronic pain and/or opioid tolerance would in particular benefit from 
LDK 52,53 when presenting in the ED with acute pain.  As a NMDA receptor antagonist it presents 
analgesic effects independent of opioid tolerance54.  
To our knowledge, there are no prospective randomized trials that evaluate the role of LDK in 
managing a variety of acute, painful conditions in the opioid tolerant patients in the ED. Furthermore, 
additional data describing its safety and efficacy in the general ED setting is warranted55. 
1.2.4 Ketamine 
Ketamine's analgesic properties in sub-anesthetic doses (0.1-0.5 mg/kg) have been recognized for 
decades (average anesthetic induction dose is 2 mg/kg)35 and S-ketamine produces analgesia at plasma 
concentrations of 100 to 200 ng/mL, which represent a very small fraction of plasma concentrations 
after general anesthesia doses (9000–25,000 ng/mL)35.  
The recommended sub-anesthetic dose of ketamine used in pain treatment or in the prehospital 
emergency setting is 0.125-0.25 mg/kg bolus given IV over at least one minute56. In these doses LDK 
show analgesic effects without sedative or hypnotic effect57. When used as per- and postoperative pain 
treatment at AUH doses are (perioperative) 0.3 mg/kg/h and (postoperatively) 0,02 mg/kg/h58. 
Studies from the ED 46,59,60,61,62 finds little to no psychoperceptual effects at the dose of 0.1 mg/kg as 
will be used in this study. 

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1.2.5 Side effects reported following anesthetic doses 
The side effects reported below are all related to doses and administration pace.  They are reported 
after ketamine is used in anesthetic doses, and thus much larger doses than in this study. 
Frequency: 
Very common: >10 % 
Common: >1 % and <10 % 
Not common: >0.1 % and <1 % 
Rare: >0.01 % and <0.1 % 
Very rare: <0.01 % 
Not known (can’t be estimated from available data) 
Immune system disorders 
Rare 
 
Anaphylaxis. 
Neuropsychological manifestations 
 
Common 
 
 
 
Frequency unknown 
 
 
Emergence reactions (post-operative delirium)1, 
vivid dream, nightmares, dizziness and 
restlessness, hallucnations2. 
 
Dysphoria, anxiety, disorientation 
Nervous system 
 
Not common 
 
 
 
 
Enhanced muscle tone and spasms (resembling a 
partial motor or generalized motor seizure). 
 
Eyes 
Common 
 
Not common 
 
Blurred vision 
 
Diplopia, increased intraocular pressure, 
nystagmus 
Heart 
Common 
 
 
Rare 
 
Transient tachycardia, elevated blood pressure 
and heart frequency 
 
Arrhythmia, bradycardia 
Vascular system 
Rare 
 
Hypotension (when used in circulatory collapse) 
Airways, thorax and mediastinum 
Common 
 
Increased vascular resistance in the lung 
circulation, increased mucus secretion, increased 

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need of oxygen, laryngospasm, transient 
respiratory depression*  
Abdominal 
Common 
 
Nausea, vomiting, hypersalivation 
Hepatobiliary dysfunction 
Frequency unknown 
 
Abnormal test of liver function 
Drug induced liver injury** 
Skin and subcutaneous tissue disorders 
Not common  
 
Transient erythema and/or morbilliform rash, 
reactions at the injection site (pain and 
reddening) 
 
1. When S-ketamine is used as single agent for anesthesia, up to 30 % of the patients are observed to have side 
effect in the recovery phase. 
2. Frequency of these side effects can be reduced significantly by using a benzodiazepine. 
*Large doses and rapid rate of administration 
** After longer use (> 3 days). 
 
2. TRIAL DESIGN, OBJECTIVES AND HYPOTHESES  
2.1 Overview 
2.1.1 Design 
This is an investigator-initiated, randomized, parallel-grouped, double-blinded, superiority trial, 
investigating the combination of IV LDK and IV morphine versus IV morphine and placebo as regards to 
analgesic effect. 
2.1.2 Hypotheses 
• The combination of IV LDK and IV morphine will be superior to IV morphine alone as regards 
analgesic effect measured as reduction on the NRS scale. 
• The combination of IV LDK and IV morphine will provide a larger reduction on the NRS scale for 
patients with a prior use of opioids than for patients with no prior use of opioids. 
• The combination of IV LDK and IV morphine will reduce the opioid consumption within the first 
hour. 
• The frequency of side effects will be similar in the two treatment groups (ketamine vs. placebo) 

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2.1.3 Location 
The study will be conducted at Aarhus University Hospital  
2.1.4 Participants 
160 patients presenting in the ED with NRS ≥ 5 will be enrolled.  
2.1.5 Objective 
To determine efficacy and safety of IV LDK as an adjunct to IV morphine for the treatment of severe 
acute pain in the ED and compare the effect in patients with a prior use of opioid and patients without. 
2.2 ALLOCATION 
Patients fulfilling all inclusion criteria and no exclusion criteria will be randomized as follows: 
Group 1 = patients with a prior use of opioids.  
Group 2 = patients without a prior use of opioids. 
Patients in group 1 are allocated randomization numbers 101-190 
Patients in group 2 are allocated randomization numbers 201-290  
There are 10 additional numbers in each group to be used if a patient is excluded after the 
administration of study medicine. 
If a patient is excluded after randomization, but before study medicine is administered, the 
randomization number can be re-used by adding and registering a, b, c and so on. 
Patients (n=160) will be randomized in a  1:1 ratio to either s-ketamine or placebo (NaCl) in blocks of 2, 
4 and 6 patients 
The randomization process will be performed by the hospital pharmacy using 
www.sealedenvelope.com. 
The randomization list is kept at the hospital pharmacy during the study and only delivered to the PI 
when the inclusion and the data analysis are completed. 
PI will be provided with numbered blinded kits including either S-ketamine or placebo ensuring 
allocation concealment. 

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The kit consist of: 
Active:  
• 
Esketamin “Orifarm” 5 mg/ml                           1x  5 ml 
• 
NatriumChloride Fresenius Kabi 20 x 10 ml    1 x 10 ml 
• 
Emballage, 1 ml, neutral syringes                2 pieces 
• 
Emballage, cardboard (with label)                    1 karton  
• 
Labels, 2 pieces, for the syringes                      2 pieces 
• 
Envelope for emergency unblinding 
Placebo: 
• 
NatriumChloride Fresenius Kabi 20 x 10 ml    1 x 10 ml 
• 
Emballage, 1 ml, neutral syringes                2 pieces 
• 
Emballage, cardboard (with label)                    1 karton  
• 
Labels, 2 pieces, for the syringes                      2 pieces 
• 
Envelope for emergency unblinding 
2.3 INTERVENTIONS 
2.3.1 Intervention groups 
 
 
Morphine + LDK 
 
 
Morphine + Placebo 
 
Prior opioid 
use 
N 40 
IV morphine (15 % of the total 24-hour 
opioid consumption) 
+ 
Ketamine 0,1 mg/kg 
N 40 
IV morphine (15 % of the total 24-hour 
opioid consumption) 
+ 
Placebo (saline) 
 
No prior 
opioid use 
N 40 
IV morphine, 0.05- 0.1 mg/kg 
+ 
Ketamine 0,1 mg/kg 
 
N 40 
IV morphine, 0.05- 0.1 mg/kg 
+ 
placebo (saline) 

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2.3.2 Concomitant interventions 
All procedures, except for the administration of study medicine and data collection for the study 
purpose, will be conducted according to the standard at Aarhus University Hospital. 
During the observational period, 120 min, relevant procedures will be registered in eCRF:  
• 
Nerve block 
• 
Repositioning of joints/fractures or casting 
• 
Paracetamol and NSAID 
2.3.3 Criteria for modification of interventions for a given trial participant and protocol violations 
The clinical team may at any time violate the protocol if they find it to be in the interest of the 
participating patient. 
2.3.4 Assessment of participant compliance 
The trial site is monitored through the electronic case report form (eCRF). In addition, the trial will be 
monitored according to the Good Clinical Practice (GCP) directive and the monitoring plan. 
2.4 BLINDING 
The trial intervention (morphine + LDK vs. morphine + placebo) will be blinded for investigators, clinical 
staff, and participants.  
Only the pharmacy providing the numbered kits and the nurse who draw the medication will be aware 
of the allocation. 
Patients will be randomized according to the allocation list.  
The randomization number will be entered directly in the eCRF. 
Study medicine is delivered by the pharmacy in blinded kits, the PI provides a study nurse (who is not 
otherwise involved in the study) with the kit and he or she will draw the study medicine in the two, 1 
ml, syringes contained in the kit, mark them with the labels in the kit and hand them over to the PI. 
Both ketamine and NaCl is colorless and without any identifying features. 

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The PI has entered the sex and weigth in the eCPR and a calculated field gives the ideal weigth. The PI 
administers the correct doses according to ideal weigth. 
Doses are marked in table 1, (ideal weight, 0.1 mg/kg). 
 
Labels (Danish): 
 
In the blinded intervention kit, a sealed opaque envelope will contain the allocation assignment which 
will allow for emergency unblinding. The decision to unblind will be at the complete discretion of the 
treating physician and clinical team. However, we do not expect scenarios where emergency 
unblinding will be necessary. In case unblinding occurs, the reason(s) will be clearly documented in the 
case report form. The patient will remain in the trial.  

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Table 1 
Ideal weight*, kg 
40 
45 
50 
55 
60 
65 
70 
75 
80 
85 
90 
95 
100 
105 
110 
Ketamine, mg 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 
10,5 
11 
Study medication, 
ml                 
(S-ketamine 5 
mg/ml or 
placebo) 
0,8 
0,9 
1 
1,1 
1,2 
1,3 
1,4 
1,5 
1,6 
1,7 
1,8 
1,9 
2 
2,1 
2,2 
*ideal weight: height (in cm) - 100  
If cancellation/postponement of treatment or withdrawal of consent occurs before the study 
medication is given, but after randomization has taken place, the randomization number will not be 
reused. Besides study medication, emergency department staff provides usual pain treatment (0.05-
0.1 mg/kg morphine or if the patient has a prior use of opioids 15% of 24 hour dose in morphine 
equivalent – in both cases titration until NRS ≤ 3.)  
The unblinded pharmaceutical staff and nurse who draws study medicine will not be involved in 
outcome evaluation or patient treatment. 
2.5 TRIAL PROCEDURES 
2.5.1 Patients 
The trial procedures will be limited to the interventions given with the first dose of morphine (see section 2.3 ) 
Data will be obtained from the study specific eCRF and from the electronic medical records. 
T0 defined as when the ED physician/nurse evaluates NRS and  the PI gives the study medication.  
The trial and observation period is T0 - 120 min. 
 
T0 
10 min 
 20 min 
30 min 
45 min 
60 min 
120 min 
NRS 
x 
x 
x 
x 
x 
x 
x 

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Patient rated 
pain relief* 
 
x 
 
 
 
 
x 
Vital 
parameters 
X 
X 
X 
X 
X 
X 
X 
Patient 
reported side 
effects** 
 
x 
 
x 
 
 
x 
Physician 
reported side 
effects*** 
 
 
 
 
 
 
x 
Provider 
satisfaction 
score**** 
 
 
 
 
 
 
x 
Patient 
satisfaction 
score 
 
 
 
 
 
 
x 
RASS***** 
 
x 
x 
x 
x 
x 
x 
 
*Patients will be asked to rate their pain relief on a 6-point scale (“worse pain,” “no,” “little,” 
“moderate,” “good,” or “complete pain relief”). 
**Patient-Reported Side effects: nausea, lightheadedness or dizziness, disorientation, euphoria, 
itching, tinnitus, double vision, abnormal dreaming or hallucinations.  
In addition, patients are encouraged to spontaneously report any other side effects/adverse advent. 
The timing of onset and resolution of all adverse effects during the observation period will be 
recorded. 
***Physician-reported side effects: nystagmus, hypertension, respiratory depression, bradycardia, 
hallucinations. 
****Provider satisfaction with pain control will be recorded on the 4-point Likert scale with 0 being 
“completely unsatisfied” and 3 being “very satisfied. 
*****Richmond Agitation-Sedation Scale (RASS) will be used to evaluate agitation or sedation. 
(appendix 2) 
TRIAGE63 and TOKS63 (tidlig opsporing af kritisk sygdom) according to the standard at AUH will be used 
to evaluate differences in vital parameters. 

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There will be no questionnaires for the participants to answer, they will be asked verbally and their 
answers will be entered in RedCap. 
2.5.2 Clinical personnel  
Prior to the beginning of patient enrollment and continuously throughout the enrollment period, the 
clinical teams involved in the treatment of patients at the participating hospital will be informed about 
the background and objectives of the trial, the inclusion/exclusion criteria, the interventions, and the 
trial procedures they are involved in. We anticipate, in-person didactics monthly with informal 
sessions.  
Provider Satisfaction Score will be used after the observation period is over (120 min after study 
medication is injected) to evaluate provider's clinical satisfaction with the treatment. Provider 
satisfaction with pain control will be recorded on the 4-point Likert scale with 0 being “completely 
unsatisfied” and 3 being “very satisfied. There will be no questionnaires for the provider, they will be 
asked verbally and their answers entered in RedCap. 
3. SETTING AND PATIENT POPULATION 
3.1 Setting 
The trial will be conducted at the ED at Aarhus University Hospital, and may be expanded to the ED at 
Regional Hospital West Jutland at a later stage. (an amendment will be added in this case) 
3.2 Inclusion criteria 
PI will screen ED patients at ED admission for the following inclusion criteria:   
1. Emergency Department admission 
2. Age ≥ 18 years and 
3. A painful condition (NRS ≥ 5) 
4. Stable vital signs defined as systolic blood pressure ≥ 90 mmHg, heart rate between 50 and 150 
per minute, respiratory rate between 8 and 30 per minute, oxygen saturation greater than or 
equal to 92%. 
Further subcategorized into 
1. Prior use of opioids (daily for one week before admission) 

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2. No prior use of opioids (daily for one week before admission) 
 
These broad inclusion criteria are chosen to investigate the effect of LDK in the entire, broad 
population with pain in the ED and the subcategorization to investigate whether LDK leads to a larger 
reduction on NRS in the group of patients with a prior use of opioids than those without a prior use of 
opioids. 
We will strive to enroll participants as soon as they fulfill the criteria in the ED. 
3.3 Exclusion criteria 
1) Initial management by trauma-team 
2) Systolic blood pressure ≥ 180 mmHg, severe untreated arrhythmia, unstable angina 
pectoris, recent myocardial infarction ( < 30 days), severe heart failure (Ejection fraction 
< 40 %) 
3) Symptoms of untreated hyperthyroidism 
4) Cirrhosis with ascites 
5) Known/suspected pregnancy, or breastfeeding 
6) Patients, for whom consent is not obtainable or psychiatric forced treatment. 
7) Previously enrolled in the trial 
8) Psychiatric illness prior to admission defined as prior psychosis/schizophrenia  
9) Diagnosed untreated glaucoma 
10) Known hypersensitivity to ketamine or to any excipient or prior use of ketamine with a 
negative experience (i.e. hallucinations) 
11) Patient clearly influenced by drugs or alcohol  
3.4 Withdrawal 
 
Each participant has the right to withdraw from the trial at any time.  In addition, the        
Investigator may discontinue a participant from the trial at any time if the Investigator considers 
it necessary for any reason including: 
• Ineligibility (either arising during the trial or retrospectively having been overlooked at screening) 

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• Significant protocol deviation 
• Withdrawal of consent 
• Loss to follow up 
 
3.5 Co-enrollment  
There will be no general restrictions on entry into other clinical trials, although this will be evaluated on 
a case-by-case basis. However, patients enrolled in this study will not be able to be enrolled in other 
acute-pain treatment projects at the time of admission in the ED and the first 120 minutes after study 
medicine is given. 
4. OUTCOMES 
4.1 Primary outcome 
4.1.1 Definition  
The primary outcome measurement is pain reduction assessed on NRS 10 minutes after study 
medication is given, T0 . 
(T0 = when the physician/nurse evaluates pain at administration of study medication) 
4.1.2 Rationale  
This study is powered to detect a difference in pain reduction of at least 1.5 on the NRS scale between 
the groups. (LDK vs placebo)  
4.2 Secondary outcomes 
4.2.1 Definitions  
Secondary outcomes:  
• Need of morphine within the 30, 60 and 120 min after administration of study medication 
• Pain intensity after 20, 30, 45, 60 and 120 min 
• Side effects  
• Patients satisfaction Score 
• Provider Satisfaction Score 

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• Comparison of pain reduction in the two parallel groups (prior opioid, no prior opioid) on all 
time intervals.  
4.2.2 Rationale 
Very few prospective studies have examined the effect of LDK as an adjunct to opioid for acute pain 
treatment in the ED setting. Almost none in the general patient population with pain and no one have 
evaluated the effect in patients having a prior use of opioids.  
Increasing the efficacy of pain treatment and reducing the incidence of adverse side effects is always a 
desirable clinical improvement, as is the reduction of resources necessary to effectively treat pain in 
the ED.  
Adding LDK to morphine may result in a better pain treatment for the patient and reduced need for 
opioids. 
 
4.3 Safety and harm 
  
4.3.1 General consideration 
The personal in the ED are highly trained in acute pain therapy. The PI is Specialty trainee in 
anesthesiology, Department of Anesthesiology AUH and she will be at trial site whenever study 
medicine is given. The doses used in this study are very low (0,1 mg/kg), and we do not expect any 
serious adverse reactions with this dose46,59,60,61. We therefore believe it is safe for both individual 
patients and at the group level to be enrolled into this study after relevant inclusion and exclusion 
criteria. 
The overall benefit and potential harm will be captured in our secondary outcomes, and the clinical 
team/PI will document any specific adverse reactions suspected to be related to the intervention - if 
there are AE or AR´s after the observation period (T0-T120 ), the patients are observed as standard on 
AUH. 
All participants are expected to receive opioids, but the amount is hypothesized to differ.  
AE as natural consequences of the reason for hospitalization will not be registered in the eCRF. (i.e. 
blood transfusion). 

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Investigators should use their knowledge of the patient, the circumstances surrounding the event, and 
an evaluation of any potential alternative causes to determine whether or not an AE is considered to 
be related to the study drug, indicating "yes" or "no" accordingly. The following guidance will be taken 
into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug 
(where applicable) 
• 
Known association of the event with the study drug or with similar 
treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications 
known to increase the occurrence of the event 
Presence of non-treatment-related factors that are known to be associated 
with the occurrence of the event 
 
4.3.2 Definitions for adverse events and reactions 
The following definitions will be used2:  
Adverse event (AE): any untoward medical occurrence in a subject to whom a medicinal product is 
administered and which does not necessarily have a causal relationship with this treatment. 
Adverse reaction (AR): all untoward and unintended responses to an investigational medicinal product 
related to any dose administered. 
Serious adverse event (SAE): any untoward medical occurrence that at any dose requires inpatient 
hospitalization or prolongation of existing hospitalization, results in persistent or significant disability 
or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death.  

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Serious adverse Reaction (SAR): an adverse drug reaction that is serious (see above) and at least 
possibly related to an investigational medicinal product related to any dose administered. 
Suspected unexpected serious adverse reaction (SUSAR): a serious adverse reaction, the nature, 
severity or outcome of which is not consistent with the reference safety information. 
 
4.3.3 Reporting 
Serious adverse reactions and events (SAE and SARs) and suspected unexpected adverse reactions 
(SUSARs) will be recorded daily in the eCRF during the intervention period. PI is to report potential 
SARs and SUSARs without undue delay to the sponsor, which in turn will evaluate the event according 
to the Danish summaries of product characteristics and report any SAR’s and/or SUSARs , which in turn 
will report these to the Danish Health and Medicine Authorities 7 days at the latest after the report has 
been received. The sponsor will yearly submit a list of all registered AEs that have occurred during the 
trial period as well as a report on safety (SAR) of the trial subjects to the Danish Medicines Agency and 
Scientific Ethics Committee. 
The sponsor will notify the Danish Medicines Agency when the trial has been completed (no later than 
90 days thereafter). The results from the clinical trial including important adverse events will be 
recorded on EudraCT. 
5. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN 
5.1 Sample size calculation 
We consider a mean reduction in pain intensity of 1 (SD ±2) on the NRS scale to be realistic in the 
control group and that the reduction should be 2.5 (SD ± 2) in the intervention group for the addition 
of LDK to be meaningful. Based on these estimates, an alpha of 5%, a power of 90% and a two-sample 
t-test (assuming that the pain reduction is normally distributed), a sample size of 78 patients is 
required; 39 in each treatment arm (two independent samples =156 patients).  
The primary (continuous) and secondary outcomes (binary and continuous variables) will be presented 
as follows: Categorical variables will be compared using Fisher’s exact test and continuous variables 

Side 30 af 50 
 
using t-tests or Wilcoxon rank-sum test as appropriate. P < 0.05 will be considered statistically 
significant. 
To investigate the hypothesis of heterogeneity in effect of LDK addition depending on prior morphine 
use, we will compare treatment effect between the two groups (no prior morphine use vs prior 
morphine use). If we assume the two groups to have equal size (78 patients) then the expected SE of 
the difference between treatment effects of the two groups (no prior morphine vs prior) will be 0.64, 
i.e. the corresponding 95% confidence interval will have a width of approximately 2.6. 
To handle potential differences in baseline pain intensity between the standard and the LDK treatment 
group, we will assess the relative (%) change in NRS from baseline (T0) to 10 min after administration 
of study medicine in a supplemental post-hoc analysis. The relative change in pain scores will be 
assessed  by multilevel mixed effect ordinal logistic regression model64. 
5.2 General considerations 
The statistical analyses and reporting will adhere to the CONSORT guidelines.65.  All tests will be two-
sided, a p-value < 0.05 will be considered significant, and all confidence intervals will have 95% 
coverage.  
Patient inclusion and exclusion will be illustrated in a CONSORT flow diagram (see Appendix 3). 
We will include measures related to feasibility including the enrolled to screened ratio, time to 
randomization, and protocol adherence/major protocol violations. All analyses will be conducted in the 
modified intention-to-treat (MITT) population defined as all randomized participants for whom 
consent was obtained.  
6. DATA COLLECTION AND DATAMANAGEMENT 
6.1 Data collection process  
The site investigator (PI) is responsible for data collection and entry. This will include the patient 
identifier (i.e. Danish Central Personal Register number), study ID, and timing of enrollment. Data will 
be obtained in eCRFs especially regarding pain therapy as well as from medical journals; all data will be 
based on measurements and assessments made by the clinical team. Data are continuously entered 

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into RedCap (Institute for Clinical Medicine, Aarhus University), which is considered as the Case Report 
Form. RedCap is a secure web application geared to support data capture for research studies66 
6.2. Variables 
6.2.1 Overview 
All patients admitted to the ED during study days with a painfull condition AUH, will be entered into a 
screening log. For those screened but not randomized, a specific reason for non-inclusion/exclusion 
will be documented. All randomized patients will be entered into the main database.  
A detailed data dictionary that clearly defines all included variables will be created prior to patient 
enrollment. The data dictionary will provide the name of the variable (including the code used in the 
database), a detailed definition of the variable, categories for categorical variables, and units and 
ranges for continuous variables.  
The number of collected variables will be kept relatively small to limit resource use and data entry 
mistakes. Below is provided a brief overview of the included variables, but details are reserved for the 
data dictionary. 
6.2.2 Baseline characteristics 
Trial related variables 
 
Study ID 
 
Inclusion criteria 
 
Exclusion criteria 
Opioids given before study medication (i.e. in ambulance) 
 
Date and time consent for data collection is obtained 
 
 
Patient demographics and characteristics  
 
Unique patient identifier (CPR number) 
             Age  
 
Sex 
 
Height 

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Weight 
 
Medications prior to enrollment 
Prior opioid use, dose, duration 
Reason for prior opioid use (cancer/non-cancer pain, postoperative, addiction) 
Cancer/non-cancer 
Site of pain/injury: 
 
Fracture/orthopedic 
 
Abdominal/flank 
Groin pain 
Postoperative pain 
 
Other/unknown 
 
Prior to randomization:  
Vital parameters 
NRS 
 
  
At 10, 20, 30, 45 60 and 120 min after randomization:  
NRS 
RASS 
Need for rescue morphine and total use of morphine 
Physician reported side effects: nystagmus, hypertension, respiratory depression, bradycardia, 
arrhythmia. 
TOKS and triage values as standard procedures 
Patient-reported side effects: nausea, lightheadedness or dizziness, dry mouth, disorientation, 
euphoria, itching, tinnitus, double vision, abnormal dreaming or hallucinations. 
Patient satisfaction. To be able to compare with other and future studies “no pain” and “worst pain 
imaginable” are chosen as anchors67. 

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Provider satisfaction with pain control will be recorded on the 4-point Likert scale with 0 being 
“completely unsatisfied” and 3 being “very satisfied. 
Protocol violation. 
 
6.3 Data quality and validity 
Data quality and validity will be optimized by having trained PI entering all data according to a detailed 
data dictionary. Research Electronic Data Capture (REDCap)  (see section 7.4) is designed such that 
data forms contain field-specific validation checks ensuring that mandatory fields are filled out and 
that continuous variables are within predefined ranges. Given its limited utility, double-data entry will 
not be performed68,69. 
6.4 Data storage and security 
REDCap66 is a professional database that provides a user-friendly interface. The REDCap data 
management system is secure, fully compliant with all regulatory guidelines, and includes a complete 
audit-trail for data entry validation. Through these mechanisms, as well as relevant training for all 
involved parties, patient confidentiality will be safeguarded. REDCap is available for free at 
participating sites.  
The consent form for each patient will be stored in a secure, locked place at Research Center for 
Emergency Medicine in Aarhus. Here they will be securely stored in locked cabinets, where only the 
principal investigator will have access. The files will be stored for 5 years after the end of the trial, 
whereupon they will be destroyed.    
Data will be handled according to all relevant Danish laws including the General Data Protection 
Regulation (“Databeskyttelsesforordningen”) and the Data Protection Act (“Databeskyttelsesloven”).  
The project will be registered with the Central Denmark Region’s internal list of research projects.   
6.5 Data access 
Each patient will receive a unique trial identification number. During the trial, the principal investigator 
will have access to the entire database.  

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Once the database is locked and data is analyzed as group A and B, two conclusions will be written 
before unblinding, one where LDK is A and one where LDK is not A. 
A de-identified version of the database will be made available to the members of the project group. 
The Good Clinical Practice unit, regulatory agencies, and other relevant entities will have direct access 
to patients’ records and to all relevant trial data including the case report form as applicable. 
 
6.6 Data obtained from patient records 
 
6.6.1 Data that will be obtained before informed consent and inclusion 
 
The electronic patient record will only be screened for in- and exclusion criteria(see page 22-23), pain 
intensity and opioids given before the informed consent, i.e in ambulance. If a patient is excluded the 
reason for exclusion will be entered in the screening log.  
No other data will be obtained. 
6.6.2 Data that will be obtained after informed consent and inclusion 
 
Reason for contact to the ED (ie abdominal pain, broken ankle)  
Use of opioids prior to the admission (yes or no, drug and dose)  
Use of other analgesic except NSAIDs and paracetamol 
 
 
Access to patient journals: 
The written informed consent gives PI, Sponsor, sponsors representatives and monitor direct access to 
all relevant data in the electronic patient record concerning the patients health, relevant for the 
execution of the trial. Furthermore for the legal monitoring and purpose of controlling the study 
including own-check, quality control and monitoring of the study that these obliged to perform. 
 

Side 35 af 50 
 
 
7. CLINICAL TREATMENT  
7.1 Screening, information and enrollment 
Patients will be screened and recruited according to the following process: 
Information on all patients “on their way” to the ED is being passed on to the PI in “Klinisk Logistic” and 
whenever a patients is referred with a pain full condition (i.e. abdominal pain, backpain or suspicion of 
broken hip) the PI markes the patient “Candidate for KetMO, Please call PI at arrival”. The visitation 
nurse is the gatekeeper at the ED, AUH and she/he is contacted by every doctor or paramedic who 
refers patients to the ED. If patients are presenting to the ED unannounced it is also the visitations 
nurse that registers the patient. The visition nurse will call the PI when a relevant patient  arrives at the 
ED or is already admitted in the ED.  
The PI screens the medical record for exclusion criteria. If the patient fulfills no exclusion criteria the 
patient will be approached and asked for inclusion criteria and risk/chance of pregnancy – if yes to 
inclusion criteria an certain no to risk of pregnancy the patient can be included in the study and the 
formal information procedure will begin. 
In as calm surroundings as possible and, if feasible, with companion, the patient will be informed, 
verbally and in writing, about the background and significance of the study, inclusion criteria, potential 
risks and benefits, as well as a brief description of the study intervention. The patient may ask 
questions and provide written informed consent utilizing the informed consent form approved by the 
Ethical Review Committee. If a patient denies participation in the trial, no data besides the screening 
log will be collected71. 
It is exclusively the PI who informs and enrolls the patients. and The information and enrolment is as 
soon as possible at admission in the ED. 
The study protocol will begin as soon as the patient have given verbal and written consent. 
The clinical management of included patients, other than pain treatment according to randomization, 
will be at the complete discretion of the treating clinical team in order to test the interventions in a 
real-life clinical scenario.  

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8. ETHICAL CONSIDERATIONS  
8.1 General considerations  
For ethical reasons, treatment of acute must be initiated as soon as possible. This is also stated in 
international guidelines70 and in a local guideline at our institution. 
We therefore often need patients to provide consent within a timeframe less than one hour (from 
information about the study until consent). If this is not possible for the patient (he or she needs longer 
time to consider), the patient will not be included 
The current trial will adhere to the revised Declaration of Helsinki as well as all applicable laws and 
regulatory guidelines.  
 
8.2 Procedures 
 
8.2.1 Ethical review committee  
 
The trial is approved by the Regional Ethics Committee.  
8.3.1 Insurance 
The patients in the study are covered by the Danish patient insurance72. 
9. MONITORING 
9.1 Good Clinical Practice monitoring 
The site will be monitored by the regional Good Clinical Practice monitoring unit affiliated with Aarhus 
University Hospital and Central Denmark Region. A detailed monitoring plan will be developed prior to 
trial commencement. 
10. TIMELINE AND ENROLLMENT 
10.1 Timeline 
 
Spring/Summer 
2021 
Autum 
2021 
Autumn/Winter 
2021 
2022 
2023 
Funding 
X 
 
 
 
 
Protocol 
development 
and 
modifications 
x 
 
 
 
 

Side 37 af 50 
 
Ethical 
approval 
 
x 
 
 
 
Registration 
with the Danish 
Medicine 
Agency 
 
x 
 
 
 
Creation of 
data dictionary  
 
x 
 
 
 
Trial 
registration 
 
x 
 
 
 
Creation of 
randomization 
list 
 
 
x 
 
 
Education of 
site personnel  
 
 
x 
x 
 
Good Clinical 
Practice 
monitoring 
 
 
 
x 
x 
Enrollment and 
assessment of 
outcomes 
 
 
 
x 
 
Writing and 
publication of 
methodology 
article 
 
 
x 
 
 
Cleaning and 
closing of the 
database 
 
 
 
 
x 
Data analysis 
 
 
 
 
x 
Main 
manuscript 
writing 
 
 
 
 
x 
Unblinding 
 
 
 
 
x 
Publication and 
presentation of 
results 
 
 
 
 
x 
 
 
10.2 Feasibility 
We expect to enroll 1 patient 3 days a week  during the study period. 160 patients must be included – 
160 days   53 weeks for inclusion of participants. 

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10.3 Enrollment  
Enrollment will be continuously performed and monitored by the PI. Formal reports outlining the 
number of pain patients and the proportion of those enrolled will be shared with the project group 
every second week during enrollment. 
12. PUBLICATION PLAN  
Two manuscripts are planned from the current trial. Prior to the clinical study, a methodology article 
will be published including a detailed description of the trial and the statistical analysis plan. The 
second and primary manuscript will include the main results including pre-defined primary and 
secondary outcomes. The manuscript will adhere to the CONSORT guidelines73,74. The principal 
investigator will be the first and corresponding author. Additional authorship will follow authorship 
guidelines from the International Committee of Medical Journal Editors75 and will include members of 
the project group. The main results will be presented at international conferences. The trial results will 
not be shared directly with the participating patients. Study findings will be published if the results are 
positive, negative or inconclusive.   
13. DATA SHARING 
Six months after the publication of the last results, all de-identified individual patient data will be made 
available for data sharing76. Procedures, including re-coding of key variables, will be put in place to 
allow for complete de-identification of the data. Data will be completely anonymized according to 
Danish law.  
All relevant trial-related documents, including the protocol, data dictionary, and the main statistical 
code, will be shared along with the data. There will be no predetermined end date for the data sharing. 
Data will be available for any research purpose to all interested parties who have approval from an 
independent review committee and who have a methodological sound proposal as determined by the 
project group of the current trial. Only the methodological qualities and not the purpose or objective 
of the proposal will be considered. Interested parties will be able to request the data by contacting the 
principal investigator. Authorship of publications emerging from the shared data will follow standard 
authorship guidelines from the International Committee of Medical Journal Editors75 and may or may 
not include authors from the project group depending on the nature of their involvement. 

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14. FUNDING  
Funding for the trial is provided by Dansk Selskab for Anæstesi og Intensiv medicin (DKK 40,000), 
Health Research Foundation of Central Denmark Region, “Akutpuljen” (DKK 220,000), Central Denmark 
Region 1,5 mio (salary for PI, PhD student). Funding is administered at the Research Center for 
Emergency Medicine, Central Denmark Region and is used for salary support, monitoring, and 
additional operational expenses. Additional funding will be applied for at various private and public 
foundations. The funding agencies or any pharmaceutical companies will have no role in the design and 
conduct of the study; collection, management, analysis, and interpretation of the data; preparation, 
review, or approval of the manuscript; or the decision to submit the manuscript for publication. 
15. TASKS AND RESPONSIBILITIES  
PI and sponsor: Overall responsibility for protocol development, funding, budget overview, data 
dictionary development, ethical approval, trial registration, daily management, trial oversight, contact 
to the pharmacy, contact to Good Clinical Practice monitoring unit and the data and safety monitoring 
board, assessment of overall recruitments and education, potential recruitment of additional sites, 
data analysis, and dissemination and presentation of results.   
PI: Responsible for site-specific enrollment and participant consent for data collection, evaluation of 
eligible patients not included, education of personnel at participating sites, reporting of site-specific 
issues or challenges to the principal investigator, participant consent for data collection. 
Daily management, education of personnel at participating sites, contact to Good Clinical Practice 
monitoring unit, data dictionary development, data entry and management, patient follow-up, budget 
overview 
Project group: Protocol development, funding, budget overview, data dictionary development, trial 
oversight, dissemination of results, responsibilities as principal investigator for short time periods.  
 
Appendix 1, Conflict of interest disclosures for project group 
 
 
Industry 
Other 

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Stine Fjendbo Galili 
None 
None 
Lone Nikolajsen 
None 
None 
Hans Kirkegaard 
None 
Chairman of the steering 
committee for DANARREST 
Jette Ahrensberg 
None 
None 
Bodil Hammer Bech 
None 
None 
 
 
Appendix 2, Richmond Agitation and Sedation Scale 
 
 
  
Richmond Agitation and Sedation Scale 
                           ( Rass) 
+4 
Combative 
Violent, immediate danger to staff 
+3 
Very Agitated 
Pulls or removes tube (s) or catheters; aggressive 
+2 
Agitated 
Frequent non-purposeful movement, fights ventilator 
+1 
Restless 
Anxious, apprehensive but movements not aggressive or vigorous 
0 
Alert and Calm 
 
-1 
Drowsy 
Not fully alert, but has sustained awakening to voice (eye opening 
and contact > 10 sec) 
-2 
Light sedation 
Briefly awakens to voice (eye opening & contact < 10 sec) 
-3 
Moderate sedation 
Movement or eye opening to voice (but no eye contact) 
-4 
Deep sedation 
No response to voice, but movement or eye opening to physical 
stimulation 
-5 
Unarousable 
No response to voice or physical stimulation 
 
 
 
 
 

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Appendix 3, CONSORT flow diagram 

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ICH E6 (R2) Good clinical practice | European Medicines Agency. Available at: 
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