A Blinded Randomized Study of Neostigmine/Glyco-pyrrolate 50 Mikrogram/kg or Sugammadex 2 mg/kg for Reversal of Neuromuscular Blockade in Elderly Patients (≥ 75 Years)
Phase: PHASE4
Conditions: Neuromuscular Blockade, Residual
Sponsor: Matias Vested

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Protocol 
Version 11, 05 October 2023 
A blinded randomized study of neostigmine/glycopyrrolate 50 mikrogram/kg or 
sugammadex 2 mg/kg for reversal of neuromuscular blockade in elderly patients 
(≥ 75 years). 
EU CT number: 2023-504230-21-00 
 
ClinicalTrials.gov number:xxxxx 
 
Matias Vested (MV), MD, PhD 
Department of Anaesthesia, Centre of Head and Orthopedics, Rigshospitalet,  
University of Copenhagen, Denmark 
________________________________________________ 
(Date and signature) 
 
Marie Louise Rovsing 
Department of Anaesthesiology,   
Bispebjerg Hospital, University of Copenhagen, Denmark  
________________________________________________ 
(Date and signature) 
 
Arash Afshari, MD, PhD 
Department of Pediatric and Obstetric Anesthesia,  
University of Copenhagen, Rigshospitalet, Denmark,   
________________________________________________ 
(Date and signature) 
 
Lars Simon Rasmussen (LSR), MD, PhD, DMSc  
________________________________________________ 
(Date and signature) 
 
Responsible department: 
Department of Anesthesia, Centre of Head and Orthopedics, 6013, Rigshospitalet,  
University of Copenhagen, Denmark 
 
Trial monitoring: 
GCP-Unit - Copenhagen University Hospital  
Bispebjerg og Frederiksberg Hospital  
Nordre Fasanvej 57, Skadestuevej 1, Parterre  
DK-2000 Frederiksberg, Denmark  
Tel. +45 3863 5620  
 
 

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Content 
Preface ............................................................................................................................................................... 4 
1. List of abbreviations ...................................................................................................................................... 4 
2. Overview ........................................................................................................................................................ 5 
3. Background .................................................................................................................................................... 8 
3.1 Elderly patients and residual neuromuscular blockade .......................................................................... 8 
3.2 Neostigmine/glycopyrrolate .................................................................................................................... 8 
3.3 Sugammadex ........................................................................................................................................... 9 
3.4 Comparison of neostigmine/glycopyrrolate and sugammadex .............................................................. 9 
4. Objective and hypotheses ........................................................................................................................... 10 
5. Trial design overview ................................................................................................................................... 10 
6. Setting and patient population .................................................................................................................... 10 
6.1 Setting .................................................................................................................................................... 10 
6.2 Inclusion criteria .................................................................................................................................... 10 
6.3 Exclusion criteria .................................................................................................................................... 11 
7. Interventions ............................................................................................................................................... 11 
7.1 Interventions ......................................................................................................................................... 11 
7.2 Monitoring ............................................................................................................................................. 12 
7.3 Concomitant treatment ......................................................................................................................... 14 
7.3.1 Treatment values ............................................................................................................................ 14 
7.3.2 Anesthesia ...................................................................................................................................... 15 
8. Sample size and recruitment strategies ...................................................................................................... 15 
8.1 Sample size ............................................................................................................................................ 15 
8.2 Recruitment strategies .......................................................................................................................... 15 
8.3. Trial timeline ......................................................................................................................................... 17 
9. Outcome ...................................................................................................................................................... 18 
9.1 Primary outcome ................................................................................................................................... 18 
9.2 Secondary outcome ............................................................................................................................... 18 
9.2.1 Subjective side effects of laryngoscope. ............................................................................................  
9.2.2 Amount of ephedrine or metaoxedrine administered .......................................................................  
9.2.3 Intubating difficulty score ...................................................................................................................  
10. Assignment of interventions ..................................................................................................................... 19 
10.1 Allocation ............................................................................................................................................. 19 

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10.2 Blinding ................................................................................................................................................ 19 
11. Data collection and management ............................................................................................................. 20 
11.1 Data collection ..................................................................................................................................... 20 
11.1.1 Study related variables ................................................................................................................. 20 
11.1.2 Preoperative variables .................................................................................................................. 20 
11.1.3 Intraoperative variables ............................................................................................................... 21 
11.1.4 Outcome variables ........................................................................................................................ 21 
11.2 Data management ............................................................................................................................... 22 
11.3 Statistical analysis ................................................................................................................................ 22 
12. Ethical considerations ................................................................................................................................ 23 
12.1 Registrations and approvals ................................................................................................................ 23 
12.2 General considerations ........................................................................................................................ 24 
12.3 Consent ................................................................................................................................................ 24 
12.4 Risk and safety issues .......................................................................................................................... 24 
12.4.1 Definitions(21) .............................................................................................................................. 25 
12.4.2 Side effects ................................................................................................................................... 25 
12.4.3 Adverse events ............................................................................................................................. 25 
12.4.4 Reporting of adverse events ......................................................................................................... 26 
12.4.5 Timeline ........................................................................................................................................ 26 
12.4.6 Suspected unexpected serious adverse reaction ......................................................................... 26 
12.4.7 Reporting ...................................................................................................................................... 26 
12.4.8 Insurance ...................................................................................................................................... 26 
13. Publication ................................................................................................................................................. 27 
14. Economy .................................................................................................................................................... 27 
References ....................................................................................................................................................... 28 
 
 
 
 
 
 

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Preface 
The “A randomized study of neostigmine/glycopyrrolate 50 mikrogr/kg or sugammadex 2 mg/kg 
for reversal of neuromuscular blockade in elderly patients (≥ 75 years)” trial will be conducted 
according to this protocol. The trial will be done according to applicable national and international 
laws, regulations and guidelines. This includes the revised version of the Declaration of Helsinki, 
European regulations, and the international Good Clinical Practice guidelines. The trial and 
protocol are developed according with Recommendations for Interventional Trials (SPIRIT) 
statement. Any substantial changes or amendments to the protocol will be clearly documented 
and communicated to all relevant parties. 
1. List of abbreviations 
AE: Adverse event 
AR: Adverse reaction 
ASA: American Society of Anesthesiologists  
CRF: Case report form 
ECG: Electrocardiogram 
eGFR: estimated glomerular filtration rate 
ICF: Informed consent form 
IDS: Intubation Difficulty Score 
MAP: Mean arterial pressure 
NMBA: Neuromuscular blocking agents 
PONV: Postoperative nausea and vomiting 
PACU: Post Anesthesia Care Unit 
SAE: Serious adverse event 
SAR: Serious adverse reaction 
SUSAR: Suspected unexpected serious adverse event 
SMPC: Summary of product characteristics 
 
TOF: Train-of-four 

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2. Overview 
 
Registry and trial 
number 
XXX 
Date of registration XXX 
Sources of monetary or 
material support 
Department of Anesthesia, Centre of Head and Orthopedics, 6013 Rigshospitalet,  
University of Copenhagen, Denmark 
Primary sponsor Matias Vested 
Contact  
Title A randomized study of neostigmine/glycopyrrolate 50 mikrogr/kg or 
sugammadex 2 mg/kg for reversal of neuromuscular blockade in elderly patients 
(≥ 75 years). 
Country of recruitment Denmark 
Condition studied Elderly patients scheduled for elective surgery 
Interventions Sugammadex 2 mg/kg 
Doses are based on actual body weight 
Comparator Neostigmine/glycopyrrolate 50 mikrogram/kg 
Doses are based on actual body weight 
Inclusion criteria 1) Patients ≥ 75 years old  
2) Informed consent 
3) Scheduled for robotic assisted laparoscopic surgery under general anesthesia 
with intubation and use of rocuronium during the entire operation  
4) American Society of Anesthesiologists (ASA) physical status classification I to 
IV 
5) Can read and understand Danish  
Exclusion criteria 1) Known allergy to rocuronium, sugammadex or neostigmine/glycopyrrolate 
2) Neuromuscular disease that may interfere with neuromuscular data 
3) Severe renal impairment defined as eGFR < 30 ml/min 
4) Indication for rapid sequence induction  

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5) Known intestinal or ureter obstruction 
6) Known peritonitis 
 
Study type Interventional  
Allocation: randomized (1:1) 
Intervention: sugammadex 2 mg/kg or neostigmine/glycopyrrolate 50 µg/kg 
Blinding: Medicine will be blinded in 10 mL syringes. 
Date of first expected 
screening 
1/6-2023 
Target sample size 40 
Recruitment status Waiting 
Primary outcomes Time to TOF > 0.9 (from beginning of administration of reversal agent until TOF > 
0.9)  
Key secondary 
outcomes 
• Key secondary outcome is sign of residual neuromuscular blockade 
within 90 minutes after administration of reversal agent defined as 
a composite (assessed upon arrival at PACU after 20 minutes and 
after 90 minutes) of either  
o Hand grip strength for 5 seconds or 
o Occurrence of double vision/blurred vision (yes/no) or 
o Ability to track objects with eyes (follow finger of 
examiner) (yes/no) or 
o Ability to sustain head lift for 5 seconds (yes/no) or 
o Ability to protrude the tongue for 5 seconds (yes/no) or 
o Tongue depressor test (prevent removal of a wooden 
tongue depressor from between the incisor teeth (yes/no) 
or 
o Ability to open the eyes for 5 seconds (yes/no) or 
o Ability to smile (yes/no) or 
o Ability to speak (yes/no) or 
o Occurrence of dysphagia/ swallowing impairment assessed 
by observing difficulties swallowing defined as the ability to 
drink 20 ml of water (yes/no) or 
o Occurrence of upper airway obstruction or 
o Subjective symptoms of muscle weakness (After each test 
is completed, patients are questioned by the research 
assistant about whether the test was difficult to complete 
or uncomfortable to perform. For example, a patient might 

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successfully maintain a 5-s eye opening yet note that it was 
“difficult to keep my eyes open” Subjective symptoms of 
muscle weakness will be recorded as normal (negative 
response) or impaired (positive response) 
Other secondary outcomes are: 
• Occurrence of episodes of desaturation defined as more than 3 
minutes with spO2 < 88% 
• New cardiac arrythmias (bradycardia or tachycardia defined as 
atrial fibrillation, atrial flutter, sinus tachycardia (>95 bpm), sinus 
bradycardia (<45 bpm)) within 180 minutes after administration of 
reversal agent 
• Occurrence of reintubation 
• Time from administration of reversal agent to patient is ready to 
leave the operating room 
 
  
  
 
 
 

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3. Background 
3.1 Elderly patients and residual neuromuscular blockade 
Numbers of elderly patients requiring anesthesia and surgery are increasing, and as a group, 
elderly patients are at high risk of postoperative complications1. Aging leads to a progressive 
impairment of organ function and a decline in physiologic reserve2 and in the elderly patient 
population, pharmacodynamics and pharmacokinetics of medications administered during 
anaesthesia may be influenced by the age-related reduction in cardiac output, liver function and 
renal function3 with a large inter-individual variation. Also, the body composition changes with age 
and elderly have lower total body water and accordingly a relative increase in body fat.  
Although the use of neuromuscular blocking agents (NMBAs) to improve surgical condition are still 
debated and awaiting larger randomized controlled trials, they are routinely administered in the 
clinical setting during anesthesia both to facilitate tracheal intubation and prevent muscle 
contractions during surgery which may impair the surgical conditions4,5. However, elderly patients 
administered NMBAs during anesthesia have an increased risk of postoperative residual 
neuromuscular block which is associated with more frequent episodes of hypoxemia, 
postoperative pulmonary complications, discomfort and longer hospital length of stay6.  
To prevent postoperative residual block it is strongly recommended to employ objective 
neuromuscular monitoring perioperatively2. Objective monitoring of the depth of the 
neuromuscular blockade is performed by train-of-four (TOF) stimulation at the ulnar nerve7. 
Neuromuscular monitoring enables the anesthetist to titrate the depth of block and to reverse the 
block if spontaneous recovery has not occurred upon conclusion of surgery. The dose of reversal 
agent depends on the depth of the blockade.   
It is possible to reverse rocuronium induced neuromuscular blockade with either 
neostigmine/glycopyrrolate (an acetylcholine esterase inhibitor) or sugammadex (a modified 
cyclodextrin). However, the optimal choice of reversal agent for rocuronium induced 
neuromuscular blockade in elderly patients is unknown. There is a need for studies investigating 
which reversal agent is optimal in elderly patients.  
3.2 Neostigmine/glycopyrrolate 
Neostigmine/glycopyrrolate, an acetylcholine esterase inhibitor, inhibits the enzyme 
(acetylcholinesterase) that breaks down acetylcholine at the neuromuscular junction. 
Neostigmine/glycopyrrolate reverses the effect of rocuronium by an increase in the concentration 
of acetylcholine at the neuromuscular junction.  
Nondepolarizing NMBDs such as rocuronium inhibit neuromuscular transmission primarily by 
competitively antagonizing or blocking the effect of acetylcholine at the postjunctional nicotinic 
acetylcholine receptor (nAChR). Binding of rocuronium to the nAChR occurs in a competitive 
fashion. If larger concentrations of acetylcholine are present at the neuromuscular junction, 

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acetylcholine will attach to the postsynaptic receptor and facilitate neuromuscular transmission 
and muscle contraction. Conversely, if larger concentrations of rocuronium are present at the 
neuromuscular junction, this will prevent muscle contraction.  
However, neostigmine has a so-called ceiling effect, i.e. some spontaneous recovery of the block 
must have occurred before neostigmine/glycopyrrolate is administered. Administration before this 
time point will not reduce the recovery time8,9.   
The time required to achieve a TOF ratio of 0.90 after neostigmine/glycopyrrolate administration 
is significantly shorter when a higher TOF count is present.  However, a large interindividual 
variability in reversal times have been reported10,11.  
The maximal effective dose of neostigmine/glycopyrrolate has not been clearly defined, but likely 
vary in relation to depth of blockade and type of NMBD administered. In general, if deeper levels 
of neuromuscular blockade are present at the end of surgery (1-2 responses to TOF stimulation), 
larger doses of anticholinesterases should be given. In these clinical scenarios, maximal doses of 
neostigmine/glycopyrrolate (70 μg/kg) should be considered. If three to four responses to TOF 
stimulation are present with observable fade of the fourth response, moderate doses of 
anticholinesterase should be administered i.e. 40-50 μg/kg of neostigmine/glycopyrrolate. In the 
elderly patients however, little is known about the optimal dose for reversal and studies in elderly 
patients suggest that neostigmine/glycopyrrolate is associated with certain side effects such as 
cardiac arrythmias12,13.   
3.3 Sugammadex 
Sugammadex is a modified γ-cyclodextrin, a selective relaxant–binding agent based on an 
encapsulating principle for inactivation of rocuronium. The complex formation of sugammadex 
and rocuronium occurs at all levels of neuromuscular blockade (profound through shallow) and 
results in a more fast-acting pharmacologic reversal when compared with 
neostigmine/glycopyrrolate.  
In contrast to neostigmine/glycopyrrolate, sugammadex can reverse rocuronium blockades within 
minutes regardless of the depth of neuromuscular blockade by doses of 2.0 to 4.0 mg/kg14–16.  
Sugammadex and the rocuronium-sugammadex complex is primarily eliminated by renal 
excretion. Because of this sugammadex is not recommended for use in patients with severe renal 
failure.  
3.4 Comparison of neostigmine/glycopyrrolate and sugammadex 
After administration of rocuronium during anesthesia it is mandatory to ensure full recovery from 
neuromuscular blockade before awakening the patient7. Residual neuromuscular block is 
associated with muscle weakness, double vision/blurred vision, impaired pulmonary function and 

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a higher risk of postoperative respiratory complications17–19.  Especially elderly patients have a 
high incidence of residual neuromuscular block20.  
This is ensured either by allowing spontaneous recovery of the blockade or by administering the 
reversal agents neostigmine/glycopyrrolate or sugammadex21.   
The possible benefit in this trial is to investigate whether neostigmine/glycopyrrolate 50 
mikrogr/kg or sugammadex 2 mg/kg provides the fastest reversal of rocuronium induced blockade 
in the elderly. This may result in different time until reversal of block and different occurrence of 
side effects and signs and symptoms of residual blockade postoperatively. The results may help to 
detect the optimal method for reversal of rocuronium induced blockade in elderly patients.  
4. Objective and hypotheses 
The aim of this study is to determine the time to TOF ≥ 0.9 after either neostigmine/glycopyrrolate 
50 mikrogr/kg or sugammadex 2 mg/kg in patients with age ≥ 75 years. The hypothesis of this 
study is that sugammadex 2 mg/kg provides a faster time to TOF ≥ 0.9 compared to 
neostigmine/glycopyrrolate 50 mikrogr/kg. 
5. Trial design overview 
This is a randomized, parallel group, blinded trial comparing neostigmine/glycopyrrolate 50 
mikrogr/kg or sugammadex 2 mg/kg for reversal of rocuronium induced blockade in elderly 
patients (≥ 75 years). Patients will be enrolled at Department of Pediatric and Obstetric 
Anesthesia, Rigshospitalet, and Department of Anaesthesiology, Bispebjerg Hospital. Forty elderly 
patients (≥ 75 years) meeting inclusion criteria will be enrolled. The primary outcome is time to 
TOF ≥ 0.9.   
6. Setting and patient population 
6.1 Setting 
The trial will be conducted at Department of Anaesthesiology, Bispebjerg Hospital, and 
Department of Pediatric and Obstetric Anesthesia, Rigshospitalet. Both departments have ample 
elective surgeries and are university hospitals, and therefore acquainted with research within this 
area.  
6.2 Inclusion criteria 
The inclusion criteria: 
- 
Age ≥ 75 years 
- 
Scheduled for robotic assisted laparoscopic surgery under general anesthesia with 
intubation and use of rocuronium for the entire duration of surgery. 
- 
American Society of Anesthesiologists physical status classification (ASA) I to IV 
- 
Informed consent (see appendix 1) 

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- 
Read and understand Danish 
These inclusion criteria have been chosen because they make sure, that it is ethically correct to 
perform the trial and because similar criteria have been used in previous studies conducted within 
this field. They are broad to make sure as many patients as possible can be included.  
6.3 Exclusion criteria 
The exclusion criteria: 
- 
Neuromuscular disease 
- 
Known allergy to rocuronium, neostigmine/glycopyrrolate or sugammadex 
- 
Severe renal impairment defined as eGFR < 30 ml/min  
- 
Indication for rapid sequence induction 
- 
Known intestinal or ureter obstruction 
- 
Known peritonitis 
Neuromuscular diseases may affect the monitoring of the effect of both rocuronium and reversal 
agents and may therefore cause imprecise data on the level of block and hence make the data 
unusable.  
7. Interventions 
7.1 Interventions 
Study drugs 
The study drugs are neostigmine/glycopyrrolate (neostigmine/glycopyrrolate “Meda”) and 
sugammadex (Bridion “MSD”). The patients will either receive a bolus of 
neostigmine/glycopyrrolate 50 mikrogr+10 mikrogr/kg or sugammadex 2 mg/kg for reversal of the 
neuromuscular blockade upon conclusion of anaesthesia defined as after removal of the 
laparoscopic instruments. Doses are based on actual body weight rounded to nearest 10 mg for 
sugammadex and nearest 0.1 mg for neostigmine/glycopyrrolate. Glycopyrrolate is added in the 
ampoule by the manufacturer: 0.5 mg per 2.5 mg of neostigmine/glycopyrrolate.  
A separate investigator will prepare the dose, based on the above-mentioned dosing schedule. To 
make the syringes similar, saline will be added to the syringes to a total volume of 10 mL. The 
separate investigator will calculate the dose and prepare syringes in a closed room.  The syringes 
will be passed to another investigator blinded to the content of the syringes. This investigator will 
bring the syringe to the operation room and passed to an anesthesiologist or an anesthetist nurse. 
They will administer the drug as a bolus over 5 seconds in an intravenous catheter.  
Patients can take their usual medicine before and after surgery according to the anaesthesia plan 
scheduled by the anaesthesiologist.  

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7.2 Monitoring 
Preoperatively  
Assessment of muscle strength: 
Preoperatively, before arriving to the operating room, an investigator will assess the patients´ 
muscle strength. After careful instruction by the investigator the patient will perform  
• Hand grip strength assessed by a dynamometer  
• Chair stand test five times 22–24 
o To test the ability to rise from a chair (termed the chairstand), a straight-backed  
chair is placed next to a wall; patients will be asked to fold their arms across their 
chest and to stand up from the chair one time. If successful, patients will be asked 
to stand up and sit down five times as quickly as possible and are timed from the 
initial sitting-position to the final standing position at the end of the fifth stand. 
Intraoperatively  
All patients will be monitored with ECG, non-invasive blood pressure and oxygen saturation. To 
make sure the temperature centrally and peripheral is kept above 35 °C and 32 °C, according to 
guidelines (GCRP Fuchs-Buder), a forced air patient warming system will be placed on the patient 
and the arm will be covered in sterile surgical covering. The temperature will be monitored with 
sensors in nose cavity, gullet, rectum or bladder and on the thenar eminence with TOF Watch SX 
monitor.  
All patients will have neuromuscular monitoring performed with TOF-Watch SX monitor connected 
to a computer for collection of neuromuscular data (Version 2.5 INT 2007, Organon, The 
Netherlands). The monitoring will be done according to international guidelines25. TOF-Watch SX 
will be placed on the arm, where there is the least monitoring equipment. Initially, the skin will be 
cleansed and rubbed with an abrasive. Small electrodes will be used and placed on the wrist over 
the ulnar nerve. The acceleration transducer will be placed on the thumb and attached in the 
associated hand adaptor. When the patient is adequately anesthetized, we will start the TOF 
Watch SX monitor and give two train-of-four (TOF) nerve stimulations followed by a tetanic 
stimulation with 50 Hz for 5 seconds. Then we will calibrate the TOF Watch SX monitor with the 
CAL2 button and start the TOF mode and measure the TOF (2 Hz for 1.5 seconds) each 15 sec. 
After securing a stable signal with less than 5% deviation for two minutes rocuronium 0.6 mg/kg 
will be injected.  
The arm will be fixed to the armrest by bandages. An intravenous catheter will when possible be 
placed in the opposite hand.  

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Postoperatively 
Patients will be observed at the post-anesthetic care unit (PACU) for at least 3 hours.  
Postoperatively patients will receive a standardized regimen according to local guidelines 
regarding:  
• Pain treatment  
• Treatment of nausea and vomiting  
• Administration of fluids (crystalloids)  
• Administration of antibiotics 
Oxygen will be administered targeting a saturation of 94-98% (or 88-92% in case of COPD or 
BMI>=40). 
If saturation is < 90% > 5 minutes patients will be placed in semi sitting position (30 degrees) and 
receive continuous positive airway pressure (CPAP).  
Immediately upon arrival at the PACU a blinded investigator will assess signs and symptoms of 
residual block26. The assessment will be repeated after 20 minutes and after 90 minutes.  
Sign of residual muscular blockade are defined as either26  
o Hand grip strength for 5 seconds or 
o Occurrence of double vision/blurred vision (yes/no) or 
o Ability to track objects with eyes (follow finger of examiner) (yes/no) or 
o Ability to sustain head lift for 5 seconds (yes/no) or 
o Ability to protrude the tongue for 5 seconds (yes/no) or 
o Tongue depressor test (prevent removal of a wooden tongue depressor from 
between the incisor teeth (yes/no) or 
o Ability to open the eyes for 5 seconds (yes/no) or 
o Ability to smile (yes/no) or 
o Ability to speak (yes/no) or 
o Occurrence of dysphagia/ swallowing impairment assessed by observing difficulties 
swallowing defined as the ability to drink 20 ml of water (yes/no) or 
o Occurrence of upper airway obstruction or 
o Subjective symptoms of muscle weakness (After each test is completed, patients 
are questioned by the research assistant about whether the test was difficult to 
complete or uncomfortable to perform. For example, a patient might successfully 
maintain a 5-s eye opening yet note that it was “difficult 

14 
 
to keep my eyes open” Subjective symptoms of muscle weakness will be recorded 
as normal (negative response) or impaired (positive response)  
As a standard during the PACU stay blood pressure, pulse and oxygen saturation will be monitored 
continuously. In addition, the following will be registered: 
• Occurrence of episodes of desaturation defined as more than 3 minutes with spO2 < 88%. 
• New cardiac arrythmias (bradycardia or tachycardia defined as atrial fibrillation, atrial 
flutter, sinus tachycardia, sinus bradycardia) within 90 minutes after administration of 
reversal agent 
• Occurrence of upper airway obstruction 
• Occurrence of reintubation 
Before discharge from the PACU an arterial blood gas analysis will be drawn.   
In case of reoperation information regarding allocation can be reached either at the allocation-
chart or by contacting the local investigator by phone 24/7.  Phone number, name of investigator 
and placement of allocation-chart will be noted in the patient record.  
7.3 Concomitant treatment  
7.3.1 Treatment values intraoperatively 
Blood pressure: Aiming at a mean arterial pressure (MAP) of 65 mmHg and a systolic blood 
pressure above 90.   
Neuromuscular monitoring continues until TOF ≥ 0.90 and stable over 2 min. In case the depth of 
neuromuscular blockade is within the range from TOF count of 2 to a TOF ratio < 0.60 at the end of 
operation the NMB is reversed with neostigmine/glycopyrrolate or sugammadex according to 
allocation. Subsequently, the patient is awakened and taken to the recovery room. 
In case TOF ratio is > 0.6 upon conclusion of anaesthesia no reversal agent will be administered.  
In case TOF count is ≤ 1 upon conclusion of anaesthesia the attending anaesthesiologist can  
either  
• decide to await reappearance of a TOF count of 2 and subsequently administer the study 
drug (time from ready to administer the reversal agent until reappearance of TOF count of 
2 will be registered) 
or  
• administer sugammadex.  

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7.3.2 Anesthesia 
General anesthesia is induced with propofol 1 – 2 mg/kg as needed to obtain loss of eyelash reflex. 
Tracheal intubation is performed after administration of rocuronium 0.6 mg/kg when TOF count is 
0.  
Tracheal intubation can be performed either with a laryngoscope or video laryngoscope.  
Anesthesia will be maintained according to local guidelines with an infusion of propofol of 
approximately 5 mg/kg/hour and remifentanil approximately 0.25–0.5 µg/kg/min.  
Supplemental doses of rocuronium will be administered according to the discretion of the 
attending anaesthesiologist either as bolus or infusion aiming at a TOF count of 1-2.  
A central venous catheter (CVK) and an arterial line may be placed either before or after induction 
of anesthesia according to the discretion of the anesthetist.  
Vasopressors (norepinephrine, ephedrine, or phenylephrine) are administered at the discretion of 
the attending anesthesiologist.  
8. Sample size and recruitment strategies 
8.1 Sample size 
The sample size calculation is based on our primary hypothesis. A previous study has found that 
time to TOF 90% after administration of sugammadex 2 mg/kg upon reappearance of T2 was 
approximately 4 minutes with a standard deviation of 2 minutes27. A Cochrane review has found 
that in adults time to TOF 90% after administration of 0.05 mg/kg of neostigmine/glycopyrrolate  
upon reappearance of T2 was approximately 12 minutes with a standard deviation of 2.5 min28. 
With a sample of 20 patients in each group we are able to detect this difference with a power of 
90% and a 5% risk of type 1 error. A total of 40 patients must be included and recruitment will 
continue until 40 patients has been enrolled, received one of the interventions and the primary 
outcome has been assessed. Up to 70 patients can be included.  
8.2 Recruitment strategies 
Patients are recruited among those referred to the Department of Anaesthesiology, Bispebjerg 
Hospital, and Department of Pediatric and Obstetric Anesthesia, Rigshospitalet, who meet 
inclusion criteria and who have no exclusion criteria. 
The principal investigator is in charge of informing the patients and obtaining informed consent 
forms. If the principal investigator is not able to interview a patient another investigator, with GCP 
experience and knowledge of anesthesia and the protocol, can interview and include the patient.  

16 
 
The anesthesiologist in charge of treatment, will go through the schedule for elective surgery and 
screen for potential candidates to the project. The anesthesiologist will then inform the principal 
investigator of any potential candidates. The principal investigator will then contact the patient at 
the hospital during the pre-anesthetic interview. Patients will be informed about the project, 
preferably 1 to 14 days before planned operation, at least 24 hours before operation. This will 
happen in an undisturbed room. The patient will be offered the possibility of being accompanied 
by a next of kin. The patient will receive information orally and written. The patient is informed, 
that it is voluntary to participate, and he/she has the right to disclaim consent without affecting 
further treatment. Patients will be offered at least 24 hours to consider giving consent. Patients 
may however, after receiving orally and written information give consent immediately. If patients 
accept to be included in the project, they need to fill out an informed consent form. This will 
preferably be obtained before patients arrive to the operation ward, and thereby avoid putting 
the patient in a situation where a decision about participating in the trial must be made in a stress-
full environment at the operation ward.  
All patients will be contacted 3 days postoperatively to be asked if any adverse events (see 12.3.2) 
have happened. 
Patients will be screened until target population of 40 patients has been achieved.  
 
 
 
 
 
 
 
 
 
 
 
 
 

17 
 
8.3. Trial timeline 
 
Pre-trial 
2 moths 
4 months 
6 months 
8 months 
10 months 
12 months 
14 months 
Development 
of protocol and 
modifications 
 
 
 
 
 
 
 
 
Ethical approval  
 
 
 
 
 
 
 
Registration 
with Danish 
Medicine 
Agency 
 
 
 
 
 
 
 
 
Trial 
registration 
 
 
 
 
 
 
 
 
Inclusion of 
patients 
 
June   
2023 
 
 
 
 
 
 
GCP monitoring 
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
Manuscript 
writing 
 
 
 
 
 
 
 
 
Publication 
 
 
 
 
 
 
 
December 
2024 
 
Inclusion of approximately 2 patients per week is expected corresponding to a duration of 
approximately 6-8 months. Inclusion: Planned to go on in the period from June 2023 through 
September 2024. Inclusion of patients will be stopped when the primary endpoint has been 
assessed in 40 patients or the maximum of 70 patients has been included. The trial will be counted 
as concluded when the last patient has registered with the primary endpoint.  
Data analysis and reporting: from September 2024 through December 2024. 
The trial will be considered as having started on the date when there is a signed declaration of 
consent from the first patient, who will thereby be considered as included. Conclusion of the study 
is when the last patient has been evaluated considering the primary outcome and has had their 3-
day follow-up call.  

18 
 
9. Outcome 
9.1 Primary outcome 
The primary outcome is the time to TOF ≥ 0.9 after administration of either sugammadex or 
neostigmine/glycopyrrolate defined as start of injection until appearance of the first TOF ratio ≥ 
0.9 followed by a stable signal with a TOF ratio ≥ 0.9 for at least two minutes.  
Time to TOF ≥ 0.9 has been chosen as the primary outcome because it is clinically relevant to 
examine whether administration of neostigmine/glycopyrrolate or sugammadex provides the 
fastest reversal of rocuronium-induced neuromuscular blockade in patients above 75 years of age. 
This patient population is at high risk of severe respiratory complications if residual blockade is 
present. Therefore, it is clinically relevant to investigate which of the two reversal agents that is 
associated with the fastest reversal.  
 
9.2 Secondary outcome 
• Key secondary outcome26 is sign of residual muscular blockade within 90 minutes after 
administration of reversal agent defined as a composite (assessed upon arrival at PACU 
after 20 minutes and after 90 minutes) of either  
o Hand grip strength for 5 seconds or 
o Occurrence of double vision/blurred vision (yes/no) or 
o Ability to track objects with eyes (follow finger of examiner) (yes/no) or 
o Ability to sustain head lift for 5 seconds (yes/no) or 
o Ability to protrude the tongue for 5 seconds (yes/no) or 
o Tongue depressor test (prevent removal of a wooden tongue depressor from 
between the incisor teeth (yes/no) or 
o Ability to open the eyes for 5 seconds (yes/no) or 
o Ability to smile (yes/no) or 
o Ability to speak (yes/no) or 
o Occurrence of dysphagia/ swallowing impairment assessed by observing difficulties 
swallowing defined as the ability to drink 20 ml of water (yes/no) or 
o Occurrence of upper airway obstruction or 
o Subjective symptoms of muscle weakness (After each test is completed, patients 
are questioned by the research assistant about whether the test was difficult to 
complete or uncomfortable to perform. For example, a patient might successfully 
maintain a 5-s eye opening yet note that it was “difficult 
to keep my eyes open” Subjective symptoms of muscle weakness will be recorded 
as normal (negative response) or impaired (positive response)  
 

19 
 
Other secondary outcomes are: 
• Occurrence of episodes of desaturation defined as more than 3 minutes with spO2 < 88%. 
• New cardiac arrythmias (bradycardia or tachycardia defined as atrial fibrillation, atrial 
flutter, sinus tachycardia (>95 bpm), sinus bradycardia (<45 bpm)) within 180 minutes after 
administration of reversal agent 
• Occurrence of reintubation 
• Time from administration of reversal agent to patient is ready to leave the operating room 
 
10. Assignment of interventions 
10.1 Allocation 
Patients will be allocated randomly at a ratio of 1:1 to receive either 2 mg/kg sugammadex or 50 
µg/kg neostigmine/glycopyrrolate. Randomization will be done at the day of operation after 
written informed consent is obtained.  An independent investigator will allocate patients in the 
two groups by using a computerized random number generator in REDCap. In REDCap patients 
also receive a number, which pseudo anonymizes data. To decrypt data a reversal key is needed. 
This will be made in a Microsoft Excel sheet and will be stored on a secure drive. Only people 
involved in the study and with the right authority will be granted access to the drive. This will be 
controlled during the study.  
10.2 Blinding 
Intervention medicine is prepared in the medicine room before the operation.  This is done under 
double control by the investigator who also performed the randomization. The project medicine, 
either sugammadex or neostigmine/glycopyrrolate, will be prepared in a syringe. The dose will be 
mixed with saline to a total of 10 mL to secure blinding. A label with patient’s initials, 
randomization number and “sugammadex or neostigmine/glycopyrrolate” is put on the syringe. It 
will be noted on a sheet which medicine each patient receives, batch number, expiration date and 
the initials of the investigator will be noted on a sheet. After conclusion of preparation the sheet 
will be placed in the accompanying envelope, which is sealed and placed in a folder together with 
the informed consent. The folder is stored in a locked room where only investigators of the study 
have access. The envelope must only be opened, if it is considered strictly necessary to know 
which group the patient belongs to with respect to further treatment. This will happen after 
agreement with the investigator responsible for the trial. Motivation for broken seal shall be 
included in the Case Report Form (CRF).  
The syringe will be handed over to an investigator who will bring it to the OR, where an anesthetist 
or nurse anesthetist will administer the reversal agent (neostigmine/glycopyrrolate or 
sugammadex).  

20 
 
The patient will at no time during hospitalization and 3-day follow up be informed about 
treatment group allocation. The patient may however be informed of this upon conclusion of data 
collection. 
The surgeon will be blinded to treatment group allocation during the operation.  
The anesthesia personnel will be blinded to treatment group allocation during reversal of the 
neuromuscular blockade, but after gathering the data, they will be unblinded.  
The investigator controlling the TOF Watch will be unblinded during the operation.  
Surgical personnel will be blinded to treatment group allocation during the operation.  
The secondary outcomes will be assessed by an investigator without access to treatment group 
allocation.  
11. Data collection and management 
11.1 Data collection 
Data will be collected on a separate computer with TOF Watch XS monitor software and noted on 
a CRF during the surgery. The collected NMB data will be stored on a closed drive after being 
pseudo anonymized. A transformation key will be made and stored in a separate secure place. All 
information for this study will be gathered from CRF, TOF Watch XS monitor software and 
electronical medical journals. 
11.1.1 Study related variables 
Patient ID 
Inclusion criteria 
Exclusion criteria 
Informed consent form 
11.1.2 Preoperative variables 
Age 
Sex 
Height 
Weight 
ASA 
Co-morbidity 
Medicine intake 
Chair stand test five times 
All patients will be assessed for frailty using the FRAIL Scale29  
• Fatigue, defined as subjective feeling of tiredness over past 4 weeks “most or all” of the 
time 

21 
 
• Resistance, is scored positive if the patient has difficulty climbing 10 steps without an assist 
device or stopping to rest 
• Ambulation, is scored positive if the patient has difficulty walking 2 blocks independently 
• Illnesses, is scored positive if the patient has 5 or more co-morbidities: hypertension, 
diabetes, cancer, asthma, chronic lung disease, heart attack, congestive heart failure, 
angina, arthritis, stroke, and kidney disease. 
• Loss of weight is scored positive if the patient has lost more than 5% of bodyweight over 
past year   
A score of 1 is assigned to each positive domain. A score of 0 is categorized as robust, 1–2 as 
prefrail, and ≥ 3 as frail. 
 
11.1.3 Intraoperative variables 
• Duration of anesthesia (induction to ready to leave the OR) 
• Duration of operation (incision to last suture) 
• Time of administration of neostigmine/glycopyrrolate or sugammadex 
• Level of NMB upon administration of reversal agent 
• Time to TOF 0 
• Time of intubation 
 
11.1.4 Outcome variables 
• Time to TOF ≥ 0.9  
• Occurrence of episodes of desaturation defined as more than 3 minutes with spO2 < 88%. 
• New cardiac arrythmias (bradycardia or tachycardia defined as atrial fibrillation, atrial 
flutter, sinus tachycardia, sinus bradycardia) within 90 minutes after administration of 
reversal agent 
• Occurrence of reintubation 
• Time from administration of reversal agent to patient is ready to leave the operating room 
• Sign of residual muscular blockade within 90 minutes after administration of reversal agent 
defined (assessed upon arrival at PACU after 30 minutes and after 90 minutes) as either  
o Hand grip strength for 5 seconds or 
o Occurrence of double vision/blurred vision (yes/no) or 
o Ability to track objects with eyes (follow finger of examiner) (yes/no) or 
o Ability to sustain head lift for 5 seconds (yes/no) or 
o Ability to protrude the tongue for 5 seconds (yes/no) or 
o Tongue depressor test (prevent removal of a wooden tongue depressor from 
between the incisor teeth (yes/no) or 
o Ability to open the eyes for 5 seconds (yes/no) or 
o Ability to lift one arm to the opposite shoulder (yes/no) or 

22 
 
o Occurrence of dysphagia/ swallowing impairment assessed by observing difficulties 
swallowing defined as the ability to drink 20 ml of water (yes/no) or 
o Ability to speek or 
o Occurrence of upper airway obstruction or 
o Subjective symptoms of muscle weakness (After each test was completed, patients 
were questioned by the research assistant about whether the test was difficult to 
complete or uncomfortable to perform. For example, a patient might successfully 
maintain a 5-s eye opening yet note that it was “difficult 
to keep my eyes open” Subjective symptoms of muscle weakness will be recorded 
as normal (negative response) or impaired (positive response)  
11.2 Data management  
The data from the CRF and from TOF Watch XS monitor software will be added to REDCap, which 
is a legal and secure web application for storing research data. The data collected in this trial will 
be secured with two-step access. CRF will be stored in a trial master file along with all the 
applications, approvals and trial relevant documents. The trial master file will be stored in locked 
premises. The ICFs will be stored in a locked drawer in a separate office. 
Upon granting of informed consent, principal investigator, sponsor, a representative of sponsor or 
third parties are authorized access to the patients´ journal to find information regarding the 
patients´ health conditions that are relevant for the conduction of the trial.  
Primary investigator will arrange for data collection and storage of CRFs and ICFs in locked 
premises. Data will be stored for 5 years after conclusion of the trial. The information about the 
patients’ health conditions, other purely private circumstances and other information that arises 
in connection with the trial are covered by the obligation of confidentiality. The information 
concerning the patients is protected by databeskyttelsesforordningen og databeskyttelsesloven. 
11.3 Statistical analysis 
Eligible patients and excluded patients will be registered at a screening list.  
Data from all randomized patients, who receive the intervention and with at least primary 
outcome, will be included in the intention-to-treat analysis. 
Patients, included in the intention-to-treat analysis, but who are categorized as major violation 
(defined as use of sevoflurane, succinylcholine, aminoglycosides, magnesium), will be excluded 
from the per-protocol analysis. 
Normally distributed variables will be reported by means and standard deviations; variables that 
are not normally distributed will be reported by medians and interquartile ranges. Student´s t-test 
is used to compare normally distributed data and Mann-Whitney test to compare not normally 
distributed data. X2-test or Fisher´s exact test will be used for frequencies when comparing the 

23 
 
two groups. Ninety-five percent confidence intervals will be used for quantifying differences.         
A p < .05 is considered statistically significant. 
Data will also be reported separately for patients ≥ 80 years and 75-80 years.  
The data analysis will be blinded. The investigator analyzing data will be blinded towards 
treatment group allocation. The treatment groups will be named A and B and after completion of 
the data analysis the treatment group allocation will be unblinded.  
12. Ethical considerations 
12.1 Registrations and approvals 
The trial will be done according to the protocol. Any modifications to the protocol which may 
impact on the conduct of the study, potential benefit of the patient or may affect patient safety, 
including changes of study objectives, study design, patient population, sample sizes, study 
procedures, or significant administrative aspects will require a formal amendment to the protocol. 
Such amendment will be agreed upon by principal investigator and sponsor and approved by the 
Scientific Ethics Committees prior to implementation and notified to the health authorities in 
accordance with local regulations. 
Administrative changes of the protocol are minor corrections and/or clarifications that have no 
effect on the way the study is to be conducted. These administrative changes will be agreed upon 
by principal investigator and sponsor and will be documented in a memorandum.  
The trial will be reported to the Scientific Ethics Committees, Danish Medicines Agency and 
Videnscenter for Dataanmeldelser. The patients in the trial are assured access to receive further 
information about the trial through the principal investigator, who as contact person is referred to 
in the patient information. The “Dine rettigheder som forsøgsperson i forsøg med medicin (Rights 
of Trial Subjects)” published by the Scientific Ethics Committee will be provided.  
General procedures for quality control and quality assurance will be followed, according to ICH 
GCP guidelines. Data will be monitored by the GCP unit. Upon granting of informed consent, 
authorization will be obtained from the patients for third parties to be able to have access to 
information about the patient´s health condition. The investigator will thus allow the GCP unit or 
the Danish Medicines Agency direct access to source data/documents with monitoring, auditing 
and/or inspection. 
Receipt control of sugammadex and neostigmine/robinul will be done according to the 
departmental standards for handling and storage of medicine as both products are standard 
medicine at the department. Both sugammadex and neostigmine/robinul are stored in the 
medicine room where temperature is controlled. 
 

24 
 
At the end of the trial, investigator and sponsor will inform the Scientific Ethics Committee and the 
Danish Medicines Agency of this within 90 days. The trial will be registered in an international 
database (www.clinicaltrials.gov), before the recruitment of patients is started.  
12.2 General considerations 
The number of elderly is increasing and elderly people reach a higher age healthier than 
previously. With increasing age the body and the organ functions change, why it is important to 
examine the effect of some of the medication used daily during anesthesia.  
Neostigmine/glycopyrrolate and sugammadex are both able to reliably reverse a rocuronium-
induced neuromuscular blockade. Anesthesia and surgery will follow guidelines apart from the use 
of the reversal agent. We think that it is justifiable that information about the use of project-
medicine will be stored in the RedCap Database. There is an option to get access to the Red Cap 
Database in an emergency situation. If necessary, the investigator can at any time unblind from a 
medical judgement independent of sponsor. This can be done through the Red Cap database. 
Unblinding of the included patients will be done after the last day-3 follow-up.  
The possible benefit in this trial is to investigate whether sugammadex or 
neostigmine/glycopyrrolate provides the fastest reversal of the rocuronium-induced 
neuromuscular blockade in the elderly and if there is a difference in side-effects between the two 
reversal agents. The results will help the clinician to make a rational choice of reversal agent in the 
elderly based on the time to reversal of neuromuscular blockade and occurrence of side effects. 
There are no personal benefits for the individual patients. 
Informed consent will be obtained before the patients arrive to the operation ward. We thereby 
wish to avoid having the patient to decide about participating in the trial at the operation ward 
since patients arriving at the operation ward may perceive this as a stressful environment. The 
inclusion and exclusion criteria used will ensure that we only investigate patients who will be able 
to tolerate being treated according to the two strategies. Intervention with respect to possible 
complications from this, are not changed either.  
12.3 Consent 
Information about the trial will be done by an investigator trained in the protocol. The patient will 
receive information orally and written. Patients will then be able to have an informed discussion 
with the investigator. Informed consents will then be gathered, and the patient will be offered the 
possibility of receiving a copy of the ICF.  
12.4 Risk and safety issues 
Both sugammadex and neostigmine/glycopyrrolate can affect the cardiovascular system and lead 
to hypotension and bradycardia or tachycardia, why strict monitoring will be done according to 
7.2. If cardiovascular side effects occur, they will be handled according to local guidelines. 

25 
 
More elderly people will need operation at some point. During all operations there is a risk of 
awareness and patients in this study will be carefully sedated and they will be monitored closely 
with TOF monitoring until they have recovered completely from neuromuscular block.  
12.4.1 Definitions 
• Adverse event; 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. 
• Serious adverse event; 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. 
• Unexpected serious adverse reaction; a serious adverse reaction, the nature, severity or 
outcome of which is not consistent with the reference safety information. 
12.4.2 Side effects 
Sugammadex: According to the product summary side effects are: 
• Common (1-10%): Bradycardia, tachycardia, coughing, hypotension. 
• Not common (0,1-1%): Allergic reaction, consciousness during anesthesia (awareness). 
• Incidence unknown: cardiac arrest  
Neostigmine/glycopyrrolate: According to the product summary side effects are: 
• Common (>10%): Bradycardia, tachycardia, dry mouth, increased peristalsis, excessive 
salivation, tiredness, reduced sweating. 
• Not common (0.1-1%): Accomodation difficulties, urinary difficulties. 
• Seldom (0.01-0.1%): 2. Degree AV-block, cardiac arrest, anaphylaxis, prolonged QT interval, 
hypotension.  
12.4.3 Adverse events 
In this trial a list of adverse events of special interest has been made. Other AE’s and AR’s will not 
be reported as the safety profile is well known and well described in the SMPC’s: 
1) Bradycardia, tachycardia, AV-block, prolonged QT interval  
2) Excessive salivation, increased peristalsis or reduced sweating 
3) Accomodation difficulties 
4) Urinary difficulties 
5) Allergic reaction or anaphylaxis 
They will be controlled and monitored by a follow-up call 3 days after operation. 
Patients with AEs/SAEs will be followed by investigator until solved. 

26 
 
12.4.4 Reporting of adverse events  
All SAE´s and SAR´s will be reported to sponsor within 24 hours of discovery. If the serious adverse 
reaction is not indicated in the product information, it is considered to be unexpected. Both 
investigator and sponsor (or sponsor-investigator) will assess the causality. The sponsor must not 
override the investigator's evaluation, so reports must be submitted even though the sponsor 
does not agree with the investigator.  The Sponsor will report SUSARs to the Danish Medicines 
Agency and Research Ethics Committee within 7 days for those that are fatal or life-threatening. 
All other SUSARs will be reported no later than 15 days from the time when the sponsor is 
informed. Sponsor will be registered in the EudraVigilance system, as this is a requirement for 
SUSAR reporting. 
Once a year, the Sponsor will submit a list of all SARs in the reporting period and a report on 
patient safety to the Danish Medicines Agency and Ethics committee and Clinical Trials 
Information System (CTIS).  
The Sponsor will notify the Danish Medicines Agency and Ethics Committee when the trial has 
completed (no later than 90 days thereafter) and if earlier than planned, within 15 days with the 
reasons for stopping the trial. In addition, the results including endpoint, SAEs and SARs will be 
reported on EudraCT not later than 1 year after last patient last visit.  
12.4.5 Timeline 
Patients will receive either sugammadex or neostigmine/glycopyrrolate for reversal of the 
neuromuscular blockade upon conclusion of anesthesia and patients will be awakened when 
complete recovery of the NMB is established (TOF ratio above 0.9 for two minutes). 
End of trial is defined as the time when the last included patient has completed the follow up call 
three days after surgery.  
12.4.6 Suspected unexpected serious adverse reaction 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs, which are expected to be a 
side effect of the trial drug, where the event has not been noted as part of the side effects of the 
drug. The patient experiencing the SUSAR will be unblinded and the incidence will be reported to 
Danish Medicine Agency. The expectedness assessment will be done by sponsor (whether SAR or 
SUSAR). 
12.4.7 Reporting 
When finished with the study either sponsor or principal investigator will submit a list of all 
adverse events registered during the trial to Danish Medicines Agency (See section 12.1).  
12.4.8 Insurance  
The patients in the present trial are covered by the patient insurance, covering all treated patients 
at the trial site at Rigshospitalet/Bispebjerg Hospital in Copenhagen in the event of a trial-related 
injury or death occurring. This is in accordance with the applicable law and with the CPMP Note 
for Guidance on Good Clinical Practices (CPMP/ICH/135/95) of July 17th, 1996. 

27 
 
13. Publication 
The results, positive, negative or inconclusive, will be submitted for publication in an international, 
English-language journal. Authorship will occur in accordance with international Committee of 
Medical Journal Editors’ rules (the Vancouver Group). Data belong to the patients and will be 
collected and stored according to this protocol. The right to data and know-how that emerges in 
connection with the trial will belong to investigators and the Department of Anaesthesia, Centre 
of Head and Orthopaedics, 6013 Rigshospitalet, University of Copenhagen, Denmark. 
The trial will be registered on www.clinicaltrials.gov and in the EudraCT database. Data describing 
the trial design, safety and efficacy will be reported in the EudraCT database within 1 year after 
completion of the trial. 
The trial results will be submitted to the Clinical Trials Information System (CTIS) portal and 
subsequently, data will be published on clinicaltrialsregister.eu.  
Tentative author list is: 
MV (first author) - other study authors fulfilling the Vancouver criteria.  
We intend to include site investigators as co-authors, if they enroll and randomize at least 3 
patients.  
14. Economy 
Matias Vested and Lars S Rasmussen have taken initiative to this study.  
The study is funded by departmental sources.  
 
 
 

28 
 
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