Conditions: Neuromuscular Block
Keywords: deep neuromuscular block sugammadex stability of anesthesia suppression of EMG activity PQRS General Anesthesia Quality of Recovery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
The investigators hypothesize that an anesthetic protocol maintaining deep neuromuscular block throughout the entire surgical procedure followed by sugammadex reversal, would suppress EMG activity and result in improved anesthetic stability by reducing the variability of the Bispectral Index of the EEG, and be beneficial by reducing the total doses of the anesthetic drugs propofol and remifentanil required to maintain an adequate level of anesthesia (BIS between 40 and 60).

Detailed description:

Arms:
arm 1: Standard Clinical Practice Group - standard neuromuscular block, with a standard rocuronium dose for intubation (0.6 mg/kg). If required, the reversal of neuromuscular block is performed with neostigmine. arm 2: Deep Neuromuscular Block group - with a standard rocuronium dose for intubation (0.6 mg/kg), followed by a constant infusion of rocuronium (10-15 ug/kg/min) to guarantee a PTC less or equal to 2 on the TOF monitor (PTC is evaluated every 5 minutes). The reversal of neuromuscular block is performed with Sugammadex (4 mg/kg).

Interventions: intervention 1: Sugammadex intervention 2: Rocuronium
Intervention descriptions: intervention 1: Reversal of deep neuromuscular block intervention 2: Maintenance of deep neuromuscular block

Protocol document:
Prot_SAP_000.pdf: 
Can adequacy of anesthesia depth and quality of recovery be influenced by 
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Clinical Study Protocol 
“Can adequacy of anesthesia depth and quality of recovery be 
influenced by the level of neuromuscular blockade: a 
randomized 
controlled 
study 
assessing 
propofol 
and 
remifentanil requirements and quality of recovery in patients 
with 
a 
standard 
practice 
of 
non-deep 
rocuronium 
neuromuscular 
blockade 
versus 
deep 
neuromuscular 
blockade reversed with sugammadex.” 
 
This document contains confidential information of the Sponsor. Do not copy or 
distribute without written permission from the Sponsor.  
Confidentiality of all information received or developed in connection with this 
protocol must be maintained by the investigators as well as all other personnel 
involved in the trial who are employed by them. 
 
 


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Table of contents 
 
Clinical Study Protocol ............................................................................................................ 1 
“Can adequacy of anesthesia depth and quality of recovery be influenced by 
the level of neuromuscular blockade: a randomized controlled study assessing 
propofol and remifentanil requirements and quality of recovery in patients with 
a standard practice of non-deep rocuronium neuromuscular blockade versus 
deep neuromuscular blockade reversed with sugammadex.” ................................. 1 
1. 
General Information .................................................................................................... 5 
a) 
Title ............................................................................................................................ 5 
b) 
Identification Code ............................................................................................. 5 
c) 
Version ..................................................................................................................... 5 
d) 
Date ......................................................................................................................... 5 
e) 
Investigator Agreement ..................................................................................... 5 
f) 
Sponsor representative ........................................................................................... 6 
g) 
Principal Investigator ........................................................................................... 6 
h) Participating sites addresses ................................................................................. 7 
i) 
Supporting institutions ............................................................................................. 7 
2. 
Protocol synopsis .......................................................................................................... 8 
Inclusion criteria ................................................................................................................ 8 
Exclusion criteria ............................................................................................................... 9 
3. 
Abbreviations .............................................................................................................. 11 
4. 
Background and rationale ...................................................................................... 12 
a) 
Investigational Medicinal Product ................................................................ 15 
b) 
Risks and benefits ............................................................................................... 16 
c) 
Treatment dose and schedule ....................................................................... 17 
d) 
Rules and regulations ........................................................................................ 17 
e) 
Study population ................................................................................................ 17 
5. 
Objectives .................................................................................................................... 18 
a) 
Primary Objective .............................................................................................. 18 
b) 
Secondary objectives ....................................................................................... 18 
6. 
Study design ................................................................................................................ 19 
a) 
Primary Endpoints ............................................................................................... 19 


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b) 
Secondary Endpoints ........................................................................................ 19 
c) 
Study type ............................................................................................................ 19 
d) 
Study Timeline ...................................................................................................... 20 
e) 
Flow-chart............................................................................................................. 21 
f) 
Randomization and blinding procedures ....................................................... 22 
g) 
Treatment ............................................................................................................. 22 
h) Treatment duration ................................................................................................ 23 
i) 
Discontinuation criteria ......................................................................................... 23 
j) 
Investigational product accountability ........................................................... 23 
k) 
Blinding and Un-blinding procedures ............................................................... 24 
l) 
Source documents and data collection ........................................................ 24 
7. 
Selection and discontinuation criteria ................................................................. 26 
a) 
Inclusion criteria .................................................................................................. 26 
b) 
Exclusion criteria ................................................................................................. 26 
c) 
Discontinuation criteria ..................................................................................... 26 
8. 
Treatment of study participants ............................................................................. 28 
a) 
Informed Consent .............................................................................................. 28 
b) 
Study procedures ............................................................................................... 28 
i. 
Assessment 1 ............................................................................................................ 28 
i. 
Assessment 2 ............................................................................................................ 29 
Anesthesia Protocol ....................................................................................................... 30 
Monitoring during surgery ............................................................................................ 32 
i. 
Assessment 3 ............................................................................................................ 33 
ii. 
Assessment 4 ............................................................................................................ 33 
iii. 
Assessment 5 ............................................................................................................ 34 
iv. 
Discontinuation Visit........................................................................................... 34 
c) 
Compliance with study treatment ................................................................ 35 
d) 
Concomitant and prohibited medication ................................................. 35 
e) 
Expenses and benefits ...................................................................................... 35 
9. 
Efficacy evaluation.................................................................................................... 36 
a) 
Efficacy measure ............................................................................................... 36 
b) 
Methods ................................................................................................................ 36 
10. 
Safety evaluation ................................................................................................... 38 


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11. 
Statistics ..................................................................................................................... 46 
a) 
Methods ................................................................................................................ 46 
b) 
Number of participants .................................................................................... 46 
c) 
Level of statistical significance ....................................................................... 47 
d) 
Study termination ............................................................................................... 47 
e) 
Missing data ......................................................................................................... 48 
f) 
Deviations ................................................................................................................. 48 
g) 
Inclusion in analysis ............................................................................................ 48 
12. 
Direct access to source documents ................................................................ 49 
13. 
Quality control and quality assurance ............................................................ 50 
14. 
Ethics .......................................................................................................................... 51 
a) 
Responsible ethics committee ....................................................................... 51 
b) 
Regulatory Approval ......................................................................................... 51 
c) 
Patient Confidentiality ...................................................................................... 51 
15. 
Data handling record keeping .......................................................................... 53 
16. 
Financing and insurance ..................................................................................... 54 
17. 
Publication policy .................................................................................................. 55 
18. 
Appendix .................................................................................................................. 57 
19. 
References ............................................................................................................... 58 
 
 
 
 


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1. General Information 
a) Title 
Short title: Can adequacy of anesthesia depth and quality of recovery be 
influenced by the level of neuromuscular blockade? 
Long title: Can adequacy of anesthesia depth and quality of recovery be 
influenced by the level of neuromuscular blockade: a randomized controlled 
study assessing propofol and remifentanil requirements and quality of recovery 
in patients with a standard practice of non-deep rocuronium neuromuscular 
blockade versus deep neuromuscular blockade reversed with sugammadex. 
b) Identification Code 
Eudra CT # 2014-005238-76 
Sponsor Protocol # 2014.145 
c) Version 
Final 2.0 
d) Date 
26th January 2016 
e) Investigator Agreement 
“I have read this protocol and agree to conduct the trial according to the 
protocol and to comply with the International Conference on Harmonisation 
Tripartite Guideline on Good Clinical Practice, as well as applicable laws and 
regulations.” 
 
 


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f) Sponsor representative 
 
 
___________________________  
______________________ 
Sollari Allegro 
 
 
 
Date 
President of the Administration Board 
Address 
Centro Hospitalar do Porto 
Largo Prof. Abel Salazar 
4099-001 Porto  
Portugal 
E-Mail: secretaria.geral@chporto.min-saude.pt 
Fax: 00351 220 900 644 
Telephone: 00351 222077500 
 
 
g) Principal Investigator 
 
 
___________________________  
______________________ 
Pedro Amorim 
 
 
 
Date 
Title: MD 
Address: 
Serviço de Anestesiologia 
Centro Hospitalar do Porto 
Largo Prof. Abel Salazar 
4099-001 Porto  
Portugal 
Email:  pamorim@vianw.pt 
Telephone: 00351 965 877 728 
 
 


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h) Participating sites addresses 
The following site will be involved in this study: 
 
Centro Hospitalar do Porto, EPE – Hospital de Santo António 
 
i) Supporting institutions 
The following institutions will provide support to the study 
 
NOVA Clinical Research Unit (NOVA-CRU) of Chronic Diseases Research 
Center of NOVA Medical School (CEDOC-FCM-UNL): 
o Study Submission 
o Monitoring 
 
 
 


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2. Protocol synopsis 
Title 
Can adequacy of anesthesia depth and quality of 
recovery be influenced by the level of neuromuscular 
blockade: a randomized controlled study assessing 
propofol and remifentanil requirements and quality of 
recovery in patients with a standard practice of non-
deep rocuronium neuromuscular blockade versus deep 
neuromuscular blockade reversed with sugammadex 
Trial Code 
Eudra CT # 2014-005238-76 
Trial Phase 
IV 
Trial Design 
This will be an interventional, randomized, unblended, 
parallel-arm single-center study 
Rationale 
We hypothesise that an anesthetic protocol maintaining 
deep neuromuscular block throughout the entire 
surgical procedure followed by sugammadex reversal, 
would suppress EMG activity and result in improved 
anesthetic stability by reducing the variability of the 
Bispectral Index of the EEG, and be beneficial by 
reducing the total doses of the anesthetic drugs 
propofol and remifentanil required to maintain an 
adequate level of anesthesia (BIS between 40 and 60). 
Participants 
Patients with an ASA score of I to III, 18 to 80 years old, 
scheduled for routine anterior cervical spine surgery in 
the Centro Hospitalar do Porto will be enrolled. 
Selection Criteria 
Inclusion criteria 
 
Patients ASA I-III 
 
Between 18 – 80 years old 
 
scheduled for routine cervical surgery 


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 
Minimum duration of surgery is 90 minutes and 
performed with total intravenous anaesthesia 
(TIVA) with the hypnotic propofol, the analgesic 
remifentanil and the neuromuscular relaxant 
rocuronium 
 
Patients that are able to and do provide a signed 
informed consent form 
 
Exclusion criteria 
 
Patients with neuromuscular diseases and severe 
cardiac and respiratory pathologies 
 
or that have any contra indication for any of the 
drugs used 
 
or that are not able to complete the baseline 
PQRS test. 
 
Indication to perform tracheal intubation using 
fibroscopy 
 
Patients who are pregnant or nursing. 
Sample Size 
Seventy patients will be enrolled. 
Duration 
1 year and 4 months divided as follows: 
 
4 months (from the preparation of the forms for 
submission to  acceptance of the National Ethics 
Committee, 
National 
Committee 
for 
Data 
Protection, and National Authority of Medicines 
and Health Products – the estimated time for 
response of the National Committees is 2 months) 
 
8 months for patient enrolment and data 
collection (an average of 2 patients per week) 
 
2 months for finishing the database and statistical 
analysis 


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 
2 months for the analysis of results and finalizing 
the Clinical Report Study 
Primary Objective 
The objective of this study is to assess if the use of deep 
neuromuscular blockade reversed with sugammadex, 
and the consequent suppression of the EMG activity, 
can improve the overall stability of an anesthetic 
procedure (guided using BIS monitoring) and allow a 
reduction in the amount of anesthetic drugs required for 
adequate anesthesia. 
Patients subjected to anterior cervical spine surgery 
under 
general 
intravenous 
anesthesia 
will 
be 
randomized to receive one of two protocols regarding 
the neuromuscular blockade: our institution’s standard 
practice of non-deep rocuronium blockade or deep 
neuromuscular blockade reversed with sugammadex 
Secondary 
Objectives 
As a secondary objective, we will study the quality of 
recovery using the PQRS scale to see if maintaining a 
deep NMB level during surgery has an impact on the 
patients’ quality of recovery. 
Primary Endpoint 
Anesthetic stability, measured by the variability of the 
Bispectral Index of the EEG 
Secondary 
Endpoint 
Quality of recovery using the PQRS scale 
Intervention 
Deep 
neuromuscular 
blockade 
reversed 
with 
sugammadex. 
 
 
 


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3. Abbreviations 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate aminotransferase 
BIS 
Bispectral Index 
CEIC 
Portuguese Central Ethics Committee “Comissão de Ética 
para a Investigação Clínica” 
CIOMS 
Council for International Organizations of Medical Sciences 
CNPD 
Portuguese Data Privacy Agency “Comissão Nacional de 
Protecção de Dados” 
DSUR 
Development Safety Update Report 
ECI 
Event of Clinical Interest 
eCRF 
Electronic Case Report Form 
EMG 
Electromyography 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Conference of Harmonization 
IMP 
Investigational Medicinal Product 
Infarmed 
Portuguese Regulatory Authority “Instituto da Farmácia e do 
Medicamento” 
MAP 
Mean Arterial Pressure 
NIMP 
Non Investigational Medicinal Product 


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NMB 
Neuromuscular blocade 
PQC 
Product Quality Complaint 
PQRS 
Physician Quality Reporting System 
PTC 
Post Tetanic Count 
SAE 
Seriouse adverse event 
SMP 
Summary of Product Characteristics 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
TCI 
Targeted controlled infusion 
TOF 
Train-of-four 
ULN 
Upper Limit Normal 
4. Background and rationale 
The Bispectral Index (BIS) of the electroencephalogram (EEG) uses a four-
electrode sensor placed on the forehead and is widely used as a quantifiable 
measure of depth of sedation and depth of anesthesia (DOA) [1-3]. Currently all 
DOA monitors are EEG based and use indexes similar to the BIS. Scientific 
evidence for the benefits of BIS guided anesthesia are abundant [4]. Insufficient 
anesthesia may cause Intraoperative awareness, which may be prevented by 
maintaining BIS values between 40 and 60 [5-7]. Excessive anesthesia, namely BIS 
below 45 or 40, is being increasingly associated with increased mortality at one 
or more years following surgery [8,9], especially if combined with hypotension 
[10]. Therefore, guiding anesthesia aiming at maintaining BIS within the 
recommended range offers important advantages. According to a recent NICE 
report it is also cost effective [11]. 
However, the presence of spontaneous electromyography (EMG) interferes with 
the EEG, in particular with frontal EEG, and studies show that EMG activity affects 
the accuracy of BIS monitoring [12-16]. The EMG interference can give 


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misleading information about depth of anesthesia. Panousis et al. reported that 
BIS values between 70 and 80 occurred intermittently above an EMG activity of 
35 dB [16]. This correlation between BIS and EMG was observed under adequate 
DOA and analgesia. One of the reasons for this is the range overlap between the 
frequencies generated by muscle activity and the frequencies originated from 
the EEG [16].  
Vivien et al. showed that increased BIS values (due to EMG) could be solved by 
the administration of a muscle relaxant [14]. This work showed that the 
magnitude of the BIS decrease following neuromuscular blockade was 
significantly correlated to both BIS and EMG values before myorelaxation, 
showing that a BIS-induced oversedation can happen if there is no adequate 
level of muscle relaxation. This conclusion is also in accordance with the work of 
Bruhn et at. [12], which shows that EMG falsely elevates BIS values in anesthetized 
patients without neuromuscular block (NMB). 
The use of NMB reduces EMG activity and can, therefore, reduce the EMG 
interference on the EEG and derived indexes. Consequently, the BIS may be 
altered not by the use of NMB but by the removal of the EMG interference. Inoue 
et al. [15] studied the effect of NMB on systemic and cerebral hemodynamics as 
well as on BIS and showed that the EMG was significantly reduced by the use of 
NMB, both in deep or moderate sedation, but that cerebral hemodynamics were 
not altered by NMB. They also found that BIS and systemic hemodynamic 
variables at moderate sedation resembled the values at deep sedation in the 
presence of NMB, but that such values were different in the absence of NMB [15]. 
Another finding was that NMB might enhance cardiovascular stability. 
Considered together, these studies suggest that if NMB is used in a way that the 
EMG interference is removed from the EEG, one can observe values of BIS that 
reflect only the depressant effect of hypnotics and opioid analgesics on the EEG, 
obtaining BIS values that are lower than those “contaminated” by EMG. This 
could lead to a reduction of the doses of other anesthetic drugs (hypnotics and 
analgesics), an attenuation of side effects from their overdosage and cost 
reduction.  
NMB is necessary to perform tracheal intubation and to avoid movement and 
muscle responses during surgery. Also, deep blockade is sometimes required. 


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However, in the past, maintenance of deep NMB was restricted by the 
nonexistence of a fast reversal drug. Because of this limitation, moderate levels 
of NMB provided by bolus or continuous infusions are often used, namely in 
combination with modern and more efficient hypnotics and analgesics. The new 
drug sugammadex allows for a prompt reversal for the relaxants vecuronium and 
rocuronium [17]. Therefore, a deep level of NMB can be maintained during 
general anesthesia allowing better surgical conditions and be promptly reversed 
for a safe, fast and comfortable recovery. 
A recent study from Dahaba et al. [18], compared BIS values before and after 
sugammadex or neostigmine NMB reversal in patients with and without EMG 
activity and showed that reversal of NMB increased BIS values because of the 
presence of EMG activity. This needs to be taken into account when relying on 
BIS monitoring for assessing unconsciousness and recovery: an increase in BIS 
after NMB reversal may not imply arousal from general anesthesia, but just the 
return of EMG activity and subsequent monitoring interference. The opposite is 
also very important, since the clinician can increase the administration of 
hypnotic or analgesic in response to a increased BIS, in a situation where the BIS 
may be high due to EMG interference; this may render patients prone to a worse 
outcome as a consequence of excessive anesthesia [8,9]. 
The objective of the proposed study is to assess if deep NMB followed by 
sugammadex reversal, and the consequent intra-operative suppression of the 
EMG, can improve the overall stability of an anesthetic procedure (using BIS 
monitoring)  and result in a reduction in the requirements of anesthetics (hypnotic 
and analgesic).  Another objective is to evaluate if quality of recovery, as 
assessed by the Post-operative Quality of Recovery Scale (PQRS)[19,20], can be 
improved by using deep NMB, more adequate doses of anesthetic drugs and 
sugammadex reversal.  
The Post-operative Quality of Recovery Scale (PQRS) was developed by a group 
of anaesthesiologists, with the intention to produce an instrument for the 
assessment of both early and long-term recovery [19, 20]. This is the first available 
tool for evaluating multiple domains of recovery - physiologic, cognitive, and 
functional recovery [19,20]. PQRS was validated in different languages (English; 
German; French; Spanish and Chinese) including a total of 701 patients. The 


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Portuguese version has been translated and is at this time already available from 
the PQRS authors. The PQRS has already been successfully used by our research 
group in a previous study. 
We hypothesise that an anesthetic protocol maintaining deep neuromuscular 
block throughout the entire surgical procedure followed by sugammadex 
reversal, would suppress EMG activity and result in improved anesthetic stability 
by reducing the variability of the Bispectral Index of the EEG, and be beneficial 
by reducing the total doses of the anesthetic drugs propofol and remifentanil 
required to maintain an adequate level of anesthesia (BIS between 40 and 60). 
Average anesthetic requirements will be assessed by using the average effect-
site concentrations of propofol and remifentanil, since they take into account 
the patient gender, weight and height and are, therefore, more representative 
of the drug requirements. 
As secondary hypothesis we also expect to observe an increase in the quality of 
recovery (assessed by the Postoperative Quality of Recovery Scale – PQRS) and 
a decrease in the amount of ephedrine and labetalol used during the surgical 
procedure (drugs used in response to haemodynamic instability), when deep 
neuromuscular block is used. 
 
a) Investigational Medicinal Product 
 
 
The goal of the current study is to obtain additional data on two different 
anesthetic approaches, which includes drugs used according to their approved 
use and doses. By design, we will only obtain additional information on 
Sugammadex, with systematic collection and evaluation of adverse events for 
this drug. As such, the Investigational Product in this study is sugammadex. 
The use of neostigmine in Group 1 fulfills criteria of a rescue medication. The 
remaining drugs are considered background medication, used according to 
approved and standard practice and no additional information will be collected 
concerning these drugs. 


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All drugs, including sugammadex, will be used according to their approved and 
standard use at the trial site. Information concerning Sugammadex is contained 
in the attached Summary of Product Characteristics. 
Sugammadex used for the trial will be supplied by MSD and will be relabeled and 
accounted for according to requirements for Investigational Medicinal Products. 
The remaining drugs used during the trial will be supplied locally by CHP, 
according to standard procedures. 
 
b) Risks and benefits 
The risks and benefits of Sugammadex are those described by the Summary of 
Product Characteristics: 
The most commonly reported adverse reactions in surgical patients were 
anaesthetic complications. 
Hypersensitivity reactions, including anaphylaxis, have occurred in some patients 
and volunteers (for information on volunteers, see Information on healthy 
volunteers below). In clinical trials of surgical patients these reactions were 
reported uncommonly and for post-marketing reports the frequency is unknown. 
These reactions varied from isolated skin reactions to serious systemic reactions 
(i.e. anaphylaxis, anaphylactic shock) and have occurred in patients with no 
prior exposure to sugammadex. 
Symptoms associated with these reactions can include: flushing, urticaria, 
erythematous rash, (severe) hypotension, tachycardia, swelling of tongue, 
swelling of pharynx, bronchospasm and pulmonary obstructive events. Severe 
hypersensitivity reactions can be fatal. 
 


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c) Treatment dose and schedule 
35 patients randomized to group 2 will be administered a 4mg/kg dose to reverse 
the neuromuscular block at the end of the surgery. 
 
d) Rules and regulations 
The study will be conducted according to ICH-GCP, the Declaration of Helsinki 
and all applicable laws and regulations, namely, but not limited to: 
 
Portuguese Clinical Research Law, 21/2014 
 
European Clinical Trials Directive 2001/20/EC 
 
European Directive concerning ICH-GCP 2005/28/EC 
 
Portuguese Data Privacy Law 67/98 
 
European Directive concerning data privacy 94/46/EC 
 
e) Study population 
Seventy patients with an ASA score of I to III, 18 to 80 years old, scheduled for 
routine anterior cervical spine surgery in the Centro Hospitalar do Porto will be 
enrolled. 
 
 
 


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5. Objectives 
a) Primary Objective 
The primary objective of this study is to assess if the use of deep neuromuscular 
blockade reversed with sugammadex, and the consequent suppression of the 
EMG activity, can improve the overall stability of an anesthetic procedure 
(guided using BIS monitoring) and allow a reduction in the amount of anesthetic 
drugs required for adequate anesthesia.  
The primary hypothesis is that there is a better anesthetic  stability in the deep 
NMB group (Group 2) and that this is translated as a reduction of the BIS signal 
variability and a reduction in the required effect-site concentrations of propofol 
and remifentanil (representative of the total drug consumption). 
 
b) Secondary objectives 
As a secondary objective, we will study the quality of recovery using the PQRS 
scale to see if maintaining a deep NMB level during surgery has an impact on 
the patients’ quality of recovery. 
The secondary hypothesis is that the quality of recovery (PQRS test) is better in 
the patients of Group 2. 
 
 
 


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6. Study design 
Patients subjected to anterior cervical spine surgery under general intravenous 
anesthesia will be randomized to receive one of two protocols regarding the 
neuromuscular blockade: 
 
Group 1 – Standard Clinical Practice Group - standard NMB, with a 
standard rocuronium dose for intubation (0.6 mg/kg). If required, the 
reversal of neuromuscular block is performed with neostigmine. 
 
Group 2 – Deep NMB group - with a standard rocuronium dose for 
intubation (0.6 mg/kg), followed by a constant infusion of rocuronium (10-
15 g/kg/min) to guarantee a PTC less or equal to 2 on the TOF monitor 
(PTC is evaluated every 5 minutes). The reversal of neuromuscular block is 
performed with Sugammadex (4 mg/kg). 
 
a) Primary Endpoints 
 
BIS signal variability using the measured standard deviation during the 
maintenance phase of anesthesia 
 
Required effect-site concentrations of remifentanil and propofol 
 
b) Secondary Endpoints 
 
PQRS results at 15 and 40 minutes after surgery (taking into account the 
patient baseline values of the PQRS test done on the pre-anesthetic visit) 
 
PQRS results at day 3 after surgery 
 
c) Study type 
This is an interventional, phase 4, double-arm, parallel, randomized, open-label, 
single-center study aiming to compare two anesthesia protocols.  


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d) Study Timeline 
 
Study Start Date: April 2016 
 
Study End Date: April 2017 
 
First Patient In: April 2016 
 
Last Patient In: April 2017 
 
Last Patient Out: April 2017 
 
Study Analysis: May 2017 
 
Publication: November 2017 
 
 
 
 


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e) Flow-chart 
Assessment  Title 
Pre-anesthesia 
 
Anesthesia 
procedure during 
surgery 
15 minutes 
PQRS Test 
40 minutes 
PQRS test 
Follow-up 
Assessment  Number 
Assessment 1 
Assessment  2 
Assessment  3 
Assessment  4 
Assessment  5 
Scheduled Day 
One the day before 
surgery 
Day 1, time 1 
Day 1, time 2: 15 
minutes after surgery 
Day 1, time 3: 40 
minutes after surgery 
3 days after surgery 
Scheduling Window 
 
>90 minutes 
5 minutes 
5 minutes 
1 days 
Informed Consent 
X 
 
 
 
 
PQRS test 
X 
 
X 
X 
X 
Medical History 
X 
 
 
 
 
Entry Criteria 
X 
X 
 
 
 
(Serious)Adverse Events 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
Patient Data online recording 
 
X 
 
 
 
Patient  randomization 
 
X 
 
 
 
Patient Satisfaction evaluation 
 
 
 
 
X 
Dispense Trial Medication 
 
X 
 
 
 
Pregnancy test 
x 
 
 
 
 


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f) Randomization and blinding procedures 
This will be an interventional, randomized and unblinded study, performed at a 
single center (Centro Hospitalar do Porto). 
Patient randomization will be done by a computer software programed with a 
varying block randomization technique (to ensure sample size due to the small 
number of patients in each group), using a uniform distribution. The software will 
be installed in the data collection computer, and the anesthesiologist will only 
know to which group the patient was randomly assigned before induction starts. 
Although block randomization is used, the computer software does not display 
information about the block assignment of future patients to the user. The 
software is programmed using the Statistical toolbox of MATLAB. 
 
g) Treatment 
Trial participants will be randomly assigned (using varying block randomization) 
to one of two groups: 
 
Group 1 – Standard Clinical Practice Group - standard NMB, with a 
standard rocuronium dose for intubation (0.6 mg/kg). If required, the 
reversal of neuromuscular block is performed with neostigmine. 
 
Group 2 – Deep NMB group - with a standard rocuronium dose for 
intubation (0.6 mg/kg), followed by a constant infusion of rocuronium (10-
15 g/kg/min) to guarantee a PTC less or equal to 2 on the TOF monitor 
(PTC is evaluated every 5 minutes). The reversal of neuromuscular block is 
performed with Sugammadex (4 mg/kg). 
 
General anesthesia will be performed with total intravenous technique using the 
hypnotic propofol, the analgesic remifentanil and the neuromuscular relaxant 
rocuronium. Target controlled infusion (TCI) will be used for propofol and 
remifentanil. Standard routine anesthesia practice for these procedures uses 
total intravenous anesthesia with propofol and remifentanil by TCI and 
rocuronium. A single bolus dose of rocuronium is given for tracheal intubation 


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and no further doses are administered during the procedure. At the end of 
surgery, NMB is reversed only if TOF is below 90% 
 
h) Treatment duration 
Study treatment will be administered during surgery only, on day one. 
 
i) Discontinuation criteria 
A patient may request to discontinue from the clinical trial at any time for any 
reason. 
The investigator in any case in which emerging effects are of unacceptable risk 
to the individual subject, will discontinue the patient from the study.  In addition, 
the investigator will to stop study for any patient with unmanageable factors that 
may interfere significantly with the trial procedures and/or the interpretation of 
results. 
If the MAP does not respond to the protocol steps described in section 8, then 
the study should be stopped for that subject. 
 
j) Investigational product accountability 
These 
requirements 
apply 
only 
to 
Sugammadex, 
which 
is 
already 
commercialized in Portugal and is used in current clinical practice at the Centro 
Hospitalar do Porto.  
The internal labeling will be performed by our pharmacy department according 
to GCP guidelines and the local regulations for clinical trials. All drugs used, 
except for Sugammadex, will be labelled according to standard practice. 


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The investigator will be responsible for the destruction of the supplies of 
Sugammadex at the study center pursuant to the GCP Guidelines, local 
regulations and the investigator’s institutional policies. 
Clinical supplies of the drug Sugammadex will be received by a designated 
person of the pharmacy department at the site, handled and stored safely and 
properly, and kept in a secured location. Clinical supplies are dispensed in 
accordance with the protocol, i.e. the pharmacy will be informed of the patient 
randomization and the need for the use of Sugammadex in the beginning of the 
surgery and the drug will be sent to the operating room. 
The investigator will keep accurate records of the clinical supplies and the 
amount dispensed for each patient assigned to Group 2. 
 
k) Blinding and Un-blinding procedures 
Not applicable. 
 
l) Source documents and data collection 
Part of data will be recorded electronically: Trial participants will be monitored 
with standard ASA monitoring. Additional monitoring (i.e. intra-arterial pressure) 
will be provided depending on patient clinical status. The monitoring equipment 
is as follows: 
 
TOF Watch SX monitor for neuromuscular block assessment 
 
BIS – Bispectral Index Monitor (Covidien)   
 
Aisys Anaesthesia Monitor (General Electrics - GE) 
 
Fresenius Orchestra  Base Primea, with TCI for propofol and remifentanil 
 
Syringe pump attached to the Fresenius Base Primea for the continuous 
infusion of rocuronium 
Data collection software (Rugloop®  Software and TOF Link) is installed on a 
Laptop computer connected to the Base Primea infusion pumps, the BIS monitor, 


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GE monitor and TOF Watch monitor, allowing for all data to be recorded online. 
The patient data files generated by the Rugllop® software will be accessed using 
the Labgrab ® software and exported to excel files. TOF watch data will also be 
exported to excel files. All online data is posteriorly recorded in a patient 
individual CD. 
All non-electronic data will be noted on the patients’ paper CRF and on the 
RugLoop® software notes toolbar. 
 
 


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7. Selection and discontinuation criteria 
a) Inclusion criteria 
1. Patients ASA I-III 
2. Between 18 – 80 years old 
3. Scheduled for routine cervical surgery 
4. Minimum duration of surgery is 90 minutes and performed with 
total intravenous anaesthesia (TIVA) with the hypnotic 
propofol, the analgesic remifentanil and the neuromuscular 
relaxant rocuronium 
5. Patients that are able to and do provide a signed informed 
consent form 
 
b) Exclusion criteria 
1. Patients with neuromuscular diseases and severe cardiac and 
respiratory pathologies 
2. Contra  indication for any of the drugs used 
3. Not able to complete the baseline PQRS test. 
4. Indication to perform tracheal intubation using fibroscopy 
5. Patients who are pregnant or nursing 
 
c) Discontinuation criteria 
A patient may request to discontinue from the clinical trial at any time for any 
reason. 
The investigator in any case in which emerging effects are of unacceptable risk 
to the individual subject, will discontinue the patient from the study.  In addition, 
the investigators will to stop study for any patient with unmanageable factors 
that may interfere significantly with the trial procedures and/or the interpretation 
of results. 


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If the MAP does not respond to the protocol steps listed in section 8, then the 
study should be stopped. 
 
 


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8. Treatment of study participants 
a) Informed Consent 
Informed consent will be obtained by a medical investigator, part of the study 
team, during Assessment 1. 
b) Study procedures 
Minimum duration of surgery is 90 minutes and general anesthesia will be 
performed with total intravenous technique using the hypnotic propofol, the 
analgesic remifentanil and the neuromuscular relaxant rocuronium. Target 
controlled infusion (TCI) will be used for propofol and remifentanil. Standard 
routine anesthesia practice for these procedures uses total intravenous 
anesthesia with propofol and remifentanil by TCI and rocuronium. A single bolus 
dose of rocuronium is given for tracheal intubation and no further doses are 
administered during the procedure. At the end of surgery, NMB is reversed only if 
TOF is below 90%. 
 
i. Assessment 1 
Assessment name: Pre-anesthesia 
Timing: One the day before surgery 
Informed Consent 
PQRS test 
Medical History 
Pregnacy test 
Entry Criteria 
(Serious)Adverse Events 
Physical Examination 


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Patient Data online recording 
Patient  randomization 
 
The day before surgery informed consent will be obtained and baseline PQRS 
test performed. Patients with neuromuscular diseases and severe cardiac and 
respiratory pathologies, or that have any contra indication for any of the drugs 
used, or that are not able to complete the baseline PQRS test will be excluded 
from the study. 
 
i. 
Assessment 2 
Assessment name: Anesthesia procedure during surgery 
Timing: Day 1, time 1 
Entry Criteria 
(Serious)Adverse Events 
Patient Data online recording 
Patient  randomization 
Dispense Trial Medication 
 
On the day of surgery, the patients will be randomly assigned (using varying block 
randomization) to one of two groups: 
 
Group 1 – Standard Clinical Practice Group - standard NMB, with a 
standard rocuronium dose for intubation (0.6 mg/kg). If required, the 
reversal of neuromuscular block is performed with neostigmine. 
 
Group 2 – Deep NMB group - with a standard rocuronium dose for 
intubation (0.6 mg/kg), followed by a constant infusion of rocuronium (10-


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15 g/kg/min) to guarantee a PTC less or equal to 2 on the TOF monitor 
(PTC is evaluated every 5 minutes). The reversal of neuromuscular block is 
performed with Sugammadex (4 mg/kg). 
 
The Hospital Pharmacy is informed of the need or not of Sugammadex and sends 
the drug to the surgery room (since the surgery will not take less than 90 minutes, 
there is plenty of time for the drug to reach the surgery room). The hospital 
pharmacy department already agreed with this procedure. 
 
The anesthesia induction and maintenance is performed with the same protocol 
in both groups with TCI of propofol and remifentanil. During the procedure, the 
remifentanil and propofol effect-site target concentrations is titrated to achieve 
and maintain a BIS value between [40-60], and alarms are activated on the 
monitor; the Mean Arterial Pressure (MAP) should be maintained between [-30%  
+30%] of the baseline patient value. 
 
Upon arrival at the surgery room, all patients will be monitored with standard ASA 
monitoring. Additional monitoring (i.e. intra-arterial pressure) will be provided 
depending on patient clinical status. The monitoring equipment is as follows: 
 
TOF Watch SX monitor for neuromuscular block assessment 
 
BIS – Bispectral Index Monitor (Covidien)   
 
Aisys Anaesthesia Monitor (General Electrics - GE) 
 
Fresenius Orchestra  Base Primea, with TCI for propofol and remifentanil 
 
Syringe pump attached to the Fresenius Base Primea for the continuous 
infusion of rocuronium 
 
Anesthesia Protocol 
The anesthesia protocol is as follows: 


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 
Baseline Mean arterial pressure is noted 
 
Induction is performed with target effect site concentration of remifentanil 
of 3 ng/ml and a constant 1% propofol infusion of 3,3 ml/kg/h until loss of 
consciousness 
 
Loss of consciousness is assessed using the standard method of loss of 
response to name calling and tapping on the forehead 
 
At loss of consciousness, the propofol effect-site concentration is noted 
and the TCI propofol target set to 25% of that concentration and then 
adjusted to maintain BIS between 40 and 60. 
 
TOF Watch monitor is calibrated according to manufactures instructions 
and the specifications of GCP of NMB monitoring [21] 
 
A bolus dose of rocuronium of 0.6 mg/kg is given, this dose is 2xED95 of 
rocuronium, to allow for tracheal intubation 
 
After tracheal intubation the muscle relaxant rocuronium administration 
protocol is performed according to the group the patient was assigned to 
(Group 1 or Group 2) 
 
During the procedure the remifentanil and propofol target concentrations 
are titrated to achieve and maintain a the BIS value between 40 and 60 
(the BIS alarms are be activated in the monitor) and the Mean Arterial 
Pressure (MAP) between [-30%  +30%] of the baseline 
 
At the end of surgery the NBM reversal protocol is as follows: 
 
Group 1: Propofol infusion is stopped after the surgical dressing, if TOF<90 
then neostigmine (40 g/kg) plus atropine (20 g/kg) are administered; 
 
Group 2: Propofol infusion is stopped after the surgical dressing and 4 
mg/kg dose of Sugammadex is administered. 
 
In both groups: 
 
time of recovery of consciousness is recorded 
 
time of extubation is recorded 


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 
the post-operatory analgesia is with iv paracetamol and iv parecoxib, 
and iv morphine if required 
 
Monitoring during surgery 
During the anesthesia procedure and for both groups of patients, the response 
protocols to BIS and MAP deviations from the target range are as follows: 
Response Protocol to BIS values above 60: 
 
If EMG activity is present, the remifentanil effect-site target concentration 
is increased by steps of 1,5 ng/ml until a maximum of 15 ng/ml; 
 
If no EMG activity is present, the propofol effect-site target concentration 
is increased by steps of 0,5 g/ml until the concentration required for loss 
of consciousness is achieved. 
Response Protocol to Mean Arterial Pressure (MAP) values outside the target 
interval: 
 
If MAP is more than 30% below the baseline value, an ephedrine bolus of 
5 mg is given every 3 minutes until the desired effect; 
 
If MAP is more than 30% above the baseline value, the remifentanil effect-
site target concentration is increased by steps of 1,5 ng/ml until a 
maximum of 15 ng/ml is achieved. If the MAP value does not decrease to 
the desired range, then the propofol effect-site target concentration is 
increased by steps of 0,5 g/ml until the value required for loss of 
consciousness is achieved; 
 
If the MAP still is outside the desired interval, then a 10 mg dose of 
Labetalol should be administer every 10 minutes until the desired effect. 
If the MAP does not respond to the previous protocol steps, then the study should 
be stopped. 
Additional rocuronium (muscle relaxant) bolus of 0.2 mg/kg are allowed in the 
following situations: 


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 
If during surgery, the surgeon mentions difficulties due to muscle 
contraction 
 
If the patient is showing spontaneous ventilation that prevents adaptation 
to mechanical ventilation 
 
i. 
Assessment 3 
Assessment name: 15 minutes PQRS Test 
Timing: Day 1, time 2: 15 minutes after surgery 
PQRS test 
(Serious) Adverse Events 
 
After the patient is moved from the surgery room to the recovery room, the PQRS 
test is performed in both groups at 15 minutes post-surgery. The PQRS tests are 
recorded in the patient’s individual CRF forms.  
 
 
ii. 
Assessment 4 
Assessment name: 40 minutes PQRS test 
Timing: Day 1, time 3: 40 minutes after surgery 
PQRS test 
(Serious) Adverse Events 
 
The PQRS test is performed in both groups of patients at 40 minutes post-surgery. 


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The main study finishes after the 40 minutes PQRS test is performed. 
 
iii. 
Assessment 5 
Assessment name: Follow-up 
Timing: 3 days after surgery 
(Serious) Adverse Events 
Patient Satisfaction evaluation 
 
At the 3rd day after surgery a telephone contact is made to identify the 
occurrence of any Adverse Event (AE) (according to Good Clinical Practice 
(GCP) guidelines and pharmacovigilance directives), as well as to evaluate 
patient satisfaction using only the PQRS questions that address this issue. If at the 
3rd day after surgery the patient is still in the hospital, than the contact is 
performed face to face by the investigator or designated researcher. The overall 
data acquisition for each patient ends at this point. 
The occurrence of SAE and AE is noted on the specific forms on the patient 
individual CRF and acted accordingly to the GPC guidelines. 
The individual patient data will be anonymized after the 3rd day contact. 
 
iv. 
Discontinuation Visit 
(Serious) Adverse Events 
Patient Satisfaction evaluation 
 


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c) Compliance with study treatment 
Protocol compliance will be monitored, including accurate prescription and 
administration of study treatment according to protocol. 
Study treatment (IMP and NIMP) will be supplied and administered by medical 
personnel, so no compliance issues are expected to occur. 
 
d) Concomitant and prohibited medication 
Allowed concomitant medication and prohibited medication are those 
described by the SoPC of the IMP and NIMPs. 
 
e) Expenses and benefits 
Participants in the study are not expected to have additional expenses due to 
their study participation, since treatment and follow-up are similar to standard 
practice. Participants may benefit from the close monitoring due to study design. 
Unscheduled visits travel expenses (until 3 days after discharge) will be 
reimbursed by the Sponsor (up to € 30) against expenditure presentation 
document). 
 
 
 


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9. Efficacy evaluation 
a) Efficacy measure 
A 25% reduction on the BIS variability (standard deviation) is considered clinically 
relevant. 
b) Methods 
All hemodynamic and brain monitoring, TOF monitoring, and infusion pumps 
data will be recorded online during surgery with a sample time of 5 seconds, 
using data collection software on a laptop connected to all monitors and 
infusion pumps. 
Data collection software (Rugloop®  Software and TOF Link) are installed on a 
Laptop computer connected to the Base Primea infusion pumps, the BIS monitor, 
GE monitor and TOF Watch monitor, allowing for all data to be recorded online. 
The patient data files generated by the Rugllop® software will be accessed using 
the Labgrab ® software and exported to excel files. TOF watch data will also be 
exported to excel files. All online data is posteriorly recorded in a patient 
individual CD. All non-electronic data will be noted on the patients’ paper CRF 
and on the RugLoop® software notes toolbar. 
The total doses of ephedrine and labetalol are used as a surrogate variable, 
since they are the drugs used in the response protocol to hemodynamic 
instability (MAP being outside the desired target range). 
The following recorded data will be analyzed per patient and compared 
between the two study groups: 
 
BIS signal variability using the measured Standard deviation during the 
maintenance phase of anesthesia 
 
BIS average value during the maintenance phase of anesthesia 
 
Duration of periods of BIS values above 60 and below 40 
 
Average effect-site concentrations of propofol and remifentanil required 
during the maintenance of anesthesia 
 
Total doses of remifentanil, propofol, ephedrine and labetalol  


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 
PQRS results at 15 and 40 minutes after surgery (taking into account the 
patient baseline values of the PQRS test done on the pre-anesthetic visit) 
 
Patient satisfaction evaluated using the specific PQRS questions  
 
 
 


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10. 
Safety evaluation 
Each patient is considered to have ended participation in the study when he/she 
has completed the last telephone contact at 3 days post-surgery to verify the 
occurrence of any adverse events (AE) according to the phamacovigilance 
guidelines, or prematurely discontinues from the trial. 
Each patient will be monitored for the occurrence of AEs immediately after the 
subject has signed informed consent through 3 days after the patient has done 
the last PQRS test (at 40 minutes after surgery).  The patient will be monitored by 
the investigator or assigned researcher at hospital discharge (usually 24-48 hours 
after surgery) and then at the 3rd day after surgery (by telephone call) to monitor 
occurrence of AEs.  If at the 3rd day after surgery the patient is still in the hospital, 
then the investigator or designated researcher will talk personally to the patient. 
Follow-up procedures related to the occurrence of Serious Adverse Events (SAE) 
may continue beyond the end of the clinical trial. 
The CRF of the patient will have the AE and SAE forms according to GCP 
guidelines and local regulations. 
 
a) Definitions and reporting 
For the purpose of this Protocol the below terms shall be defined as follows: 
 
Adverse Event (AE) 
“Adverse Event” or “AE” shall mean any untoward medical occurrence in a 
Study subject who is administered the Study Drug regardless of whether or not a 
causal relationship with the Study Drug exists. By way of example and without 
limitation, an AE can be any unfavorable and unintended sign (for example, an 
abnormal laboratory finding), symptom, or disease temporally associated with 
the use of the Study Drug. 
 


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Serious Adverse Event (SAE) 
“Serious Adverse Event” or “SAE” shall mean any untoward medical occurrence 
in a Study subject who is administered the Study Drug that results in death, a life-
threatening drug experience, requires inpatient hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability/incapacity, or is 
a congenital anomaly/birth defect, cancer, or is a new cancer if the cancer is 
the condition of the study, or overdose. Other important medical events that 
may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed previously should also be considered “serious”. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
“Suspected Unexpected Serious Adverse Reaction” or “SUSAR” shall mean any 
Serious Adverse Event, the nature, severity or frequency of which is not consistent 
with information in the most current investigator’s brochure, or with respect to a 
marketed product the most current Summary of Product Characteristics or 
Package Insert. 
 
Drug Exposure during pregnancy or lactation 
All reports of Study Drug exposure during pregnancy or lactation (including a 
female partner of a male Study subject using the Study Drug), whether 
associated with an AE or not, will be reported to INFARMED and CEIC will be 
notified in accordance with the timelines and contact information for an SAE.  
Principal Investigator will follow pregnancies to term to obtain the outcome of 
the pregnancy.  The outcome of the pregnancy will be forwarded to INFARMED 
and CEIC. Sponsor will also forward these reports to MSD that is the supplier of the 
Study Drug.  
 
Event of Clinical Interest (ECI) 
An "Event of Clinical Interest" is a non-serious adverse event or occurrence that is 
designated to be of special interest and must be reported to the sponsor as 


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though it were a serious adverse event. The following events are considered 
events of clinical interest for this trial: 
1. 
An overdose of Sponsor's products that is not associated with 
clinical symptoms or abnormal laboratory results is to be reported as a 
non-serious ECI, using the terminology "accidental or intentional overdose 
without adverse effect.” 
2. 
An elevated AST or ALT lab value that is ≥3 x the upper limit of 
normal (ULN) and an elevated total bilirubin lab value that is ≥2 x ULN and, 
at the same time, an alkaline phosphatase lab value that <2 x ULN, as 
determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing is to be reported as a non-serious ECI. 
Note:  These criteria are based upon available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of 
abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology. 
3. 
Events of hypersensitivity: serious adverse events suggestive of 
hypersensitivity and/or possible events of anaphylaxis will be considered 
events of clinical interest. In case of hypersensitivity, additionally to the 
CIOMS the reporting investigator will also fill in from 211-PV031 (provided in 
attachment) and submit it within the same timelines as indicated above. 
 
Overdose 
In this current trial, an overdose of sugammadex is considered a dose greater 
than the maximum dose recommendation of sugammadex (i.e., any dose 
greater than 16 mg/kg). In previously-conducted clinical trials, there was one 
case of an accidental overdose with 40.0 mg/kg reported without significant 
undesirable effects. In a human tolerance study, sugammadex was tolerated 
well in doses up to 96.0 mg/kg. Please refer to the SPC for further information. 
 
Product Quality Complaint 


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A product quality complaint (PQC) is any written, electronic or oral 
communication that alleges a product defect. A PQC includes suspected 
product counterfeit, diversion or tampering. A PQC does not include Product 
Complaints alleging an AE. 
 
Planned Hospitalization 
A hospitalization planned by the subject prior to signing the informed consent 
form is considered a therapeutic intervention and not the result of a new SAE and 
should be recorded as medical history. If the planned hospitalization or 
procedure is executed as planned, the record in the subject’s medical history is 
considered complete. 
However, if the event/condition worsens during the trial, it must be reported as 
an AE or SAE. 
 
Medication Error 
A medication error is any preventable event that may cause or lead to 
inappropriate medication use, including unintended accidental exposure or 
subject or patient harm while the medication is in the control of a health care 
professional, subject or patient, or consumer. Such events may be related to 
professional practice, clinical trials, health care products, procedures, and 
systems, including prescribing, order communication, product labeling, 
packaging, 
and 
nomenclature; 
compounding, 
dispensing, 
distribution, 
administration, education, monitoring, and use. 
 
Potential Medication Error 
A potential medication error is an individual case safety report of information or 
complaint about product name, labeling, or packaging similarities that does not 
involve a subject or patient (eg, if a subject reports that one of the investigational 


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products looks like a different product, the report would be considered a 
potential medication error). 
 
Trial Procedure Related Events 
A clinical trial procedure related event is an AE that could be associated with 
the trial procedures, rather than the investigational product or its administration. 
Trial procedures include all treatment procedures and medical procedures for 
physical examinations, medical investigations, and laboratory assessments or 
other activities specified in the protocol for the purpose of the clinical trial. 
 
b) Reporting 
SAE and SUSAR Reporting 
 
SAE and SUSAR reports and any other relevant safety information will be 
forwarded by the Principal Investigator to the following CHP e-mail:  
ensaiosclinicos.farmacia@chporto.min-saude.pt.  
 
Sponsor will forward to INFARMED and CEIC, any SAE and SUSAR 
information, including, but not limited to, all initial and follow-up 
information involving any Study subject in the Study.  
 
Notification will be made in the form of a completed CIOMS I within one 
(1) business days of learning of the SAE or SUSAR.  
 
All SAE and SUSAR information will be transmitted in the English language 
and contains the reporter’s name and the Study subject identifier code.  
 
SUSAR information will be reported unblinded.  
 
Randomization codes for all other SAEs will be provided to INFARMED at 
end of Study. 
 
The reporting investigator will provide a causality assessment for all 
reported SAEs. 
 
Sponsor will ensure timely reporting of SUSAR to the relevant competent 
authorities. 
 
As supplier of the drug under study, MSD will be informed on SAE and 
SUSAR 
by 
the 
Sponsor 
to 
the 
following 
e-mail: 


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pharmacovigilance.portugal@merck.com, or by Fax: +351 214 465 799, 
preferably on the same day competent authorities will be notified.  
o By timely it is meant that SUSAR concerning death of a subject or 
life-threatening situations will be submitted within 7 calendar days 
after such a case is known by an investigator of this study, and 
within 15 calendar days for all other SUSAR.  
 
DSUR Reporting 
Sponsor will remain responsible for redacting and submitting to all relevant parties 
the Development Safety Update Reports (DSUR) according to the applicable 
legislation. The Sponsor also will forward the final DSUR to the Competent 
Authorities and to MSD. 
 
Product Quality Complaint Reporting 
In the event Sponsor will become aware of a defect or possible defect in the 
Study Drug, Sponsor will notify INFARMED and MSD within one business day of first 
becoming aware of the possible defect.   
 
Other Information 
MSD may will provide the Sponsor/Principal Investigators, at Study initiation and 
on an ongoing basis, with information regarding the Study Drug, including but 
not limited to safety information.  The Sponsor and Principal Investigator agree to 
hold this information in confidence. 
 
 
 
c) Safety Monitoring 


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Monitoring Adverse Events 
Subjects will be monitored for the occurrence of SAEs immediately after the 
subject has signed informed consent. Subjects enrolled in the study will be 
monitored for both AEs and SAEs. 
Subjects will be questioned and/or examined by the investigator or a qualified 
designee for evidence of AEs. The questioning of subjects with regard to the 
possible occurrence of AEs will be generalized such as, "How have you been 
feeling since your last visit?” The presence or absence of specific AEs should not 
be elicited from subjects. 
Subjects having AEs will be monitored with relevant clinical assessments and 
laboratory tests, as determined by the investigator. 
AEs, actions taken as a result of AEs, and follow-up results must be recorded in 
the CRF, as well as in the subject's source documentation. Follow-up laboratory 
results should be filed with the subject's source documentation. 
For all AEs that require the subject to be discontinued from the trial and SAEs, 
relevant clinical assessments and laboratory tests will be repeated as clinically 
appropriate until final resolution or stabilization of the event(s). 
 
Monitoring Laboratory Assessments 
Assessments of laboratory parameters will be performed locally. These laboratory 
values will be reported to the investigator by the laboratory and the investigator 
will review them for significance and consideration as an AE.  
 
d) Assessment of Adverse Events 
Assessment of Severity 
Where the determination of AE severity rests on medical judgment, the 
determination of severity must be made with the appropriate involvement of a 
medically-qualified investigator. 


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The severity of AEs will be graded according to the following definitions: 
Mild: awareness of sign, symptom, or event, but easily tolerated; 
Moderate: discomfort enough to cause interference with usual activity 
and may warrant intervention; 
Severe: incapacitating with inability to do normal daily living activities or 
significantly affects clinical status, and warrants intervention; 
 
Assessment of Causality 
A medically qualified investigator must assess the relationship of any AE 
(including SAEs) to the use of the investigational product, as unlikely related, 
possibly related, or probably related, based on available information, using the 
guidelines listed below: 
Unlikely related: no temporal association, or the cause of the event has 
been identified and attributed to other disease or drug; or the drug, 
biologic, or device cannot be implicated based on available information; 
Possibly related: temporal association, but other etiologies are likely to be 
the cause; however, involvement of the drug, biologic, or device cannot 
be excluded based on available information; 
Probably related: temporal association, other etiologies are possible, but 
unlikely based on available information. 
 
 
 


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11. 
Statistics 
a) Methods 
Differences in age, weight, and height between the groups will be analyzed with 
t-test. 
Continuous data will be analyzed using independent samples t test, or RM 
ANOVA for repeated measurements. 
Univariate analyses will be conducted using chi-square analysis or Fisher exact 
test where appropriate, to analysis de PQRS recovery result at discrete time 
points, and repeated measures ANCOVA for continuous data. 
Statistical analysis of the subcategories of the PQRS test will be performed using 
the Cochran Mantel – Haenszel test on the proportions of recovery for each 
group with continuity correction over two measurement periods. 
 
b) Number of participants 
Sample size calculation with a power of 0.80 and an  of 0.05, considering the 
primary hypothesis of a reduction in the BIS variability (measured as the standard 
deviation) and a reduction in the propofol and remifentanil drug consumption 
(measured as the average effect-site concentration required) during 
maintenance of anesthesia. 
To estimate the standard deviation of our population, we searched our 
database for standard clinical practice cases with: online data recording; 
cervical spine surgery; BIS average values within the recommended target 
values [40-60]; TCI anesthesia with propofol and remifentanil.  
A total of 12 patients data were analyzed (mainly due to the lack of online 
recording during the procedures), the average BIS standard deviation was 
8.7±3.14, and the average propofol and remifentanil effect-site concentrations 
were 2.68±0.9 g/ml and 2.83±0.8 ng/ml, respectively. 


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A 25% reduction on the BIS variability (standard deviation) was considered 
clinically relevant, and gave a minimum sample size of 26 per group. 
A reduction on propofol average effect-site concentration of 20% was 
considered clinically relevant, and gave a minimum sample size of 34 per group. 
A reduction on remifentanil average effect-site concentration of 20% was 
considered clinically relevant, and gave a minimum sample size of 24 per group. 
Considering the above results and the possibility of patient exclusion due to 
external complications during surgery, a total of 35 patients per group will be 
included in the study. 
The secondary variable, result of the PQRS test was not used in the sample size 
calculation, since there are no studies on the comparison of recovery after two 
different interventions and the data regarding sample calculation that the 
authors of PQRS showed us are for the recovery at 3 days post-surgery, which is 
not comparable to our study. Therefore we did not considere adequate to 
estimate a percentage difference for which we do not know the clinical reality. 
The surrogate variables, consumption of ephedrine and labetalol will be 
analyzed since these drugs are used in the response protocol to target 
deviations, but they are not considered for the sample size calculation. 
 
c) Level of statistical significance 
The sample was calculated at a significance level of 95%. A p-value below 0.05 
is considered statistically significant. 
 
d) Study termination 
Data analysis is planned for the end of the trial. No early study termination is 
planned. 
 


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e) Missing data 
Participants with missing primary endpoint data will not be included in the 
analysis.  
 
f) Deviations 
Any change to the statistical plan will be submitted to the competent 
authorities prior to its implementation. 
 
g) Inclusion in analysis 
All data will be included for the analysis (Intention to treat). 
 
 


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12. 
Direct access to source documents 
The investigator will grant direct access to paper and/or electronic 
documentation pertaining to the clinical study (e.g. CRFs, source documents 
such as hospital patient charts and investigator study files) to authorized 
individuals, as the clinical trial monitors, auditors or health authority inspections. 
The objective of these accesses is to ensure the trial is being conducted 
according to local laws and regulations and ICH-GCP. 
All site facilities related to the study conduct can be visited during an audit (e.g. 
pharmacy, laboratory, archives). 
The investigator agrees to co-operate and provide assistance at reasonable 
times and places with respect to any monitoring or auditing activity. 
 
 


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13. 
Quality control and quality assurance 
The study will be conducted in accordance with the current approved protocol, 
ICH GCP, relevant regulations and standard operating procedures. 
Regular monitoring will be performed according to ICH GCP. Data will be 
evaluated for compliance with the protocol and accuracy in relation to source 
documents. Following written standard operating procedures, the monitors will 
verify that the clinical trial is conducted and data are generated, documented 
and reported in compliance with the protocol, GCP and the applicable 
regulatory requirements. 
Inspections and Audits 
The Principal Investigator will notify the Administration of CHP within twenty-four 
(24) hours in the event that any regulatory authority notifies the Study site of a 
pending inspection/audit that concerns the Study or Institution’s ability to 
perform clinical research.  In addition, Principal Investigator will forward to 
Administration of CHP any written communication received as a result of the 
inspection/audit within twenty-four (24) hours of receipt of such communication 
and allows CHP to assist in responding to any citations involving the Study Drug.  
Such responses shall be made as soon as possible under the circumstances or 
within any earlier deadline set by the issuing regulatory authority. Principal 
Investigator also will provide to Administration of CHP copies of any documents 
provided to any inspector or auditor. In the event the regulatory authority 
requests or requires any action to be taken to address any citations, Principal 
Investigator and Administration of CHP agree to take such action as necessary 
to address such citations. 
 
 
 


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14. 
Ethics 
Written informed consent will be obtained from all patients. Research will be 
carried out in compliance with the Declaration of Helsinki. 
The Investigator will ensure that this study is conducted in full conformity with 
relevant regulations and with the ICH Guidelines for Good Clinical Practice E6. 
a) Responsible ethics committee 
The study will be submitted to the Portuguese Central Ethics Committee CEIC and 
only start recruitment after receiving its positive opinion. 
b) Regulatory Approval 
The study will be submitted to the Portuguese Regulatory Authority INFARMED 
and only start recruitment after receiving its approval. 
c) Patient Confidentiality 
The study will be submitted to the Portuguese Data Privacy Agency CNPD and 
only start recruitment after receiving its approval for data collection. 
The trial staff will ensure that the participants’ anonymity will be maintained. The 
participants will be identified within the trial by a numeric code. The numeric 
code correspondence to the participant can only made at the investigative site 
here that participant is being followed. 
Trial data will be recorded only by authorized trial personnel. Trial data will only 
be accessed by authorized personnel. 
Patients’ data during surgery will be recorded on a research laptop with a code 
generator, which protects patient anonymity by generating a code for each 
individual patient.  
All paper records (CRF) with the PQRS test results at the different time points will 
use the designated individual patient code. The patient CRF’s will be kept on a 
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will be kept on the research laptop (with restricted permissions) and each patient 
will also have its own individual data CD. 
 


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15. 
Data handling record keeping 
Clinical trial data will be maintained in the Case Report Form developed for the 
trial. All hemodynamic and brain monitoring, TOF monitoring, and infusion pumps 
data will be recorded on the hospitals computers. PQRS paper questionnaires will 
be filled out by the trial participants and kept in the participant’s clinical chart.  
Remaining source documentation is to be maintained as part of the participant’s 
clinical chart. Deviations from this documentation method will be documented. 
All data are to be attributable, legible, contemporaneous, original and 
accurate. 
 
 
 


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16. 
Financing and insurance 
The study received a grant from Merck Sharp & Dohme and  IMP (sugammadex) 
will be supplied by Merck Sharp & Dohme. 
The study was designed and will be conducted, analyzed and interpreted by the 
investigator according to publications policy. 
A clinical trial insurance for the trial participants and the investigators will be 
contracted by the study Sponsor. 
 
 


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17. 
Publication policy 
All study data and results are owned by the Investigator/Sponsor. Only the 
principal investigator and the research team will have access to all research 
data and results during the study.  Investigator/Sponsor agree however that the 
final results generated during the study may be used  by MSD for any scientific or 
business purpose. In the addition to the publication process Sponsor/Principal 
Investigator shall only use the research data and results generated during the 
course of the study for internal, non-commercial teaching and research 
purposes. Sponsor/Investigator agree not to provide any commercial third party 
with access to or with the right to use the data or results for any purpose without 
the written permission of MSD. 
Principal Investigator has the right to publish or publicly present the results of the 
Study and MSD shall have the right to review and comment on any Public 
Presentation. For this purpose, the Principal Investigator shall provide 45 days, 
written notice to MSD prior to submission for publication or presentation to permit 
MSD to review drafts of abstracts and manuscripts for publication which report 
any results arising out of the study. Such 45 days notice period shall not 
commence until MSD has received all the relevant data associated with the 
public presentation in order for MSD to properly review and comment on the 
public presentation.  
If the parties disagree concerning the accuracy and appropriateness of the 
data analysis and presentation, and/or confidentiality of MSD’s Confidential 
Information, Sponsor/Principal Investigator agree to meet MSD’s representatives 
at the clinical study site or as otherwise agreed, prior to submission of a public 
presentation, for the purpose of making good faith efforts to discuss and resolve 
any such issues or disagreements. Principal Investigator agrees to acknowledge 
MSD in any public Presentation using the following language: “Supported in part 
by a research grant from Investigator-Initiated Studies Program of Merck Sharp & 
Dohme Corp. The opinions expressed in this paper are those of the authors and 
do not necessarily represent those of Merck Sharp & Dohme Corp.” 
In making a public presentation, Sponsor/Principal Investigator shall comply with 
all laws, regulations and accepted guidelines of peer reviewed medical journals 


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and any specific guidelines established by congress and/or journals to which the 
public presentation will be submitted. Sponsor/Principal Investigator represent 
that designated authors and contributors shall meet the minimum requirements 
of International Committee of Medical Journals Editors. 
The Principal Investigator anticipate to write two papers. One focusing on the 
primary objective of the study and the other on the secondary objective. 
The journals at which Principal Investigator intend to submit are Anesthesia & 
Analgesia and the British Journal of Anaesthesia. 
The Principal Investigator also anticipate to submit two abstracts. The scientific 
meetings that he is considering are the EuroAnaesthesia 2018 and the American 
Society of Anesthesiologists Annual Meeting (ASA) 2017. 
 
 
 


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18. 
Appendix 
 
PQRS Physician Quality Reporting System 
 
Summary of Product Characteristics Sugammadex, last updated on 25-
Jul-2013 
 
 
 


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19. 
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[10] 
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Panousis P, Heller AR, Burghardt M, et al. “The effects of 
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[19] 
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Royse CF, Chung F, Newman S, et al. “Predictors of patient satisfaction 
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