Comparing Analgesic Efficacy of Systemic Lidocaine Against Placebo in General Anesthesia in Bariatric Surgery: Prospective, Randomized, Double-blinded, Placebo Controlled, Mono-Center Study
Phase: PHASE3
Conditions: Pain, Postoperative
Sponsor: Miodrag Filipovic, Prof. Dr. med.

  
 
COALAS protocol version 2.0 CTU 17/026 28/12/2018 
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Comparing Analgesic Efficacy of Systemic       
Lidocaine against Placebo in General Anesthesia 
in Bariatric Surgery: prospective, randomized, 
double-blinded, placebo controlled, monocenter 
study 
 
Clinical Study Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMPARING ANALGESIC EFFICACY OF SYSTEMIC LIDOCAINE AGAINST 
PLACEBO IN GENERAL ANESTHESIA IN BARIATRIC SURGERY: A PROSPEC-
TIVE, RANDOMIZED, DOUBLE-BLINDED, PLACEBO CONTROLLED, MO-
NOCENTER STUDY  
[EVALUATING ANALGESIC EFFICACY OF SYSTEMIC LIDOCAINE IN BARI-
ATRIC SURGERY IN A PROSPECTIVE, RANDOMIZED, DOUBLE BLINDED, PLA-
CEBO CONTROLLED STUDY] 
 
 

  
 
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STUDY TYPE 
Prospective, randomized, double-blinded, placebo controlled 
 
STUDY CATEGORIZATION 
In this clinical trial the analgesic effect of intravenously administrated lidocaine is com-
pared with placebo. Despite longstanding use as an antiarrhythmic agent and its use in 
many clinical trial as analgesic, lidocaine is not licensed for this indication and applica-
tion. Therefore, the study is assigned as category B.  
 
STUDY REGISTRATION 
The study will be registered in both the national (kofam.ch) and international (clinicaltri-
als.gov) clinical trial databases prior to start. 
 
SPONSOR, SPONSOR-INVESTIGATOR OR PRINCIPAL INVESTIGATOR 
The Sponsor and Sponsor/Investigator is Prof. Dr. med. Miodrag Filipovic, Vice-
Chairman, Klinik für Anästhesiologie, Intensiv-, Rettungs- und Schmerzmedizin, Kan-
tonsspital St. Gallen, St. Gallen, Switzerland.  
Study coordination and contact information: 
Prof. Dr. med. Miodrag Filipovic, Kantonsspital St. Gallen, Klinik für Anästhesiologie, 
Intensiv-, Rettungs- und Schmerzmedizin, Rorschacher Strasse 95, CH-9007 St. Gallen, 
Switzerland  
Email: miodrag.filipovic@kssg.ch, Tel. +41 (0)71 494 15 05 
 
INVESTIGATIONAL PRODUCT 
Lidocaine, systemic application 
 
PROTOCOL VERSION AND DATE 
Version 2.0, 12 / 2018 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of the Kantonsspital St. Gallen. 
The information may not - in full or in part - be transmitted, reproduced, published, or disclosed to others 
than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies) without prior written 
authorisation from the sponsor except to the extent necessary to obtain informed consent from those who 
will participate in the study. 
 
 

  
 
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SIGNATURE PAGE 
 
Study number: CTU 17/026 
Study title: Comparing Analgesic Efficacy of Systemic Lidocaine against Placebo in 
General Anesthesia in Bariatric Surgery: prospective, randomized, double-blinded, pla-
cebo controlled, monocenter study 
 
The Sponsor/Investigator and trial statistician have approved the protocol version 2.0, 
and confirm hereby to conduct the study according to the protocol, current version of the 
World Medical Association Declaration of Helsinki, ICH-GCP guidelines if applicable and 
the local legally applicable requirements. 
 
SPONSOR/INVESTIGATOR 
Prof. Dr. med. Miodrag Filipovic 
Kantonsspital St. Gallen 
Klinik für Anästhesiologie, Intensiv-, Rettungs- und Schmerzmedizin 
 
________________________ 
Place/Date 
 
________________________ 
Signature 
 
STATISTICIAN 
Not named yet 
 
________________________ 
Place/Date 
 
________________________ 
Signature 
 
 

  
 
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Table of contents 
COMPARING ANALGESIC EFFICACY OF SYSTEMIC       LIDOCAINE AGAINST PLACEBO 
IN GENERAL ANESTHESIA IN BARIATRIC SURGERY: PROSPECTIVE, RANDOMIZED, 
DOUBLE-BLINDED, PLACEBO CONTROLLED, MONOCENTER STUDY ............................... 1 
TABLE OF CONTENTS.............................................................................................................. 4 
STUDY SYNOPSIS .......................................................................................................................... 7 
ABBREVIATIONS ......................................................................................................................... 10 
COMPENDIOUS FLOW CHART ...................................................................................................... 11 
1. STUDY ADMINISTRATIVE STRUCTURE ............................................................................ 12 
1.1 SPONSOR, SPONSOR-INVESTIGATOR ..................................................................................... 12 
1.2 MONITORING INSTITUTION ..................................................................................................... 12 
1.3 DATA SAFETY MONITORING COMMITTEE ................................................................................ 12 
2. ETHICAL & REGULATORY ASPECTS................................................................................ 13 
2.1 STUDY REGISTRATION ........................................................................................................... 13 
2.2 CATEGORIZATION OF STUDY .................................................................................................. 13 
2.3 COMPETENT ETHICS COMMITTEE (CEC) ................................................................................ 13 
2.4 COMPETENT AUTHORITIES (CA) ............................................................................................ 13 
2.5 ETHICAL CONDUCT OF THE STUDY ......................................................................................... 14 
2.6 DECLARATION OF INTEREST .................................................................................................. 14 
2.7 PATIENT INFORMATION AND INFORMED CONSENT ................................................................... 14 
2.8 PARTICIPANT PRIVACY AND CONFIDENTIALITY ......................................................................... 15 
2.9 EARLY TERMINATION OF THE STUDY ....................................................................................... 15 
2.10 PROTOCOL AMENDMENTS .................................................................................................... 15 
3. BACKGROUND & RATIONALE ........................................................................................... 16 
3.1 INVESTIGATIONAL PRODUCT - LIDOCAINE ............................................................................... 16 
3.2 DATA CURRENTLY AVAILABLE ............................................................................................... 18 
3.3 DOSE RATIONALE ................................................................................................................. 19 
3.4 EXPLANATION FOR CHOICE OF PLACEBO ................................................................................ 19 
3.5 RISKS AND BENEFITS ............................................................................................................ 19 
3.6 STANDARDIZED PROCEDURES ............................................................................................... 21 
4. STUDY OBJECTIVES .......................................................................................................... 21 
4.1 PRIMARY STUDY OBJECTIVE .................................................................................................. 21 
4.2 SECONDARY STUDY OBJECTIVE ............................................................................................. 21 
4.3 OTHER OBJECTIVES OF INTEREST .......................................................................................... 22 
5. STUDY OUTCOMES ............................................................................................................ 22 
5.1 PRIMARY OUTCOME ............................................................................................................... 22 
5.2 SECONDARY OUTCOME ......................................................................................................... 22 
5.3 OTHER OUTCOMES OF INTEREST ............................................................................................ 22 
5.4 SAFETY OUTCOMES ............................................................................................................... 22 
6. STUDY DESIGN ................................................................................................................... 23 
6.1 GENERAL STUDY DESIGN AND JUSTIFICATION OF DESIGN ........................................................ 23 

  
 
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6.2 METHODS OF MINIMIZING BIAS ............................................................................................... 23 
6.3 RANDOMIZATION ................................................................................................................... 24 
6.4 BLINDING PROCEDURES ........................................................................................................ 24 
6.5 UNBLINDING PROCEDURES .................................................................................................... 24 
7. STUDY POPULATION .......................................................................................................... 24 
7.1 INCLUSION ............................................................................................................................ 24 
7.2 EXCLUSION ........................................................................................................................... 24 
7.3 RECRUITMENT AND INFORMED CONSENT ................................................................................ 25 
7.4 ASSIGNMENT TO STUDY GROUPS ........................................................................................... 25 
7.5 CRITERIA FOR WITHDRAWAL / DISCONTINUATION OF PARTICIPANTS ......................................... 25 
8. STUDY INTERVENTION ...................................................................................................... 26 
8.1 GENERAL INFORMATION ........................................................................................................ 26 
8.2 IDENTITY OF INVESTIGATIONAL PRODUCTS ............................................................................. 29 
8.3 PACKAGING, LABELLING AND SUPPLY ................................................................................... 29 
8.4 ADMINISTRATION OF EXPERIMENTAL AND CONTROL INTERVENTIONS ........................................ 30 
8.5 DOSE MODIFICATIONS ........................................................................................................... 30 
8.6 COMPLIANCE WITH STUDY INTERVENTION ............................................................................... 31 
8.7 TRIAL SPECIFIC PREVENTIVE MEASURES ................................................................................. 31 
8.8 CONCOMITANT INTERVENTIONS (TREATMENTS) ...................................................................... 31 
8.9 IMPS / MEDICAL DEVICE ACCOUNTABILITY ............................................................................ 32 
9. STUDY ASSESSMENTS ...................................................................................................... 32 
9.1 STUDY FLOW CHARTS / TABLE OF STUDY PROCEDURES AND ASSESSMENTS ............................. 32 
9.2 ASSESSMENTS OF OUTCOMES ............................................................................................... 32 
9.3 ASSESSMENTS OF SAFETY OUTCOMES ................................................................................... 33 
9.4 PROCEDURES AT EACH VISIT ................................................................................................. 34 
10. STATISTICAL METHODS .................................................................................................. 34 
10.1 STATISTICAL CONSIDERATIONS ............................................................................................ 34 
10.2 HYPOTHESIS ....................................................................................................................... 35 
10.3 DETERMINATION OF SAMPLE SIZE ........................................................................................ 35 
10.4 PLANNED ANALYSES........................................................................................................... 35 
10.5 PRIMARY AND SECONDARY ENDPOINT ANALYSES .................................................................. 35 
10.6 INTERIM ANALYSIS .............................................................................................................. 36 
10.7 DEVIATION FROM THE ORIGINAL STATISTICAL PLAN ............................................................... 36 
10.8 HANDLING OF MISSING DATA AND DROP-OUTS ...................................................................... 36 
11. SAFETY ANALYSIS ........................................................................................................... 37 
11.1 DRUG STUDIES .................................................................................................................... 37 
11.2 DEFINITION AND ASSESSMENT OF (SERIOUS) ADVERSE EVENTS AND OTHER SAFETY RELATED 
EVENTS ...................................................................................................................................... 37 
11.3 ASSESSMENT OF CAUSALITY ............................................................................................... 38 
11.4 UNEXPECTED ADVERSE DRUG REACTION ............................................................................ 38 
11.5 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSAR) .................................... 38 
11.6 ASSESSMENT OF SEVERITY ................................................................................................. 38 
11.7 REPORTING OF ADVERSE AND SERIOUS ADVERSE EVENTS ................................................... 39 
11.8 SAFETY FOLLOW-UP ............................................................................................................ 39 
11.9 SAFETY SOP ...................................................................................................................... 40 
12. QUALITY ASSURANCE & CONTROL ............................................................................... 41 

  
 
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12.1 DATA HANDLING AND MANAGEMENT.................................................................................... 41 
12.2 STORAGE OF DATA ............................................................................................................. 41 
12.3 MONITORING AND AUDITING ................................................................................................ 41 
12.4 CONFIDENTIALITY ............................................................................................................... 41 
13 PUBLICATION AND DISSEMINATION POLICY ................................................................. 42 
14 FUNDING AND SUPPORT .................................................................................................. 42 
15 INSURANCE ........................................................................................................................ 42 
REFERENCES ......................................................................................................................... 43 
 
 
 

  
 
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Study synopsis  
 
Sponsor / Sponsor/Investigator 
Prof. Dr. med. Miodrag Filipovic 
Study Title 
Comparing analgesic efficacy of systemic lidocaine in general anesthesia in bariatric 
surgery 
Short Title / Study ID 
Systemic lidocaine versus placebo 
Protocol Version and Date 
2.0, 12 / 2018  
Trial registration 
outstanding submission to kofam.ch 
Study category and rationale 
As a clinical trial, we are comparing lidocaine 1% I.V. as an additional analgesic therapy 
to placebo with minimal expected additional risks to the participants due to our interven-
tion, this study is assigned to category B. Lidocaine 1% I.V. is authorized in Switzerland 
but not used according to the approved indication. 
Clinical Phase 
Phase III 
Background 
Postoperative pain is a common problem in today`s surgery, although pain management 
techniques have improved in the last years. Systemic application of lidocaine has gained 
interest since several studies have shown its analgesic, anti-inflammatory and anti-
hyperalgesic properties. This study will be conducted to evaluate the analgesic efficacy 
of systemic lidocaine in addition to total intravenous anesthesia in morbidly obese pa-
tients undergoing laparoscopic bariatric surgery. 
Objective 
To investigate if intravenous administration of lidocaine in patients undergoing bariatric 
surgery reduces postoperative pain intensity within the first four hours after completion 
of surgery. 
Hypothesis 
Perioperative treatment of patients undergoing bariatric surgery with lidocaine reduces 
the proportion of those suffering from more intensive pain (any development of 
VAS/NRS score > 3, in hourly measurements) within the first four hours from currently 
65% to 35%. 
 
 
 

  
 
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Outcome 
Primary: proportion of patients suffering from higher pain intensity (any development of 
VAS/NRS score > 3, in hourly measurements) within the first four hours after completion 
of bariatric surgery. 
Secondary: average maximal pain intensity during first four hours and during 48 hours, 
total opiate consumption, postoperative nausea and vomiting, time to first defecation and 
length of hospitalization. 
Study design 
Prospective, randomized, double blinded, placebo controlled trial 
Inclusion / Exclusion criteria 
Inclusion: elective laparoscopic bariatric surgery, ASA classification I – III, age 18 – 80, 
informed consent  
Exclusion: no written consent, allergy to the investigational product, cardiac arrhythmia 
(pacemaker), liver dysfunction (Child-Pugh classification A, B or C), pregnancy, central 
nervous disease, chronic pain and pre-existing opiate prescription, expected non-
compliance, drug/alcohol abuse 
Study Product / Intervention 
“lidocaine group” 
- 1.5 mg/kg lean body mass lidocaine (lidocaine 1%) bolus I.V. as general anesthesia 
steady state concentration is accomplished 
- 1.5 mg/kg lean body mass/h lidocaine I.V. with beginning of surgical procedures 
- after completion of surgery: transfer to PACU, pain evaluation (VAS/NRS score ques-
tionnaire, see appendix for detailed questionnaire) for 48 hours, nurse –based pain 
treatment as appropriate 
- duration of intervention: lidocaine infusion up to four hours from completion of surgery, 
or till transfer to surgical ward 
Control Intervention 
“placebo group”      
- 0.15 ml/kg lean body mass saline 0.9% bolus I.V. as general anesthesia steady state 
concentration is accomplished 
- 0.15 ml/kg lean body mass/h saline 0.9% I.V. with beginning of surgical procedure 
- after completion of surgery: transfer to PACU, pain evaluation (VAS/NRS score ques-
tionnaire) for 48 hours, nurse –based pain treatment as appropriate  
- duration of intervention: saline infusion up to four hours from completion of surgery, or 
till transfer to surgical ward 
Number of Participants 
63 participants per group + 10% to account for drop-outs (sum. 140 patients),  
2 test (allocation of VAS/NRS score ≤ 3 to 65% of interventional group), p-value 0.05, 
power 90% 
 
 

  
 
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Study Duration 
Estimated duration for the main investigational plan (from start of screening of first par-
ticipant to last participant processed and finishing the study) will be approximately two 
years 
Investigator 
Prof. Dr. med. Miodrag Filipovic 
Kantonsspital St. Gallen 
Klinik für Anästhesiologie, Intensiv-, Rettungs- und Schmerzmedizin 
Study Centre 
Single center, Kantonsspital St. Gallen 
Klinik für Anästhesiologie, Intensiv-, Rettungs- und Schmerzmedizin 
Rorschacher Strasse 95 
CH-9007 St. Gallen 
Switzerland 
Statistical Considerations: 
Sample size of 63 subjects per group was estimated to achieve 90% power and to de-
tect 65% redistribution of VAS/NRS score ≤ 3 in favour of the “lidocaine group“.                    
To account for drop-outs, 140 subjects were recruited and randomized. 
GCP Statement 
This study will be conducted in compliance with the protocol, the current version of the 
Declaration of Helsinki, the ICH-GCP as well as all national legal and regulatory re-
quirements.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
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Abbreviations 
 
AE Adverse Events  
ASA American Society of Anesthesiologists 
BMI Body Mass Index 
CA Competent Authority (e.g. Swissmedic) 
CEC Competent Ethics Committee 
CRF Case Report Form  
eCRF Electronic Case Report Form  
CTCAE Common terminology criteria for adverse events 
EKOS Ethikkommission Ostschweiz 
GCP Good Clinical Practice  
GMP Good Manufactoring Practice 
HFG Humanforschungsgesetz (Law on human research) 
HMG Heilmittelgesetz  
HRA Federal Act on Research involving Human Beings 
ICU Intensive Care Unit 
IL-6 Interleukin-6 
IMC Intermediate Care Unit 
IMP Investigational Medicinal Product 
LBM lean body mass 
MD Medical Device 
MEGX Monoethylglycinexylidide  
NMDA N-Methyl-D-Aspartat 
NRS Numeric Rating Scale 
OSA obstructive sleep apnea 
PACU post anesthesia care unit 
PONV Postoperative Nausea and Vomiting 
SAE Serious Adverse Event 
SDV Source Data Verification  
SIRS Systemic Inflammatory Response Syndrome 
SOP Standard Operating Procedure 
SPC Summary of product characteristics 
SUSAR Suspected Unexpected Serious Adverse Reaction  
TIVA Total Intra Venous Anesthesia 
TMF Trial Master File 
VAS Visualized Analogue Scale  

  
 
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Compendious Flow Chart 
 

  
 
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1. STUDY ADMINISTRATIVE 
STRUCTURE  
1.1 Sponsor, Sponsor-Investigator 
The Sponsor and Sponsor/Investigator is Prof. Dr. med. Miodrag Filipovic, Vice-
Chairman, Klinik für Anästhesiologie, Intensiv-, Rettungs- und Schmerzmedizin, Kan-
tonsspital St. Gallen, St. Gallen, Switzerland. 
1.2 Monitoring Institution 
The Monitoring Institution is the Clinical Trials Unit, Kantonsspital St. Gallen,  
        
St. Gallen, Switzerland. 
1.3 Data Safety Monitoring Committee 
A Data Safety Monitoring Committee will not be required. 
 
 

  
 
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2. ETHICAL & REGULATORY 
ASPECTS 
2.1 Study registration 
The study will be registered in both the national (kofam.ch) and international (clinicaltri-
als.gov) clinical trial databases prior to start. 
2.2 Categorization of study 
As a clinical trial, we are comparing lidocaine 1% I.V. as an additional analgesic therapy 
to placebo with minimal expected additional risks to the participants due to our interven-
tion, this study falls is assigned to category B. Lidocaine 1% I.V. is authorized in Switzer-
land but not used according to the approved indication. 
2.3 Competent Ethics Committee (CEC) 
Prior to beginning the clinical study, the Principal Investigator shall ensure that approval 
has been obtained from the Competent Ethics Committee (Ethikkommission Ostschweiz 
(EKOS)). All significant changes in the conduct of the study and any unanticipated prob-
lems posting risks to the participants shall be reported to the CEC. Interruption or 
premature termination of the study shall be reported within 15 days to the CEC. The 
regular end of the study shall reported within 90 days, with submission of the final study 
report within one year after study end. 
2.4 Competent Authorities (CA)  
The trial was categorized as “Category B Clinical Trial”, being a trial evaluating a thera-
peutic product, which is authorized in Switzerland but not used according to the ap-
proved indication. Therefore, the trial requires an authorization from a Competent Au-
thority (Swissmedic). The study will begin once approval from required authorities has 
been received. 
 
 
 

  
 
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2.5 Ethical Conduct of the Study 
The study will be carried out in accordance to the protocol and with principles enunciat-
ed in the current version of the Declaration of Helsinki, the guidelines of Good Clinical 
Practice (GCP) issued by ICH, the Swiss Law and Swiss regulatory authority’s require-
ments. The CEC and regulatory authorities will receive anual safety and interim reports 
and be informed about study stop/end in agreement with local requirements.  
2.6 Declaration of interest  
None of the involved parties have any relevant conflicts of interest to disclose. 
2.7 Patient Information and Informed Consent 
The investigators will explain to each participant the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits, any discom-
fort it may entail and grant enough time for consideration. Each participant will be in-
formed that the participation in the study is voluntary and that he/she may withdraw from 
the study at any time and that withdrawal of consent will not affect his/her subsequent 
medical assistance and treatment. The participant must be informed that his/her medical 
records may be examined by authorised individuals other than their treating physician. 
All participants for the study will be provided a participant information sheet and a con-
sent form describing the study and providing sufficient information for participant to 
make an informed decision about their participation in the study. 
The patient information sheet and the consent form will be submitted to the CEC and to 
the competent authority to be reviewed and approved. The formal consent of a partici-
pant, using the approved consent form, must be obtained before the participant is sub-
mitted to any study procedure. 
The participant should read and consider the statement before signing and dating the 
informed consent form, and should be given a copy of the signed document. The con-
sent form must also be signed and dated by the investigator and it will be retained as 
part of the study records.  
Please refer to appendix for a copy of the Patient Information Brochure. 

  
 
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2.8 Participant privacy and confidentiality  
The Investigator affirms and upholds the principle of the participants’ right to privacy and 
that they shall comply with applicable privacy laws. Especially, anonymity of the partici-
pants shall be guaranteed when presenting the data at scientific meetings or publishing 
them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Subject confidentiality will be 
further ensured by utilizing subject identification code numbers to correspond to treat-
ment data in the computer files. 
For data verification purposes, authorized representatives of the Sponsor (/Investigator), 
a competent authority (e.g. Swissmedic), or an ethics committee may require direct ac-
cess to parts of the medical records relevant to the study, including participants’ medical 
history. 
2.9 Early termination of the study  
The Sponsor/Investigator may terminate the study prematurely according to certain cir-
cumstances, for example: 

ethical concerns, 

insufficient participant recruitment, 

safety issues,  

alterations in accepted clinical practice, making the continuation of a clinical trial 
unwise  

early, strong evidence of benefit or harm of the experimental intervention 
2.10 Protocol amendments 
Substantial amendments are only implemented after approval of the CEC and CA re-
spectively. Under emergency circumstances, deviations from the protocol to protect the 
rights, safety and well-being of human subjects may proceed without prior approval of 
the Sponsor and the CEC/CA. Such deviations shall be documented and reported to the 
Sponsor and the CEC/CA as soon as possible. 
All Non-substantial amendments are communicated to the CA as soon as possible if 
applicable and to the CEC within the Annual Safety Report (ASR).  

  
 
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3. BACKGROUND & RATIONALE  
3.1 Investigational product - Lidocaine 
The systemic application of lidocaine and other local anesthetics has been restricted to a 
few indications for a long time, for example the treatment of cardiac arrhythmias (1,12). 
For several years, systemic use of local anesthetics experiences a revitalization due to 
their approved and beneficial effects in daily routine of anesthesiology and treatment of 
chronic pain (2 - 4). Primarily, lidocaine has been known for its blocking effect on volt-
age-gated sodium channels and the associated inhibition of neuronal transmission, ba-
sis for anti-arrhythmic and anti-nociceptive properties (5 - 9). Furthermore, it shows so-
called alternative effects, which require considerably lower dosage as the mentioned 
effect on voltage gated sodium channels (10, 11). These specific drug concentrations 
can be found in patients` blood after receiving either an epidural injection or systemic 
application of lidocaine (3, 13, 14). Anti-hyperalgesic, anti-inflammatory properties and 
the reduction of bronchial hyperactivity are among these alternative effects (15 - 19). In 
addition, perioperative hypercoaguability seems to be reduced (20). Most of these quali-
ties apply for all local anesthetics, but have just been suitable for lidocaine in clinical 
practice due to its advantageous features and the well reviewed potential of side effects 
during the treatment of cardiac arrhythmias (21, 22, 52). Anti-nociceptive and anti-
hyperalgesic properties might be a result of G-protein receptor modification, as well as 
an interaction with glyceinergic synaptic neurons and an inhibition of NMDA receptors. 
This might also be an explanation for the influence on inflammatoric and hemostatic me-
diators (6, 23, 24). Lidocaine conducts a modification of an excessive inflammatory re-
sponse due to surgical intervention and hereby induced postoperative complications as 
suppressed gastrointestinal function, pain and sepsis (25 - 27). Careful titration allows a 
high degree of selectivity in the inhibition of sensory neurons, in contrary to higher con-
centrations, which also affect other modalities of neuronal signaling. The same principle 
applies for cardiac actions. Blocking sodium channels in the conduction system, as well 
as the muscle cells of the heart, raises the depolarization threshold, making the heart 
less likely sensitive to initiate or conduct early action potentials that may cause an ar-
rhythmia. When used as an injectable, it typically initiates its effect within four minutes 
and lasts for 30 minutes to three hours. Lidocaine is metabolized by hepatic cells to 95% 
mainly by cytochrome P450 3A4 to the pharmacologically active metabolites monoethyl-

  
 
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glycinexylidide (MEGX) and then subsequently to the inactive glycine xylidide. MEGX 
has a longer half-life than lidocaine, but also is a less potent sodium channel blocker. 
(47 - 49) Lidocaine elimination in patients with liver cirrhosis was examined by Wojcicki 
et al.. Their findings indicated higher plasma concentrations of lidocaine and lower con-
centration of MEGX, dependent on the stage of liver dysfunction (Child-Pugh A to C). 
(57) Current studies, setting the focus on abdominal surgery, indicated that the systemic 
application of lidocaine was associated with fewer intensity of pain at rest and during 
mobilization and resulted in a decrease of patients’ opiate consumption. Studies evaluat-
ing patients receiving orthopedic and neurosurgical interventions did not show any bene-
fit from lidocaine I.V. (28 - 30). This discrepancy is most likely explained by the different 
development of inflammation due to visceral and somatic pain induction. Noteworthy is 
the fact, that local anesthetics can suppress the overreacting immune-signaling due to 
surgical intervention, without interfering with the physiological immune-signaling. Studies 
showed an inhibition of white blood cells’ priming (as a principle for immune-reaction, the 
prearrangement of granulocytes to a following inducing signal leads to a up to 20-times 
exaggerated release of superoxides) due to the implementation of systemic lidocaine. 
Interestingly, lidocaine impedes the priming, which represents a common reaction to 
tissue damage induced by surgery, without inhibiting the classic activation of neutrophil 
granulocytes. (31) A major reason for patients’ discomfort, prolonged recovery, length of 
hospital stay and thereby resulting, higher morbidity and increased financial costs, are 
post-surgical complications, especially gastrointestinal dysfunction and postoperative 
nausea and vomiting (PONV) due to surgical inflammation and increased opiate con-
sumption. Average incidence of PONV after abdominal surgery in general anesthesia 
ranges between 25 – 30%. Pathogenic mechanisms are complex but are traced back to 
the nerval and inflammatory response and stimulation after surgical interventions. A 
study by Groudine et al. showed that patients receiving systemic lidocaine during radical 
prostatectomy regained gastrointestinal motility faster and required less opiates after the 
intervention compared to an application of placebo during surgery. (32, 33) However, 
lidocaine seems to be profitable to patients undergoing abdominal surgery as meta 
analyses demonstrate. Inhibition of myenteric plexus reflex as a target might play a role 
in the effectiveness of systemically administered lidocaine, as well as a reduction of in-
terleukin-6 (IL-6) which could be significantly reduced in a study examining patients re-
ceiving systemic lidocaine during colorectal surgery (32, 34). 

  
 
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3.2 Data currently available  
A meta-analysis by Weibel et al. has investigated 45 studies related to the preoperative 
application of lidocaine referring to a reduction of postoperative pain, early regaining of 
gastrointestinal motility, length of hospital stay, development of PONV, total opiate con-
sumption, surgical complications and occurrence of adverse effects due to intervention. 
Most studies compared lidocaine with a placebo, two studies compared the systemic 
application with epidural analgesia. Findings show that lidocaine was capable to reduce 
postoperative pain within the first four hours after surgery compared with placebo. How-
ever, there was no evidence for reduction of postoperative pain for the time beyond. The 
positive effect of lidocaine on postoperative pain was just verified in patients receiving 
major or laparoscopic bowel surgery. Considering that lidocaine had positive effects on 
regaining gastrointestinal function, length of hospital stay, development of PONV and 
total opiate consumption in these patients. However, data is lacking for patients with 
high need for opiates, as commonly seen in bariatric surgery. The occurence of adverse 
effects was examined in 17 studies, but there was no evidence of higher risk for lido-
caine intoxication, cardiac arrhythmias or death. (41) Another meta-analysis from 
McCarthy et al. also showed a reduction of postoperative pain and total opiate consump-
tion in patients receiving major bowel surgery. Compared to control groups, participants 
receiving systemic lidocaine required up to 85% less opiates. Positive effects on gastro-
intestinal function and length of hospital stay could also be confirmed. De Oliveira et al. 
examined the effects of systemic lidocaine compared to placebo, laying their focus on 
patients scheduled for bariatric surgery. They also confirmed opiate sparing effects and 
a higher level of satisfaction after 24 hours of patients treated with lidocaine, however no 
other study focused on this kind of patient collective. (50) In summary, the systemic ap-
plication of lidocaine as an additional analgesia is a safe and meanwhile an approved 
method, also implemented in the perioperative setting of abdominal, thoracic and ortho-
pedic surgery at the Kantonsspital St. Gallen. (3) Although several studies suggested a 
beneficial outcome for patients treated with systemic lidocaine in major bowel surgery, 
just few compared its efficacy to an epidural analgesia (EDA). Staikou et al. examined 
postoperative pain levels, length of hospitalization and gastrointestinal function of pa-
tients undergoing large bowel surgery and either treated with systemic lidocaine or EDA 
and showed that patients treated with lidocaine were not inferior to the analgesic effect 
of EDA. (35, 36) 

  
 
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19 
3.3 Dose Rationale 
Though varying dosages are described in current studies, updated literature recom-
mends a bolus of 1.5 mg/kg bodyweight lidocaine 1% for induction of anesthesia fol-
lowed by a continuous infusion with 1.5 mg/kg bodyweight/h until transfer to the PACU. 
Determination of dose adjustment in obese patients has been described in literature by 
Janmahasatian et al. Total bodyweight or BMI measurement will not give reliable infor-
mation about biological activity and metabolism. Therefore, an approach to measure 
body composition via lean body mass (LBM) function has been recommended. (58) 
Based on these recommendations, dosage of lidocaine in our study will be determined 
via scaled LBM, assuming a standard patient with 70 kg weight and 170 cm height. A 
detailed version of the calculator can be found in the appendix. Furthermore, originally 
indicated for treatment of major arrhythmias and status epilepticus, the use of systemic 
lidocaine 1% I.V. is authorized in Switzerland but not used according to the approved 
indication. (10, 37 - 40, 52) 
3.4 Explanation for choice of placebo 
A placebo, a pharmaceutically inert agent, will be used to detect and prove superiority of 
a new treatment, i.e. investigation of additional analgesic agents in opposition to no ad-
ditional treatment. A placebo-controlled trial is regarded as the gold standard to detect 
efficacy of a new treatment. Participants of the study will be fully informed of the risks 
involved in assignment to the placebo group, though management in the placebo group 
equals our current clinical routine and no standard treatment will be withheld from this 
group of patients. This is specifically true for the analgesic regime. The agent used as 
placebo will be saline 0.9% as an injectible. Adverse effects due to rapid infusion can be 
neglected, as participants will receive minor volumes of saline 0.9%. Further information 
about saline 0.9% will be provided in the summary of product characteristics in the ap-
pendix. 
3.5 Risks and Benefits 
Just a few studies described the occurrence of adverse effects in patients treated with 
systemic lidocaine. A recently published work showed a comparable incidence of ad-
verse effects in patients treated with systemic lidocaine versus treatment with placebo. 
(51) Historically, treatment of cardiac dysrhythmias after myocardial infarction was per-

  
 
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20 
formed with lidocaine I.V. and studies described minor side effects like dizziness and 
„ear ringing“ after continuous infusion of 2 up to 6 mg/min lidocaine 2%. (52) Anyway, 
indication for systemic lidocaine needs to be strictly evaluated and, according to pa-
tients` risk potential for advert effects thoroughly selected. Contraindications for the ap-
plication of systemic lidocaine comprise identified allergies to local anesthetics, a reduc-
tion in hepatic function as well as serious cardiac arrhythmias. First signs of intoxication 
occur after reaching plasma levels of 5 µg/ml and more. Based on their effect on voltage 
gated sodium channels, neurological and central nervous stimulation become apparent, 
followed by inotropic and bathmotropic effect-related cardiac failure. (42, 43) Based on 
anti-inflammatory effects, a higher susceptibility to infection has been discussed and has 
been confirmed in small investigations with rats. However, most studies showed a suffi-
cient function of leucocytes and furthermore postulated anti-bacterial properties in vitro 
and in vivo. (44 - 46) Further information about expectation of adverse effects and safety 
reference information can be found in the prescribing information for lidocaine 1%, pro-
vided by Streuli Pharma. Obesity is a major factor for postoperative respiratory compli-
cations, especially in patients with confirmed or suspected obstructive sleep apnea 
(OSA). Increased risk of perioperative morbidity and mortality developes because of po-
tential difficulty in maintaining patients` airway. Aggravation of OSA due to sedation, an-
algesia or extended effects and accumulation of narcotic agents, especially opiates, has 
been described. (53) Generally, regional analgesic techniques, like epidural analgesia 
should be considered to reduce or eliminate the requirement for systemic opiates, how-
ever difficulties in location and correct placement of epidural catheters can occure due to 
impeded anatomical proportions in obese patients. Practice guidelines for the manage-
ment of patients with OSA, have been published by the American Society of Anesthesi-
ologists, recommending well-considered use of sedatives and opiates for the peri- and 
postoperative course in this group of patients. (54) The application of lidocaine as an 
additional analgesia during  bariatric surgery gives hope to reduce the before mentioned 
complications and adverse effects due to increased opiate consumption, to assure a 
postoperative phase more comfortable and less branded by side effects for the patient. 
Therefore, the study was designed to investigate if the proportion of patients suffering 
from higher pain intensity (any development of VAS/NRS score > 3, in hourly measure-
ments) within first four hours after bariatric surgery can be reduced by preoperative lido-
caine infusion. Secondary endpoints will include the total opiate consumption of patients, 

  
 
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21 
occurence of adverse effects due to opiates, time to first defecation and total length of 
hospitalization. 
3.6 Standardized procedures  
Since our institute cares for anesthesia in up to 150 patients per year in bariatric sur-
gery, we want to optimize the outcome and postoperative analgesia for patients and 
guarantee a phase free of pain and other complications. The intervention is usually pro-
ceeded laparoscopically, with an average length of 120 minutes. Overweight patients 
with a mean BMI of 38 points, receive general anesthesia (TIVA and initial fentanyl ap-
plication of 0.6 - 1.0 mg I.V.). After completion of surgery, patients are transferred to 
PACU for further observation and treatment. Emphasizing, these patients require almost 
double amount of opiates in the perioperative setting, than patients receiving laparo-
scopic appendectomy or hemicolectomy, as well as during the postoperative phase. The 
adverse effects of an increased opiate consumption like nausea, vomiting, hypopnea, 
pruritus and reduced gastrointestinal function are commonly aggravating the symptoms 
of pre-existing diseases like sleep apnea syndrome, reduced functional residual capaci-
ty, due to higher intraabdominal mass and thereby caused dyspnoea. Based on in-
creased pain levels, these patients receive up to 1.0 mg fentanyl during the first four 
hours after completion of surgery to cope with pain. Additionally, PONV, induced by opi-
ates, presents a major discomfort for these patients. 
 
4. STUDY OBJECTIVES  
4.1 Primary study objective 
To investigate if intravenous administration of lidocaine 1% I.V. in patients undergoing 
bariatric surgery reduces postoperative pain intensity within the first four hours after 
completion of surgery. 
4.2 Secondary study objective 
To investigate if the experienced average maximal pain intensity and the total opiate 
consumption of patients who underwent bariatric surgery can be reduced during the first 
four hours and 48 hours by perioperative lidocaine infusion. 

  
 
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22 
4.3 Other objectives of interest 
Other objectives of interest are as follows: 
- Monitoring of PONV and its distribution between the groups.  
- Comparing time to first defecation after completion of surgery in both groups in regard 
of a beneficial effect in the “lidocaine group”. 
- Comparing length of hospitalization of both groups in regard of a beneficial effect in the 
“lidocaine group”. 
5. STUDY OUTCOMES 
5.1 Primary outcome  
Any development of VAS/NRS score > 3, in hourly measurements within the first four 
hours after completion of bariatric surgery.  
5.2 Secondary outcome 
Average experienced maximal pain during the first four hours and 48 hours (in hourly 
measurements on PACU and in eight-hourly measurements on surgical ward) is as-
sessed by VAS/NRS score. The total amount of opiates (given during surgery and on 
PACU and administrated on surgical ward).  
5.3 Other outcomes of interest 
- any event of postoperative nausea and vomiting (subdivided by event of no nausea 
(PONV = 0), event of nausea without vomiting (PONV = 1) and event of nausea with 
vomiting (PONV = 2)) during first 48 hours after completion of surgery  
- time to first defecation (quantified in hours) 
- duration of hospitalization (quantified in days) 
5.4 Safety outcomes 
Vital parameters (blood pressure, pulse rate, oxygen saturation) will be recorded digitally 
by the electronic acute care patient data management system (ACPDMS) during the 
peri- and postoperative phase and according to institutional standards. Incidence of any 
potential adverse events (AE) requiring treatment attributable to lidocaine (e.g. local skin 
reactions, nausea, vomiting, dizziness, ear ringing, etc.), serious adverse events (SAE) 
(cardiac arrhythmia with relevant hemodynamic outcome, cardiac arrest) or adverse 

  
 
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23 
events related to opiates (respiratory adverse events, ileus). Other outcomes of interest, 
precisely PONV will not be accounted for an AE. 
 
6. STUDY DESIGN  
6.1 General study design and justification of design  
The study design will be randomized, double blinded and placebo controlled. All patients 
complying our inclusion criteria will be included to the selection procedure. Patients will 
be informed about the study sequence during preoperative anesthesiological consulta-
tion to give their informed consent. Patients` data will be subsequently integrated to the 
eCRF. Each participant will be linked with a unique identification code which will be used 
for continuing process. Furthermore, information about sex, date of birth, date of sur-
gery, indication, BMI, ASA classification, medical history and allergies will be recorded. 
Patients denying informed consent will be excluded from the pool of selected patients. 
The intervention to be studied will either be the additional application of systemic lido-
caine 1% dosed 1.5 ml/kg LBM to general anesthesia in bariatric surgery or the applica-
tion of placebo. Patients, randomly assigned to one study group, will be surveyed for 48 
hours after completion of surgery, experienced pain, occurrence of PONV, time to first 
defecation and length of hospitalization will be monitored. The population to be studied 
will include 140 patients listed for bariatric surgery at the Kantonsspital St. Gallen and 
fulfilling criteria for inclusion, respectively without criteria for exclusion. Patients, medical 
practitioner, nurses and investigators will be blinded by utilization of equal appearance 
and packing of IMPs, which will be fabricated individually for each patient and on request 
one to two days before surgery by the pharmacy of the Kantonsspital St. Gallen. Each 
patient will self-evaluate his maximal experienced pain eight-hourly during a sequence of 
48 hours after completion of surgery. Study observation ends with study nurses` final 
visit on second postoperative day 2pm respectively +/- 30 minutes.  
6.2 Methods of minimizing bias  
Measures taken to minimize or avoid bias include randomization and blinding of partici-
pants after they have given their informed consent. Blinding of medical practitioner and 
medical personel will be conducted by provision of equal looking and packing of IMPs, 

  
 
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24 
which will be fabricated individually for each patient and on request one to two days be-
fore surgery by the pharmacy of the Kantonsspital St. Gallen.  
6.3 Randomization  
Patients selected to participate will be randomized automatically after giving their in-
formed consent using a computerized block randomization process (10 patients per 
block). Patients will be randomized 1:1 to either “lidocaine group” or “placebo group”. 
6.4 Blinding procedures  
All patients will be blinded to their randomization. Attending physician and other person-
nel responsible for patients` care (peri- and postoperative) will be blinded. Syringes used 
for application of interventional drugs will be blinded, labelled as “interventional drug”. 
Unblinding, in case of SAE or suspected unexpected serious adverse reactions and to 
guarantee patients safety, will be executed by the Principal Investigator.  
6.5 Unblinding procedures  
Should it be necessary to unblind a patient for safety or regulatory reasons, the Principal 
Investigator shall look up the randomization, which will be kept in a separate envelope, 
containing information about randomization and leads back to specific IMP of each par-
ticipant of the study. 
 
7. STUDY POPULATION  
7.1 Inclusion 
Adult patients listed for elective laparoscopic bariatric surgery, age between 18 – 80 will 
be screened for inclusion.  
7.2 Exclusion 
The presence of any of the following exclusion criteria will lead to exclusion of the partic-
ipant: 
- Patients without informed consent, contraindication to the class of drugs under study, 
e.g. known hypersensitivity or allergy to class of drugs or the investigational product, 
cardiac arrhythmias, liver dysfunction (Child-Pugh classification A, B or C)   

  
 
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25 
- Women who are pregnant or breast feeding 
- Patients suffering from central nervous diseases, which affect structure and function 
of the brain or the spinal cord (including autism, bipolar disorders, catalepsy, depres-
sion, encephalitis, epilepsy, locked-in syndromes, meningitis, multiple sclerosis, mye-
lopathy Tourette’s syndrom and neurodegenerative disorders like Alzheimer’s dis-
ease, Huntington’s disease and Parkinson’s disease) 
- Chronic pain with pre-existing enteral or transdermal opiate prescription or any known 
drug or alcohol abuse.  
- Patients with previous enrolment into the current study, enrolment of the investigator, 
his/her family members, employees and other dependent persons will be excluded 
from the screening 
7.3 Recruitment and informed consent 
Patients’ recruitment will take place during preoperative anesthesiological consultation, 
which regularly takes place two to three weeks prior hospitalization. Patients will be 
screened for eligibility using a checklist based on inclusion and exclusion criteria and 
previous medical history. Informed consent will be obtained in all patients prior to inclu-
sion to the study and randomization process. Patients denying inclusion to the study will 
be documented as having been screened. 
7.4 Assignment to study groups  
Patients given their informed consent will be randomly assigned to either the “lidocaine 
group” or the “placebo group”. Randomization will be conducted by the statistician of the 
study using a computerized block randomization process (10 patients per block). Pa-
tients will be randomized 1:1 to either “lidocaine group” or “placebo group”. 
7.5 Criteria for withdrawal / discontinuation of participants  
The criteria for withdrawal of participants are either the request of participants to be 
withdrawn from the study or SAE, related to exercise of IMPs or other medication aplli-
cated during general anesthesia, including signs of cardiac arrhythmia or other evidence 
of drug incompatibility resulting in hemodynamic instability.  
 

  
 
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8. STUDY INTERVENTION  
8.1 General information 
Patients will randomly be allocated either to the “lidocaine group“, or the “placebo 
group”. The only difference between both groups will be the implementation of a system-
ic lidocaine infusion during perioperative phase. Allover management and techniques of 
anesthesia will be handled as described in the current “Standard Anaesthesie KSSG”. It 
includes detailed description of anesthesiological procedures for specific surgical inter-
ventions. Patients listed for bariatric surgery receive detailed information about anesthe-
siological techniques, course and management of adverse effects due to medical side 
effects or surgical complications during the preoperative anesthesiological consultation. 
On the day of surgery, the patient will receive premedication of 1 mg paracetamol p.o. 
one hour before planned intervention. Apart from the study intervention, standard anes-
thetic technique and pain management (related to practice of the anesthesiological 
standard of the Kantonsspital St. Gallen will be used in all the patients at the discretion 
of the attending anesthesiologist (use of alternative aminoamid local anesthetics, as ad-
ditional analgesic will be prohibited during treatment and hospitalization of patients in-
cluded to the study). After securing intravenous line, monitoring will be installed. Base-
line parameters will be observed and recorded in the ACPDMS. Fentanyl (≈ 0.002 … 
0.003 mg/kg) will be given intravenously two minutes before the induction of anesthesia 
in both groups. Airway management in patients with a mean BMI > 35 kg/cm2 is per-
formed by fiberoptic nasal intubation in awake condition. Nasal drops (0.25 ml cocainhy-
drochloride 10%) will be applicated and transcricoidal application of 2 ml lidocaine 1% 
for anesthesia of the upper airway will be performed before advancing the fiberscope 
into the trachea. As soon as vocal cords are crossed, induction of general anesthesia 
will be induced with etomidate 0.2 mg/kg bodyweight. Thereafter the nasotracheal tube 
is placed. Anesthesia will be maintained by target controlled infusion of propofol 1% and 
remifentanil 40 µg/ml according to institutional standards in all patients. Neuromuscular 
blockade will be achieved by bolus followed by continuous administration of rocuronium 
as clinically necessary. 
Study intervention: Patients in the “lidocaine group” will receive 1.5 mg/kg lean body 
mass of lidocaine 1% bolus intravenously after induction of general anesthesia (as soon 

  
 
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27 
as general anesthesia’s steady state is accomplished), followed by a continuous infusion 
of lidocaine 1% with 1.5 mg/kg lean body mass/h during surgery and continued for four 
hours after completion of surgery or until the discharge from the PACU, whatever comes 
first. Patients in “placebo group” will receive 0.15 ml/kg lean body mass of saline 0.9% 
bolus I.V. after induction of general anesthesia (as soon as general anesthesia’s steady 
state is accomplished), followed by continuous infusion of NaCl 0.9% I.V. with 0.15 ml/kg 
lean body mass/h during surgery and continued for four hours after completion of sur-
gery or until the discharge from the PACU, whatever comes first. Maintenance of gen-
eral anesthesia and optional application of additional opiates for pain treatment (fentanyl 
0.1 - 0.2 mg as an intravenous bolus) during surgery is under discretion of the attending 
anesthesiologist and is related to the practice of standardized pain management and will 
be equal in both groups. Similarly, postoperative treatment in the PACU and further on 
the surgical ward, are under discretion of the clinically responsible physicians, relating to 
current practice of standardized pain management at the Kantonsspital St. Gallen 
(Schmerzkarte KSSG).  
 

  
 
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A detailed graphical version of study sequences is provided in german as follows:
Periode 
 
Ort 
Intervention 
 
Details 
Anmeldung 
 
Studien-
koordination  
Screening 
 
Ein- / Ausschlusskriterien 
evaluieren 
 
 
 
I 
 
 
 
 
 
erfüllt 
 
 
 
 
 
I 
 
 
PAS Termin 
 
PAS 
Informed consent 
 
Aufklärung und Einwilligung 
durch Patienten 
 
 
 
I 
 
 
 
 
 
erfüllt 
 
 
 
 
 
I 
 
 
PAS Termin 
 
PAS 
Randomisierung 
 
Zuteilung zur Gruppe Lidocain 
oder Placebo 
 
 
 
I 
 
 
OP Datum 
 
OPS 03 
Intervention COALAS 
 
 
- IMP Bolus ab AN steady state 
- anschliessend Beginn IMP 
Perfusor  
- Datenerfassung ACPDMS 
(Medis, Vitalparameter) 
- AE, SAE, ADR erfassen 
 
 
 
Transfer 
 
 
POD 0 
 
PACU 
VAS Monitoring  
VAS Evaluationsbogen 
 
- IMP Perfusor bis 4 Std. ab 
“OP-Ende” od. Transfer auf 
Abteilung 
- VAS 1.,2.,3.,4. Std.  
- Datenerfassung ACPDMS 
(Medis, Vitalparameter) 
- Prim./Sek. Variablen im CRF 
erfassen 
- AE, SAE, ADR erfassen 
 
 
 
Transfer 
 
 
POD 0 
 
ABTEILUNG 
VAS Monitoring 2pm, 10pm 
 
Studienvisite 10am, 2pm 
 
- Erinnerung des Pat. durch 
Pflege- Studienpersonal 
- Prim./Sek. Variablen im CRF 
erfassen 
- AE, SAE, ADR erfassen 
POD 1 
 
ABTEILUNG 
VAS Monitoring 6am, 2pm, 10pm 
 
Studienvisite 10am, 2pm 
 
- Erinnerung des Pat. durch 
Pflege- Studienpersonal 
- Prim./Sek. Variablen im CRF 
erfassen 
- AE, SAE, ADR erfassen 
POD 2 
 
ABTEILUNG 
VAS Monitoring 6am, 2pm 
 
Studienvisite 10am, 2pm 
(Safety follow-up) 
 
- Erinnerung des Pat. durch 
Pflege- Studienpersonal 
- Prim./Sek. Variablen im CRF 
erfassen 
- AE, SAE, ADR erfassen 
 
 
 
 
 
 
POD X 
 
Studien-
koordination 
Safety follow-up 
 
- telefonisch / ambulant 
- AE, SAE, ADR erfassen 
 
 table 2: study sequence describing process and daily course, POD X will be postoperative day seven or day of patients discharge 

  
 
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29 
 
 
8.2 Identity of Investigational Products 
Lidocaine hydrochloride 1% by Streuli Pharma is a sterile, nonpyrogenic solution of lido-
caine hydrochloride in water for injection for parenteral administration. Dosage of 1.5 
mg/kg LBM will be calculated individually. Injection of 1.5 mg/kg LBM bolus will be per-
formed as soon as steady state concentration of general anesthesia is accomplished. 
Steady infusion of lidocaine 1.5 mg/kg/h LBM will be initiated with the beginning of surgi-
cal procedures and estimated duration of infusion will be four hours after completion of 
surgery (expecting an average of two hours of surgery and four hours monitorization in 
PACU till transfer to surgical ward). Dosage and average duration of application repre-
sents references in current literature. 
Additional IMP in placebo group will contain saline (Natrii chloridum 0.9%), which will be 
provided by Grosse Apotheke Dr. G. Bichsel AG. Dosage of 0.15 ml/kg LBM will be cal-
culated individually and represents an equivalent amount (in ml) of IMP used in the in-
terventional group. Injection of 0.15 ml/kg LBM bolus will be performed as soon as 
steady state concentration of general anesthesia is accomplished. Steady infusion of 
NaCl 0.9% 0.15 ml/kg/h LBM will be initiated with the beginning of surgical procedures 
and estimated duration of infusion will be four hours after completion of surgery (expect-
ing an average of two hours of surgery and four hours monitorization in PACU till trans-
fer to surgical ward).  
8.3 Packaging, Labelling and Supply 
Lidocaini hydrochloridum (Lidocaine Streuli®) will be provided by Streuli Pharma AG, 
Switzerland (Swissmedic registration number: 300 16). 
Saline (Natrii chloridum 0.9%) will be provided by Grosse Apotheke Dr. G. Bichsel AG, 
Switzerland (Swissmedic registration number: 298 00). 
Syringes and ampulles containing the IMPs (Lidocaine 1% or Saline 0.9%) used during 
the study will be labelled notably. Distinct labels for ampulles and syringes include in-
formation about IMPs`origin, charge number, dedicated patient`s ID, fabrication and ex-
piration date (see appendix for a detailed graph of IMP labels). Blinded personel (practi-
tioner, nurses, surgeon, etc.) will not be able to distinguish between the containing IMPs 

  
 
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30 
due to identical appearance and labeling. An additional code to reproduce its origin will 
also be visible. No special storage conditions are needed for the IMPs. Prepackaging, 
assembly, blinding procedure and labeling of syringes will be organized by the pharmacy 
of the Kantonsspital St. Gallen. Personel related to the peri- and postoperative course 
(anesthesiology, surgery, PACU, follow-up on surgical ward) will be blinded by the 
above-mentioned methods. Study specific labeled syringes will be fabricated individually 
for each patient and on request one to two days before surgery and will be delivered to 
the OR on the day of surgery and preparation of syringes (connection to syringe pump) 
will be conducted by anesthesiological employees. 
To ensure product safety for human consumption/application, Good Manufactoring Prac-
tice will be conducted. 
8.4 Administration of experimental and control interventions  
Experimental Intervention („lidocaine group“) 
Lidocaine 1% will be administered I.V., 1.5 mg/kg lean body mass will be given as bolus 
when general anesthesia steady state concentration is accomplished, 1.5 mg/kg lean 
body mass/h will be given as continuous infusion with beginning of surgical procedures  
and up to four hours from completion of surgery, or till transfer to surgical ward.    
Control Intervention (“placebo group”) 
The management of patients in the placebo group equals our current clinical routine and 
no standard treatment is withheld from this group of patients. This is specifically true for 
the analgesic regime.  
Saline 0.9% will be administered I.V., 0.15 ml/kg lean body mass will be given as bolus 
when general anesthesia steady state concentration is accomplished, 0.15 ml/kg lean 
body mass/h will be given as continuous infusion with beginning of surgical procedures 
and up to four hours from completion of surgery, or till transfer to surgical ward. 
8.5 Dose modifications  
If SAE will be recognized, infusion of investigational product will be stopped and ar-
rangements conducted to treat potential adverse effects and ensure patients` safety. 
The Principal Investigator will be informed about the incident within 24 hours. 

  
 
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8.6 Compliance with study intervention  
Patients will be informed during preoperative anesthesiological consultation and give 
their informed consent. Patients denying informed consent will be excluded from the 
pool of selected patients. During consultation, patients will be informed about general 
study sequences, process of drug administration, differences between the interventional 
and placebo group and the postoperative sequence. The detailed version of patients’ 
information is given in the appendix. In addition, general information about risk of anes-
thesia and perioperative adverse events are explained during the pre-anaesthesia visit 
and are part of the “Consent to Anaesthesia” (“Patienteneinwilligung”) according to insti-
tutional practice.  
8.7 Trial specific preventive measures 
Apart from the study intervention, standard anesthetic technique will be used in all pa-
tients at the discretion of the attending anesthesiologist. Medication and treatment plans 
which are permitted before and/or during the trial include the medication and treatment 
plans listed in the „Kantonsspital St. Gallen – Standard Anästhesie“. Equipment and 
medication for resuscitation and treatment of adverse events occurring during and after 
anaesthetic procedures are available in all operation theatres, the PACU and intensive 
care unit according to institutional standards. In addition, trained personal is continuous 
available in these locations. Accordingly, no study specific measures are necessary. Vi-
tal parameters (blood pressure, pulse rate, oxygen saturation) will be recorded and pos-
sible deviations resulting in clinical relevant consequences treated immediately by at-
tending anesthesiologist. Incidence of any potential AE, SAE due to application of IMPs 
will be documented and treated (e.g. local skin reactions, nausea, vomiting, dizziness, 
ear ringing, cardiac arrhythmia with relevant hemodynamic outcome or cardiac arrest) or 
adverse events related to opiates (e.g. hypoventilation). 
8.8 Concomitant Interventions (treatments)  
Apart from the study intervention, standard anesthetic technique and perioperative med-
ication will be used in all the patients at the discretion of the attending anesthesiologist. 
Accordingly, different treatment options and drugs are allowed. These include current 
medical treatment options applied by the Kantonsspital St. Gallen. Patients will be in-

  
 
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32 
formed about treatment options during preoperative anesthesiological visit. Induction of 
anesthesia will be performed in line with the „Standard Anästhesie“ of the Kantonsspital 
St. Gallen. These treatments will have no impact on the effect of the IMPs. Postopera-
tive pain management will be performed according to current clinical standards 
(Schmerzkarte KSSG). 
8.9 IMPs / Medical Device Accountability  
IMP Lidocaine will be provided by Streuli Pharma AG, Switzerland and IMP saline will be 
provided by Grosse Apotheke Dr. G. Bichsel AG, Switzerland. Storage and distribution 
will be organized by the pharmacy of the Kantonsspital St. Gallen, as well as prepackag-
ing, assembly, blinding procedure and labeling. Adequate records about maintenance, 
shipment to the site, return or disposal of remaining or expired IMPs, physical location, 
dates of receipt, expiry, use and return, stock numbers and quantities received, used or 
destroyed will be recorded, referring to GMP. The pharmacy of the Kantonsspital St. 
Gallen is certified with the cantonal approval of manufacturing (kantonale Herstellungs-
bewilligung). 
 
9. STUDY ASSESSMENTS  
9.1 Study flow charts / table of study procedures and as-
sessments 
Please refer to appendix for a detailed graph of the study procedures and assessment 
plans. 
9.2 Assessments of outcomes  
Assessment of Pain 
Pain will be assessed by the visual analogue scale (VAS) or the numeric rating scale 
(NRS), respectively, 0 indicating no pain and 10 maximal possible pain sensation. 
VAS/NRS scoring systems are validated and frequently used methods to evaluate varia-
tions in pain intensity. The VAS/NRS score will be recorded by trained nurse practition-
ers in the PACU, respectively on the surgical ward, once per hour during the first four 
hours after completion of surgery. Analysis of the primary outcome (any development of 

  
 
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33 
VAS/NRS score > 3, in hourly measurements within the first four hours after completion 
of surgery) will be dichotomized accordingly. Thereafter, VAS/NRS score will be as-
sessed by a patient questionnaire for self-evaluation and in addition by trained nurse 
practitioners during their daily round (10am and 2pm respectively +/- 30 minutes) during 
the first 48 hours after completion of surgery. Missing postoperative VAS/NRS scores, 
required for primary and secondary endpoints, will be handled as interpolation values, 
calculating an average score between last recorded scores before and after the missing 
value. 
Secondary endpoints 
- Average maximal pain intensity during first four hours and during 48 hours 
- total amount of opiates as documented in the electronical anesthesia records during 
surgery and on PACU 
- total amount of opiates applicated on surgical ward, recorded in the charts. Values will 
be categorized in total amount in mg, average amount in mg/h and indexed amount in 
mg/kg bodyweight/h 
- any event of postoperative nausea and vomiting (subdivided by event of no nausea 
(PONV = 0), event of nausea without vomiting (PONV = 1) and event of nausea with 
vomiting (PONV = 2)) during first 48 hours after completion of surgery 
- time to first defecation after completion of surgery (quantified in hours) 
-   total time spent in hospital after completion of surgery (quantified in days) 
9.3 Assessments of safety outcomes  
Vital parameters (blood pressure, pulse rate, oxygen saturation) will be recorded digitally 
by the electronic acute care patient data management system (ACPDMS) during the 
peri- and postoperative phase and according to institutional standards.. During the entire 
surgical and anaesthetic procedure and in the PACU trained personnel will be present 
monitoring vital parameters and the patient clinical status. Every deviation to normal 
course will be treated and recorded according clinical standards of the institution. SAE  
related to the administration of the IMP will cause an immediate cessation of the drug 
administration and will be reported to the Sponsor Investigator not later than 24 hours 
after the event.  

  
 
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9.4 Procedures at each visit 
Each patient will be visited after surgical treatment and transfer to PACU/ICU by a study 
nurse or the Study Investigator. The VAS/NRS score (registration of any development of 
VAS/NRS score > 3) will be assessed by trained nurse practitioners in the PACU/ICU in 
hourly measurements during the first four hours after completion of surgery, respectively 
until discharge to the surgical ward. Thereafter, VAS/NRS score will be assessed by a 
patient questionnaire for self-evaluation and in addition by trained nurse practitioners 
during their daily round (10am and 2pm respectively +/- 30 minutes) during the first four 
hours and during 48 hours after completion of surgery. VAS/NRS scores and vital pa-
rameters will be recorded. Incidental questions about upcoming study process will be 
answered. Infusion of the investigational product will be stopped four hours after the end 
of surgery (or before the transfer of the patient from the PACU to the surgical ward, 
whichever occurs first). Pain evaluation will take place every eight hours by recording 
the maximum VAS/NRS score experienced within this period. Recording of VAS/NRS 
scores will be stopped at 2pm respectively +/- 30 minutes on second postoperative day. 
Completion of study investigation will be finalized by collecting the study documents at 
study nurses final visit on second postoperative day at 2pm respectively +/- 30 minutes.  
10. STATISTICAL METHODS  
10.1 Statistical considerations 
Determination of sample size was performed by retrospective analysis of 50 patients` 
records, listed for bariatric surgery at the Kantonsspital St. Gallen in the year 2015. Ex-
perienced pain score determined as VAS/NRS score, amount of opiates required and 
occurence of PONV in the postoperative periode were reviewed and examined. Com-
pared to other laparoscopically performed surgeries, patients undergoing a bariatric in-
tervention reported higher postoperative pain levels and required more opiates. In total, 
35 of 50 patients showed an average VAS/NRS score > 3 during the first four hours after  
surgery. This accounts for 65% regarding the whole population examined. Average 
VAS/NRS score after eight hours was > 3 in 35% of patients. 

  
 
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10.2 Hypothesis 
Null hypothesis: perioperative treatment of patients undergoing bariatric surgery with 
lidocaine has no impact on postoperative quality of analgesia. 
Alternative hypothesis: perioperative treatment of patients undergoing bariatric surgery 
with lidocaine reduces the proportion of patients suffering from more intensive pain (any 
development of VAS/NRS score > 3, in hourly measurements) within the first four hours 
from currently 65% to 35%.   
10.3 Determination of Sample Size  
With an expected postoperative VAS/NRS score (any development during first four 
hours after completion of surgery) of > 3 points in patients undergoing elective bariatric 
surgery of 65% in the control group, the expected frequency of VAS/NRS score  ≤ 3 is 
65% in the interventional group. A two group test with a 0.05 two-sided significance level 
will have 90% power to detect a redistribution of VAS/NRS score ≤ 3 points in favour of 
interventional group when the sample size in each group is 63. Assuming a 10% dropout 
rate, 140 subjects will be recruited and randomized. Sample size was calculated accord-
ing to Jaykaran et al. with a sample size calculation for 2 tests using web-based sample 
size calculator on biomath.info. (55, 56) 
10.4 Planned Analyses  
Following populations will be analyzed 
- Interventional group (patients receiving lidocaine 1% I.V. in addition to general anes-
thesia) 
- Control group (patients receiving saline 0.9% as placebo I.V. in addition to general 
anesthesia) 
- whole population (evaluation of secondary endpoints) 
10.5 Primary and secondary endpoint analyses 
Potential differences between the two groups in the distribution of dichotomous data will 
be analysed by 2 statistics. Continuous data will be analyzed by parametric or non-
parametric test for unpaired comparison as appropriate. Statistics will be calculated with 
SPSS. We will consider the null hypothesis refuted if p-value is < 0.05.  

  
 
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10.6 Interim analysis 
No interim analysis will be performed.  
10.7 Deviation from the original statistical plan  
Should any deviations from the statistical plan be necessary, these shall be detailed in 
an amendment to the study protocol and declared in any publications. Unplanned interim 
analysis, not described in the original study protocol shall be registered in an amend-
ment to the protocol. 
10.8 Handling of missing data and drop-outs 
Missing postoperative VAS/NRS scores, required for primary and secondary endpoints, 
will be handled as interpolation values, calculating an average score between last rec-
orded scores before and after the missing value. Missing data for secondary endpoint 
PONV or time to first defecation will be handled as no occurence of PONV (PONV 0) or 
no defecation yet. In case of drop-out, data collected till patients drop out will be ne-
glected and not taken into account of statistical consideration of the study. 
 
 

  
 
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11. SAFETY ANALYSIS 
11.1 Drug studies 
During the entire duration of the study, all AE, ADR and all SAE, related to the applica-
tion of IMPs (severity of possible AE related to lidocaine will be discussed in chapter 
11.6) are collected, fully investigated and documented in source documents and case 
report forms (CRF). Study duration encompassed the time from when the participant 
signs the informed consent until study nurses final visit on second postoperative day at 
2pm respectively +/- 30 minutes.  
11.2 Definition and assessment of (serious) adverse events 
and other safety related events 
An AE is any untoward medical occurrence in a patient or a clinical investigation partici-
pant administered a pharmaceutical product and which does not necessarily have a 
causal relationship with the study procedure. An AE can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not related to the 
medicinal product. 
A SAE is classified as any untoward medical occurrence that: 

results in death 

is life-threatening 

requires in-patient hospitalization or prolongation of existing hospitalization 

results in persistent or significant disability/incapacity 

is a congenital anomaly/birth defect 
In addition, important medical events that may not be immediately life-threatening or re-
sult in death, or require intensive care treatment, but may require intervention to prevent 
one of the other outcomes listed above should also usually be considered serious. 
SAE should be followed until resolution or stabilization. Participants with ongoing SAE at 
study termination (including safety visit) will be further followed up until recovery or until 
stabilization of the disease after termination.  
 

  
 
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11.3 Assessment of Causality 
Both Investigator and Sponsor-Investigator make a causality assessment of the event to 
the study drug, based on the criteria listed in the ICH E2A guidelines: 
Relationship 
Description 
Definitly 
Temporal relationship; Improvement after dechal-
lenge; Recurrence after rechallenge (or other proof 
of drug cause)  
Probably 
Temporal relationship; Improvement after dechal-
lenge; No other cause evident  
Possibly 
Temporal relationship; Other cause possible  
Unlikely 
Any assessable reaction that does not fulfil the 
above conditions  
Not related 
Causal relationship can be ruled out  
11.4 Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  
11.5 Suspected Unexpected Serious Adverse Reactions (SU-
SAR) 
The Sponsor Investigator evaluates any SAE that has been reported regarding serious-
ness, causality and expectedness. If the event is related to the investigational product 
and is both serious and unexpected, unblinding will be carried out by the Sponsor Inves-
tigator to re-evaluate the event and eventually classify it a SUSAR. In this case, the 
Sponsor Investigator will give report including full detail about patient and incident to the 
local ethics committee within 15 days. In case of fatal SUSAR, reporting to local ethics 
committee will be given within seven days. Swissmedic will be informed about non-fatal 
SUSAR within 15 days and in case of fatal SUSAR within seven days. 
11.6 Assessment of Severity 
Severity of possible AE due to the application of IMPs will be classified as follows. 
- Mild: numbness and tingling in the fingers and toes, numbness and unusual sensations 
around the mouth, a metallic taste in the mouth, ringing in the ears, or lightheadedness 
and dizziness, local skin reactions (redness, urticaria) 
- Moderate: mild side effects with the addition of nausea and vomiting, severe dizziness, 
decreased hearing, tremors, changes in blood pressure and pulse 

  
 
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- Severe: drowsiness confusion, muscle twitching, convulsions, loss of consciousness, 
cardiac arrhythmias with hemodynamic instability, cardiac arrest 
Events classified as severe adverse reactions due to IMPs will be included to the defini-
tion of SAE. Any other event, not applicable to the classification will be documented in 
the electronic anesthesia protocol and the CRF and assessed by the investigator if dis-
continuation and/or further treatment is required. 
11.7 Reporting of Adverse and Serious Adverse Events  
Fatal, life-threatening or relevant events according patients` health will be defined as 
SAE. Safety outcomes will not be defined as SAE as long as the Investigator considered 
these events to be exceptional. Primary, secondary and safety events will be recorded 
on single CRF, though not reported as an SAE, unless the Investigator considered these 
events to be exceptional. 
All events not fitting as primary, secondary or safety outcomes will be reported within 24 
hours to the Sponsor Investigator of the study and will again be evaluated by the Spon-
sor Investigator. Unblinding will be performed by the Sponsor Investigator to evaluate a 
suspected unexpected serious adverse reaction. SAE resulting in death will be reported 
to the local Ethics Committee within a week.  
All suspected new risks and relevant new aspects of known adverse reactions that re-
quire safety-related measures, i.e. so called safety signals, must be reported to the 
Sponsor/Investigator within 24 hours. The Sponsor Investigator must report the safety 
signals within seven days to the local Ethics Committee (local event via local Investiga-
tor) and to Swissmedic due to study category B. 
An annual safety report is submitted once a year to the local Ethics Committee via local 
Investigator and to Swissmedic due to study category B via the Sponsor Investigator. 
Any amendment or modification in study sequence and resulting in changed safety con-
ditions for participants will be reported. 
11.8 Safety follow-up 
Regulatory follow-up will take place seven days after surgery (postoperative day seven) 
or on day of patient`s discharge, whatever comes first (labeled as “POD X” in the study 
sequence). Follow-up of patients terminating the study (either regulatory or prematurely) 
with reported ongoing SAE, or any ongoing AEs or vital signs being beyond alert, will be 

  
 
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40 
conducted by the Sponsor Investigator / study nurses. Patients will either be contacted 
by phone or mail or by consultation of their general practitioner, or in case of hospitaliza-
tion or out-patient treatment, visited on ward. During follow-up SAE and AE will be eval-
uated and documented in the CRF. If treatment is necessary, patients will be given an 
appointment for out-patient treatment or hospitalization. 
11.9 Safety SOP 
The Sponsor’s standard operating procedures (SOP) provide more detail on safety re-
porting. During the entire duration of the study, all AE and all SAEs are collected, fully 
investigated and documented in source documents and CRF. Study duration encom-
passed the time from when the participant signs the informed consent until the last pro-
tocol-specific procedure has been completed, including a safety follow-up period.  

  
 
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12. QUALITY ASSURANCE & 
CONTROL 
12.1 Data Handling and Management 
Data collected will be documented and stored in an electronic data system (electronic 
case report form (eCRF)). All data collected will be treated in confidence and storage 
system will be validated and compliant to GCP. 
12.2 Storage of Data 
All data collected will be stored in the eCRF generated by Secu Trial (compliant to GCP, 
provided by interActive Systems GmbH) and administered by the CTU data manager. 
Non-electronic data will be stored in the study administration office. Period of data ar-
chiving will be ten years (subject to the regulations of article 45 KlinV). 
12.3 Monitoring and Auditing  
Monitoring will be performed by the CTU St. Gallen according to a Monitoring Plan.  
12.4 Confidentiality 
The investigator affirms and upholds the principle of the participants’ right to privacy and 
shall comply with applicable privacy laws. Particularly the anonymity of the participants 
shall be guaranteed when presenting the data at scientific meetings or publishing them 
in scientific journals. Individual subject medical information obtained as a result of this 
study is considered confidential and disclosure to third parties is prohibited. Subject con-
fidentiality shall be protected by assigning each participant a unique alphanumerical 
identifier to be used in lieu of their name in the study database. For data verification pur-
poses, authorized representatives of the Sponsor (Investigator), a competent authority 
(e.g. Swissmedic), or an ethics committee may require direct access to the medical rec-
ords relevant to the study, including participants’ medical history.  
 

  
 
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42 
13 PUBLICATION AND DISSEM-
INATION POLICY  
The study will be published in a peer-reviewed scientific journal. This study protocol and 
the raw dataset will be published as well. The publication process shall be under the di-
rection of the Principal Investigator.  
14 FUNDING AND SUPPORT  
Funding is being sought from our institution’s research fund. 
15 INSURANCE  
The Kantonsspital St. Gallen will assure that every patient included in the study is in-
sured for any complications developed as a consequence of the study. For further infor-
mation and insurance certificate see “risk management” of the Kantonsspital St. Gallen. 
 
 

  
 
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43 
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