Pilot Study: Postoperative Pain Reduction by Pre Emptive N-Acetylcysteine
Phase: PHASE4
Conditions: Postoperative Pain
Sponsor: Radboud University Medical Center

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RESEARCH PROTOCOL 
 
Pilot study: postoperative pain reduction by pre emptive N-Acetylcysteine 
 
September 2017 
 
 
Project team 
Drs. C.E. Mulkens1 
Dr. M.A.H. Steegers1 
Dr. J. Bruhn1 
Drs. B.A.M. Snoeker2 
Drs. M. Staatsen3 
Dr. G.D. Slooter4 
Prof. K.C.P. Vissers1 
1 Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Centre, 
Nijmegen 
2 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, 
Amsterdam  
3 Department of Anesthesiology, Maxima Medical Centre, Veldhoven  
4 Department of surgery, Maxima Medical Centre, Veldhoven 

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PROTOCOL TITLE ‘Pilot study: postoperative pain reduction by pre emptive fluimucil’ 
 
Protocol ID 
<include protocol ID given by sponsor or 
investigator> 
Short title 
N-Acetylcysteine for postoperative pain reduction 
EudraCT number  
2016-003144-36 
Version 
3 
Date 
September 2017 
Coordinating investigator/ 
project leader 
 
C.E. Mulkens, MD 
Resident anesthesiology, department of 
Anesthesiology, Pain and Palliative Care, 
Radboudumc 
Geert Grooteplein-Zuid 10 
P.O. Box 9101, 717 
6525 GA Nijmegen, the Netherlands 
Chantal.Mulkens@radboudumc.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
 
K.C.P. Vissers, MD, PhD 
Department of Anesthesiology, Pain and Palliative 
Care, Radboudumc 
Kris.Vissers@radboudumc.nl 
024-3666353 
G. Slooter, MD, PhD 
Department of Surgery, Maxima Medical Centre 
G.Slooter@mmc.nl 
(040) 888 85 50 
Sponsor: 
Radboudumc Nijmegen 
Subsidising party 
n.a. 
Independent expert  
G.J. van Geffen, MD, PhD 
Department of Anesthesiology, Pain and Palliative 
Care, Radboudumc 
Geert-Jan.vanGeffen@radboudumc.nl 
024-3651539 

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Pharmacy  
Farmaceutisch centrum Maxima 
Postbus 7777 
5500 MB Veldhoven 
040 888 9020 
Radboud Apotheek 
Geert Grooteplein Zuid 8 
6525 GA Nijmegen 
024 361 9191 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. Dr. G.J. Scheffer 
 
 
Principal Investigator: 
Prof. Dr. K.C.P. Vissers 
 
 
Coordinating investigator: 
Drs. C.E. Mulkens 
 
 
Investigator: 
Dr. M.A.H. Steegers 
 
 
Investigator: 
Dr. J. Bruhn 
 
 
Investigator: 
Drs. B.A.M. Snoeker 
 
 
Investigator: 
Dr. G.D. Slooter 
 
 
Investigator: 
Drs. M. Staatsen 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................10 
2. 
OBJECTIVES ................................................................................................................11 
3. 
STUDY DESIGN ...........................................................................................................12 
4. 
STUDY POPULATION ..................................................................................................14 
4.1 
Population (base) ...................................................................................................14 
4.2 
Inclusion criteria .....................................................................................................14 
4.3 
Exclusion criteria ....................................................................................................14 
4.4 
Sample size calculation ..........................................................................................14 
5. 
TREATMENT OF SUBJECTS .......................................................................................16 
5.1 
Investigational product/treatment ............................................................................16 
5.2 
Use of co-intervention (if applicable) ......................................................................16 
5.3 
Escape medication (if applicable) ...........................................................................16 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................17 
6.1 
Name and description of investigational  product(s) ...............................................17 
6.2 
Summary of findings from non-clinical studies ........................................................17 
6.3 
Summary of findings from clinical studies ...............................................................17 
6.4 
Summary of known and potential risks and benefits ...............................................17 
6.5 
Description and justification of route of administration and dosage .........................17 
6.6 
Dosages, dosage modifications and method of administration ...............................17 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................17 
6.8 
Drug accountability .................................................................................................17 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................19 
8. 
METHODS ....................................................................................................................20 
8.1 
Study parameters/endpoints ...................................................................................20 
8.1.1 
Main study parameter/endpoint .......................................................................20 
8.1.2 
Secondary study parameters/endpoints (if applicable) ....................................20 
8.2 
Randomisation, blinding and treatment allocation ..................................................20 
8.3 
Study procedures ...................................................................................................20 
8.4 
Withdrawal of individual subjects ............................................................................21 
8.5 
Replacement of individual subjects after withdrawal ...............................................22 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................22 
8.7 
Premature termination of the study .........................................................................22 
9. 
SAFETY REPORTING ..................................................................................................23 
9.1  
Temporary halt for reasons of subject safety ..........................................................23 
9.2 
AEs, SAEs and SUSARs ........................................................................................23 
9.2.1 
Adverse events (AEs) ......................................................................................23 
9.2.2 
Serious adverse events (SAEs) .......................................................................23 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................24 
9.3 
Annual safety report ...............................................................................................25 
9.4 
Follow-up of adverse events ...................................................................................25 
9.5 
Data Safety Monitoring Board (DSMB) / Safety Committee ....................................25 

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10. 
STATISTICAL ANALYSIS ..........................................................................................27 
10.1 
Primary study parameter(s) ....................................................................................27 
10.2 
Secondary study parameter(s) ...............................................................................28 
10.3 
Interim analysis (if applicable) ................................................................................28 
11. 
ETHICAL CONSIDERATIONS ...................................................................................29 
11.1 
Regulation statement .............................................................................................29 
11.2 
Recruitment and consent........................................................................................29 
11.3 
Objection by minors or incapacitated subjects (if applicable) ..................................29 
11.4 
Benefits and risks assessment, group relatedness .................................................29 
11.5 
Compensation for injury .........................................................................................29 
11.6 
Incentives (if applicable) .........................................................................................30 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................31 
12.1 
Handling and storage of data and documents ........................................................31 
12.2 
Monitoring and Quality Assurance ..........................................................................31 
12.3 
Amendments ..........................................................................................................31 
12.4 
Annual progress report ...........................................................................................32 
12.5 
End of study report .................................................................................................32 
12.6 
Public disclosure and publication policy ..................................................................32 
13. 
STRUCTURED RISK ANALYSIS...............................................................................33 
13.1 
Potential issues of concern .....................................................................................33 
13.2 
Synthesis ...............................................................................................................34 
14. 
REFERENCES ..........................................................................................................35 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
ABR form, General Assessment and Registration form, is the application 
form that is required for submission to the accredited Ethics Committee (In 
Dutch, ABR = Algemene Beoordeling en Registratie) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
NAC 
N-Acetylcysteine (Fluimucil) 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie 
IB1-tekst) 
Sponsor 
The sponsor is the party that commissions the organisation or performance 
of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party 
that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
VAS 
Visual Analog scale 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Title: postoperative pain reduction by pre emptive N-Acetylcysteine. 
 
Rationale: Despite current available analgesic drugs, post-surgical pain management 
remains challenging. A potential new target for analgesic drugs are group-II metabotropic 
glutamate receptors subtypes (mGlu2 and mGlu3 receptors), since growing evidence from 
animal models show that activation of these receptors produce s analgesic effects in 
inflammatory and in neuropathic pain states. . N-Acetylcysteine (NAC) is a safe agent and 
with little to no side effects. NAC can induce analgesia by activating the glutamate:cystein 
antiporter, causing endogenous activation of the mGlu 2/3 receptors. However, this has only 
been investigated once in the peri-operative setting, were it showed preliminary promising 
result of reduction in opiate necessity. In healthy subjects there was a significant reduction in 
pain ratings to laser stimuli and amplitudes of laser evoked potentials after NAC. Based on 
these promising results, we hypothesize that pre emptive intravenous NAC can reduce 
postoperative pain and thereby cause less necessity for escape analgesics like opiates. 
 
Objective: In patients receiving NAC we hope to see less postoperative pain and thereby 
less usage of escape pain medication compared to patients receiving placebo. 
 
Study design: This pilot study will be a multi centre randomised, double blinded, placebo 
controlled pilot study. Subjects will be randomized to placebo or NAC treatment before 
surgery and will be followed till 1 week after surgery. 
 
Study population: 60 patients with informed consent for surgical unilateral inguinal hernia 
repair, otherwise ASA 1-2 classification and age > 18 years, will be enrolled.  
 
Intervention (if applicable): Group 1 receives a bolus of 150 mg/kg NAC intravenous 1 hour 
prior to surgery. Group 2 receives saline in equivalent volumes also 1 hour prior to surgery. 
 
Main study parameters/endpoints:  
Primary objective 
To evaluate the efficacy of intravenous NAC in comparison with placebo in terms of pain 
relief after unilateral inguinal hernia repair measured by a visual analogue scale (VAS 0-100) 
at day 1 after surgery. 
Secondary objectives 

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1. Difference in pain scores (VAS 1-100) between NAC and placebo direct after surgery, 
before discharge and in following 3 days postoperative. 
2. Difference in time before first pain medication is administered postoperative between NAC 
and placebo. 
3. Difference in total consumption of opiates in the hospital (mg) between NAC and placebo. 
4. Difference in time from surgery to discharge between NAC and placebo. 
5. Difference in postoperative pain medication at home necessary to reach adequate pain 
relief between NAC and placebo (Acetaminophen /NSAID’s/opiates). 
6. If there is a difference in 5, is there also a difference in adverse effects of pain medication 
(like nausea, obstipation) between NAC and placebo.  
7. safety of intravenous NAC 150 mg/kg in terms of nausea, vomiting, anaphylactoid or 
allergic reactions (presenting as dyspnea, urticaria) 
  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Patients will need to be admitted earlier in the hospital prior to surgery, 
to make sure they receive study medication in time.  
An intravenous line will be placed on the holding to be able to administer study medication, 
however, this same line can be used during and after surgery. During administration of the 
study medication subjects will be monitored respiratory and hemodynamically, to ensure 
possible side effects of NAC are captured. 
Oral NAC is safe agent and even over the counter available in the Netherlands. Subjects will 
have little extra risks due to the intravenous NAC given in this concentration. The main risk is 
the occurrence an anaphylactoid reaction, which is easily treated by antihistaminic and 
seldom described as serious in the literature. [1-5] Careful monitoring of subjects will ensure 
any potential side effect or adverse event are noticed and treated as quickly as possible. 
Side effects will be documented and presented. 
After discharge patient receive a diary and will record: 1) VAS at predetermined time, 2) pain 
medication used, 3) side effects of pain medication (nausea, obstipation, dizziness) and 4) 
overall satisfaction. 
Total time investment of participants should not exceed more than 2 hours in total. 
 

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1. INTRODUCTION AND RATIONALE 
In 2008 it was estimated that approximately 240 million surgical procedures were done 
worldwide on a yearly basis, and over the last years this number has probably grown even 
further.[6] Inguinal hernia repair is one of the most performed surgeries  in ambulatory 
setting.[7] Despite currently available analgesic drugs, post surgical pain management 
remains challenging in this group of patients, as the pain score  appears inadequate (mean 
VAS of 5.8 +/- 1.22 cm) one day after surgery with the use of common analgesics.[8, 9] 
Beside accounting for patient discomfort, pain is also a major contributor to prolonged length 
of hospital stay and is a health care quality indicator.[10, 11] 
With multimodal pain management the intention is to reduce pain with less side effects of 
analgesics. Multimodal pain management is the combination of different pharmacologic 
mechanisms of action, which work by acting at different sites within the central and 
peripheral nervous system, thereby having an additive or synergistic effect and reducing the 
necessity of opiates. [12] 
With this in mind, a potential new target for analgesic drugs are group- II metabotropic 
glutamate receptors subtypes (mGlu2 and mGlu3 receptors) localized in the spinal cord and 
other regions of the nociceptive system. Growing evidence from animal models show that 
activation of these receptors occur via the glutamate:cystein antiporter and can induce 
analgesia in models of inflammatory and neuropathic pain.[13-17] They depress pain 
transmission at synapses between primary afferent fibers and second order sensory neurons 
on the dorsal horn of the spinal cord.[18] 
N-Acetylcysteine (NAC) is on the market since 1968and is an over the counter available 
agent, mostly known for its role as mucolytic agent in cystic fibrosis and for the treatment of 
acetaminophen intoxication. It is a safe agent with little to no side effects. [1-5] Recent 
studies have shown NAC can inhibit nociceptive transmission in rats and in healthy 
humans.[15, 19] NAC can induce analgesia by activating the glutamate:cystein antiporter, 
causing endogenous activation of the mGlu2/3 receptors. 
Therefore, NAC can potentially become a cheap and safe additive in the multimodal pain 
management. However, evidence for usage of NAC in the context of multimodal pain 
management is still lacking. Only one available study in humans  evaluated the effect of NAC 
in the perioperative setting.[19] Despite being a randomised controlled trial, there are several 
limitations  in this study; the study arms are too small and only morphine consumption is 
presented. Also, blinding might have not as good as suggested since oral NAC has a typical 
flavour and the placebo was lemonade. Due to these limitations, still no answer on the 
question whether NAC can be an additive in current multimodal painmanagement is 
provided. 
Therefore, we would like to conduct a randomised, double blinded, placebo controlled pilot 
study to investigate whether pre emptive intravenous NAC can reduce postoperative pain 
after surgical inguinal hernia repair. Primary endpoint will be pain score on day one after 
surgery, and secondary outcomes postoperative analgesic consumption, time to first 
necessity for pain medication, hospital stay and adverse effects of analgesic medication.

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2. OBJECTIVES 
Primary Objective:  
To evaluate the efficacy of intravenous NAC in comparison with placebo in terms of pain 
relief after unilateral inguinal hernia repair measured by a visual analogue scale (VAS 0-100) 
at day 1 after surgery. 
 
Secondary Objective(s):  
1. Difference in pain scores between NAC and placebo direct after surgery, before discharge 
and in following 3 days postoperative. 
2. Difference in time before first pain medication is administered postoperative between NAC 
and placebo. 
3. Difference in total consumption of opiates in the hospital (mg) between NAC and placebo. 
4. Difference in time from surgery to discharge between NAC and placebo. 
5. Difference in postoperative pain medication at home necessary to reach adequate pain 
relief between NAC and placebo ( Acetaminophen /NSAID’s/opiates). 
6. If there is a difference in 5, is there also a difference in adverse effects of pain medication 
(like nausea, obstipation) between NAC and placebo.  
7. safety of intravenous NAC 150 mg/kg in terms of nausea, vomiting, anaphylactoid or 
allergic reactions (presenting as dyspnea, urticaria) 
 
 

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3. STUDY DESIGN 
 
The study will be a multi centre double blinded randomized placebo controlled trial, which 
will be conducted at the Maxima Medical Centre, Veldhoven and Radboudumc, Nijmegen.  
We will investigate whether pre emptive intravenous NAC will reduce postoperative pain in 
patients with unilateral inguinal hernia repair. Subjects who are scheduled for laparoscopic 
inguinal hernia repair will be screened at the pre operative screening clinic according to 
screening criteria (see section 4). After patients have  given oral and written informed 
consent (IC), subjects will be randomized to either NAC or placebo and will be 
prospectively followed till 1 week after surgery. Participants and investigators enrolling 
subjects can not foresee assignment because of central allocation is used to conceal 
allocation. 
We expect this pilot study will take 6 months, starting at first inclusion. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consequences for patients 
At specific time points the following measurements will be performed. 
History taken: is part of standardized care, and will be done during the preoperative 
screening. 
Screening of all subjects 
eligible for participation study 
according to screening criteria 
Informed consent 
Evaluable subjects enrolled into 
trial (N=60) 
Randomization 
No 
End 
Placebo Group, 
N=30 
NAC Group,  
N=30 

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Study medication: subjects will receive an intravenous line to administer either NAC or 
placebo intravenously. Oral NAC is safe agent and even over the counter available in the 
Netherlands. Subjects will have little extra risks due to the intravenous NAC given in this 
concentration. The main risk is the occurrence an anaphylactoid reaction, which is easily 
treated by antihistaminic and seldom described as serious in the literature. [1-5] Careful 
monitoring of subjects will ensure any potential side effect r adverse event are noticed and 
treated as quickly as possible. 
Physical examination: is part of standardized care, and will be done during the pre operative 
screening (measurement of bloodpressure and pulse). 
Diary: Patient will record VAS on predetermined time, analgesic medication taken, side 
effects of analgesic medication, overall satisfaction. 
Vital signs: is part of standard care peri operatively, however, extra measurements of 
heartrate (HR), bloodpressure (BP) and oxygenation (SpO2) during administration of study 
medication will take place to ensure possible side effects of NAC are captured.

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4. STUDY POPULATION 
4.1  Population (base)  
Subjects will be identified at the pre operative screening at the Maxima Medical Centre, 
Veldhoven, the Netherlands or at the pre operative screening at Radboudumc, Nijmegen, 
the Netherlands. Sixty evaluable subjects (male or female) will be enrolled in the trial. 
 
We will randomize patients in one of the following two groups: 
1. Receive intravenous placebo prior to inguinal hernia repair. 
2. Receive intravenous NAC prior to inguinal hernia repair. 
 
4.2  Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
Subjects scheduled for laparoscopic unilateral inguinal hernia repair. 
 
- 
ASA 1 or 2. 
- 
Age >18 years. 
 
4.3  Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
 
- 
Pregnancy or lactating 
- 
Allergy to NAC 
- 
History of chronic pain 
- 
Use of opioids or neuropathic analgesics 
- 
Use of NAC prior to trial (< 1 month of planned surgery) 
- 
Contra indication for the use of NSAID’s 
- 
Previous inguinal hernia repair on the same side (a redo operation) 
- 
Alcoholism 
- 
Diabetes Mellitus 
- 
Asthma or Chronic Obstructive Pulmonary Disease 
- 
Known renal function disorders (MDRD <60) 
- 
Known liver failure (bilirubine >1.5x upper limit of normal) 
- 
No written IC by patient 
 
4.4 Sample size calculation 
The sample size is powered to find a significant difference in pain 24 hours after surgery. 
The primary outcome will be the VAS between the two groups. Assuming a clinical 
relevant difference of 1(cm) on the VAS between groups, with a mean of 5.8 and a 
standard deviation of 1.22 after 24 hours and a power of 80%, then 25 patients are 
needed in each group (t-test, alpha=0,05; double sided),  taking in to account a possible 
loss to follow up of 20%, a total of 30 patients will be included in each group. 

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If this pilot study shows promising results we aim to set up a further larger study where 
there will be an extended focus on NAC and reduction of postoperative pain. 
 

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5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
The following NAC infusion regimen will be conducted. One hour prior to surgery, the 
patients will receive 150 mg/kg in 200 ml intravenous bolus over 15 minutes.  
During NAC infusion, patients vital signs will be adequately monitored. 
 
Patients who are not included in the treatment arm of the study will receive intravenous 
saline instead with identical look of NAC in the same timeframe and dosage (200ml). 
 
5.2 Use of co-intervention (if applicable) 
Subjects will receive standard recipes for postoperative analgesics, which they can take at 
home if they experience pain. Standard regime for postoperative pain will be: 
Acetaminophen 4 dd 1 gram oral 
Naproxen 2 dd 500 mg oral 
Oxynorm  5 mg oral, only on request with a maximum of 6 times a day 
 
5.3 Escape medication 
During hospital stay escape medication for acute pain will be the regimen as described 
above. If this regimen is insufficient, sufentanil or morphine intravenously can be given 
with on the recovery ward by judgement of the anaesthesiologist to achieve adequate 
pain reduction.  
 

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6. INVESTIGATIONAL PRODUCT 
6.1 Name and description of investigational  product 
 
N-Acetylcysteine, concentrate for intravenous admission 200 mg/ml. 
 
6.2 Summary of findings from non-clinical studies 
The summary is provided in the SPC for N-Acetylcysteine supplied with this protocol. 
 
6.3 Summary of findings from clinical studies 
The summary is provided in the SPC for N-Acetylcysteine supplied with this protocol. 
 
6.4 Summary of known and potential risks and benefits 
Oral NAC is an over the counter agent in the Netherlands. Intravenous NAC is almost 
exclusively used for Acetaminophen intoxication. Side effects of intravenous NAC are 
rare. In 0,1-1% anaphylactoid reactions occur like bronchospasm, dyspnea, pruritis, 
flushing or rash. In the literature this incidence is higher, 8.4% with a higher incidence in 
asthmatics.[4] However, the side effects are easily managed with antihistaminic and non 
were life threatening.[5]  
 
6.5 Description and justification of route of administration and dosage 
Although preferred route of administration is oral, since this is cheaper and less 
anaphylactoid reactions are seen (2% vs 6%), we choose for the intravenous admission 
after good consultation with the clinical pharmacist. [1]The main reason to choose for the 
intravenous route is primary a problem with blinding the oral route. Also, the oral 
bioavailability of NAC is only 4%, and since there appears to be a dose-response curve 
we hypothesized that if there is no effect seen after high dose intravenously, none will be 
seen in the oral route. [20] 
 
6.6 Dosages, dosage modifications and method of administration 
The given dosage will be 150 mg/kg in 200 ml of saline intravenously over a period of 15 
minutes. This is the same bolus as is given intravenously for acetaminophen intoxication 
and therefore well described and investigated in the literature.[1, 2, 4, 5] 
  
6.7 Preparation and labelling of Investigational Medicinal Product 
 
Preparation will be done by the hospital pharmacy or pharmacis. 
  
6.8 Drug accountability 
NAC will be delivered by the producer of NAC, Zambon Nederland BV. The delivered 
NAC has a concentration of 200 mg/ml. After randomization of the patient, the hospital 

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pharmacy or pharmacis will prepare the medication for reconstitution in the clean room 
according to local protocol. Reconstitution shall be understood as a simple process of 
diluting the NAC with saline for the purpose of administering it. Normally this process can 
be done by a nurse on the ward, however to extend shelf life and ensure blinding this will 
be done in the clean room by the pharmacy. 
The medication will be stored (with a maximum of seven days as described by 
manufactor) according protocol until surgery of the patient. Study medication will be 
labelled with “NAC or placebo”, together with patient identity. The pharmacy or pharmacis 
will deliver the appropriate study label to the clinic on the day the patient is planned for 
his/ her surgery. After administration the medication bags will be stored and collected for 
evaluation of correct dosing. 

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7. NON-INVESTIGATIONAL PRODUCT 
Not applicable 
 
 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
Primary objective is to evaluate the efficacy of intravenous NAC in comparison with 
placebo in terms of pain relief after unilateral inguinal hernia repair measured by a 
visual analogue scale (VAS 0-100) at day 1 after surgery. 
8.1.2 Secondary study parameters/endpoints (if applicable) 
 
Pain scores (VAS 1-100) direct postoperatively , before discharge and in 
following 3 days postoperative. 
 
Time to first necessity of pain medication after surgery. 
 
Total consumption of in hospital opiates/ analgesics. 
 
Time to discharge. 
 
Analgesic medication taken at home by patient (registered by patients in diary). 
 
Adverse effect of analgesic medication (nausea, obstipation, sedation) 
 
Safety of intravenous NAC (nausea, vomiting, dyspnea, urticaria) 
 
 
8.2 Randomisation, blinding and treatment allocation 
 
Participants and investigators enrolling subjects can not foresee assignment because 
of central allocation is used to conceal allocation. We used blocked randomization to 
form the allocation list for the two comparison groups because of the small sample 
size. We used a computer random number generator to select random permuted 
blocks and an equal allocation ratio. 
 
Breaking of the randomization code will be done in case of any SAE or SUSAR. 
Study medication will be administered by blinded personnel. Patients, hospital staff 
that are involved in the care of the patient (surgeon, anaesthesist, nurses) and 
outcome investigators (including primary data collectors) are all blinded for treatment 
allocation. 
 
8.3 Study procedures 
Patients shall be informed about the study during their visit to the surgery outpatient 
clinic and if they are scheduled for unilateral laparoscopic inguinal hernia repair. . 
Patients will be asked if they consent to be approached by the investigator and if so 
they will receive study information and the informed consent form. The patients will be 
asked by the investigator over the phone if they have any questions and in case of 
informed consent they will be asked to fill in the form and sent this back in the 
provided envelope.  
 
 
 

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Measurements at baseline 
Patient characteristics are obtained through history taking and physical exam (and if 
thought necessary by anaesthesist also laboratory values) during the regular 
preoperative screening. This is part of standard care. 
 
Date of birth 
 
Gender 
 
Medical history 
 
Current pain score (VAS 0-100) 
 
Intoxication (smoking, alcohol, drugs) 
 
Allergies 
 
Medication 
 
Physical examination (heart sounds, breath sounds, airway, baseline 
bloodpressure and pulse) 
 
Administration of study medication 
Patient will be admitted to the day clinic prior to his/ her surgery. For the 
administration of the study medication, they will be admitted to the recovery ward, 
were patients will receive an intravenous canula. The administration of study 
medication will start an hour before surgery and infusion will take 15 minutes. 
During administration of study medication vital signs (saturation, non invasive 
bloodpressure and pulse) will registered every 5 minutes. Also injection site will be 
monitored for reaction. In case of an anafylactoid reaction to NAC, the protocol 
“anaphylatoide reactie” will be followed. 
 
Surgery 
Prior to surgery patient will receive general anesthesia according to the local 
protocol of the Maxima Medical Centre. This will be standard care that the patient 
would receive also without being included in this study. 
All patients receive premedication with acetaminophen and naproxen. 
General anesthesia will consist of anti emetic (granisetron), propofol, sufentanil, 
rocuronium and for maintenance sevoflurane. No dexamethasone will be 
administred. In case of residual muscle relaxants, sugammadex will be 
given.Dosage of analgesic medication will be recorded. 
 
After surgery 
Patients will be monitored on the recovery ward according to local protocol. Pain 
scores (VAS 1-100) will be registered as well as need for analgesic medication. 
Adverse effects of analgesic medication (nausea, sedation) will be recorded. 
Discharge from the recovery ward will be no different than according to local 
protocol after surgery. On the ward also painscores (VAS 0-100) will be registered 
every hour till discharge home. Need for analgesic medication and adverse effects 
will be recorded. In case of nausea droperidol 1.25 mg or metoclopramide 10 mg 
can be given.  
 
 

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Home 
Patients will be asked to fill in a diary for the first 3 days after surgery. In this diary 
they are asked to fill in pain scores (VAS 0-100) on certain times, as well as used 
analgesic medication and, in case of adverse effects of this medication, also these 
adverse effects. Patients will receive a call on day 1 to make sure the diary is filled 
in and not forgotten. The diary is, and if not received patients will be called at 
home after 1 week. If patients don’t have internet or prefere a paper diary this is 
also possible. Data filled in online with be directly saved in the secured database 
of castor, were only authorized personnel has access to. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. Reason for withdrawal from the study will be recorded. 
 
8.5 Replacement of individual subjects after withdrawal 
If subjects decide to withdraw before receiving the study medication, they will be 
omitted from the data collection and will be replaced by a new study object. If the 
subject had received study medication, they will be included in the analysis for the arm 
where the subject was allocated to (intention to treat analysis).  
 
8.6 Follow-up of subjects withdrawn from treatment 
After withdrawal subjects will not be followed for research purposes, but will continue 
to receive normal, standard of care follow-up by their treating physician. 
 
8.7 Premature termination of the study 
The data safety monitoring board will be informed in case of a serious adverse event. 
The trial will be terminated prematurely after consulting the DSMB if there might be an 
increased risk to the subjects enrolled, for example if the treatment causes 
unanticipated harm to the subject or in case of a SUSAR . Subject safety will continue 
to be monitored by the investigator for the duration of the trial. 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to [the investigational product / 
trial procedure/ the experimental intervention]. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be 
recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events.. 
 
 

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The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal 
product; 
- 
Investigator’s Brochure for an unauthorised medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline  to the METC : 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 

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The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will 
be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  
 
9.3 Annual safety report 
 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol  
 
9.5 [Data Safety Monitoring Board (DSMB) / Safety Committee 
According to the NFU-classification this trial has a low risk. For this reason a Data Safety 
Monitoring Board will be established to perform ongoing safety surveillance and interim 
analyses on the safety data.  
The DSMB will consist of: Dr. J. Hofland (Anesthesiologist), Dr. C. Slagt (Anesthesiologist) 
and Dr. A. Morariu (Anesthesiologist). None of these persons have a conflict of interest 
with Drs. C.E. Mulkens.  
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coordinating investigator of the study. Should the investigator decide not to fully 
implement the advice of the DSMB, the investigator will send the advice to the reviewing 
METC, including a note to substantiate why (part of) the advice of the DSMB will not be 
followed. 
 

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10. STATISTICAL ANALYSIS 
Statistical analysis will be performed using Rstudio software. Descriptive analysis will be 
carried out for baseline characteristics: age, gender, ASA-classification, intoxications and 
co-morbidities. Also length of surgery and used anaesthetic technique of both groups will 
be described. Nominal and ordinal data will be presented by number and percentage. 
Continuous data will be presented depending on normal distribution with either mean and 
standard deviation or (in case of no normal distribution) median with range.  
 
Inferential statistics will be performed for both primary and secondary outcomes. We will 
determine if data is normally distributed or not and do statistical analysis accordingly. In 
case of normal distribution we will use an unpaired t-test. In case of a non normal 
distribution we will perform a log transformation on the data, however, if still no normal 
distribution we will use the non parametric test Mann Whitney U (Wilcoxon rank sum). 
P values <0.05 will be considered significant. P values will be calculated with various 
tests depending on presence of normal distribution or not. 
  
Statistical analysis will be based on an intention-to-treat analysis. 
Missing data will be described thoroughly, and will be investigated on whether it is 
missing completely at random (MCAR), missing at random (MAR) or not missing at 
random (NMAR). In case patients received treatment the data known will be used in 
analysis. We expect to not have many missing data due to the follow up by phone. We 
expect that in case of missing data this will be completely at random. Therefore, we 
chose not to use imputating techniques but listwise deletion in case of missing data. In 
case there is more missing than 5% or a suspicion of MAR, we will rethink the use of 
imputating techniques. 
 
10.1 Primary study parameter(s) 
The primary outcome will be the mean VAS (1-100) between the two groups at day 1 
after surgery. Pain scores are ordinal data and therefore a non parametric test should be 
used. However, one can discuss whether the VAS can’t be interpreted as continuous 
data, and therefore (if normally distributed) parametric tests can be used with more 
statistical power. Here we decided to treat VAS as continuous data and therefore use 
parametric test, the unpaired t- test..  
 

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10.2 Secondary study parameter(s)  
 
Pain scores (VAS 1-100) direct postoperatively, before discharge and in 
following 3 days postoperative. Ordinal data, but like with the primary outcome 
we will treat VAS as continuous data and therefore in case of normal distribution 
unpaired t test.Time to first necessity of pain medication after surgery. 
Continuous data, two groups; depending on normal distribution unpaired t test or 
Mann Whitney U. 
 
Cumulative consumption of in hospital opiates. Continuous data, two groups; 
depending on normal distribution unpaired t test or Mann Whitney U. 
 
Time to discharge. Continuous data, two groups; time to event; Kaplan Meier 
analysis.  
 
Analgesic medication taken at home by patient. Continuous data, two groups; 
depending on normal distribution unpaired t test or Mann Whitney U. 
 
Adverse effect of analgesic medication (nausea, obstipation, 
sedation)Dichotomous data, unpaired and 2 groups; Fisher exact. 
 
safety of intravenous NAC 150 mg/kg in terms of nausea, vomiting, 
anaphylactoid or allergic reactions (presenting as dyspnea, urticaria) 
 
10.3 Interim analysis (if applicable) 
there will be no interim analysis. 
 

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11. ETHICAL CONSIDERATIONSRegulation statement 
The current pilot study will be conducted according to the principles of the declaration of 
Helsinki, current version 2008, and in accordance with the legislations issued b the 
WGBO, WMO, WBP and BIG 
 
11.2 Recruitment and consent 
Patients shall be informed about the study during their visit to the surgery outpatient clinic 
and if they are scheduled for unilateral laparoscopic inguinal hernia repair. Patients will be 
asked if they consent to be approached by the investigator and if so they will receive 
study information and the informed consent form. The patients will be asked by the 
investigator over the phone if they have any questions and in case of informed consent 
they will be asked to fill in the form and sent this back in the provided envelope. 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable 
 
11.4 Benefits and risks assessment, group relatedness 
Oral NAC is safe agent and even over the counter available in the Netherlands. Subjects 
will have little extra risks due to the intravenous NAC given in this concentration. The 
main risk is the occurrence an anaphylactoid reaction, which is easily treated by 
antihistaminic and seldom described as serious in the literature. [1-5] Careful monitoring 
of subjects will ensure any potential side effect r adverse event are noticed and treated as 
quickly as possible. 
The possible benefit for subjects lays in the fact that NAC can reduce postoperative pain 
and reduce the necessity of opioids postoperatively.[19] 
The burden for the subjects is, next to receiving study medication, minimal. They receive 
no different care during surgery,  or after surgery. The subject is asked to fill in a diary for 
the first 3 days after surgery, which should not take more than 1 hour in total in time 
investment and is non-invasive. 
 
11.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to 
research subjects through injury or death caused by the study. 

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The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
11.6 Incentives (if applicable) 
Not applicable 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Data will be handled anonymously through coding. Subjects will only be able to be linked 
to the coded investigation product through the source document which contains the 
linking between subject and investigation number. The handling of personal data 
complies with the Dutch Personal Data Protection Act (in Dutch: de Wet Bescherming 
Persoonsgegevens, WBP). All subject data will be stored in locked offices. Access to 
subject information will be limited to trial personnel only and to the DSMB in case of any 
SAE. Any data, including photographs, videos, and interviews with the subjects that may 
be published in abstracts, scientific journals, marketing material or presented at medical 
meetings will reference an unique subject code and will not reveal the subjects identity 
without the express approval of the subject. Subjects will be asked for approval at the 
start of the trial as part of the IC. The research data will be saved for 15 years. When we 
want to use these data for another study, patients will be asked for permission first.  
 
12.2 Monitoring and Quality Assurance  
According to the NFU critereria, “kwaliteitsborging mensgebonden onderzoek 2.0” this 
study will be of low  risk because of the administration of NAC intravenously. The given 
dosage is considered safe and is extensively been investigated previously. Extra 
monitoring of the subjects will take place. The medication will all be prepared by the 
pharmacy/ pharmaceut so the chance of dosage error is limited to a minimum. However, 
the nurses are not used to NAC intravenously and they will receive training before the trial 
starts. The expected possible side effect however are no different than of most other 
medication given intravenously. 
We will monitor according to the NFU criteria. 
 
12.3 Amendments  
 Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
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- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
12.6 Public disclosure and publication policy 
Data will be fully anonymised. Because the sponsor and investigator are the same, there 
are no arrangements. Plans are to publish the findings of this study in a prominent 
magazine in the work field of pain and anesthesiology. 

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13. STRUCTURED RISK ANALYSIS  
 
13.1 Potential issues of concern 
 
Much is known about NAC and its action in the human body. However, not much is known 
about the possible new effect on postoperative pain. There have been many reasons to 
subscribe NAC in the past. It is an frequently used drug, which nowadays is even for sale 
in local drugstores without subscription in the Netherlands. Although not to investigate a 
probable role as new analgesic agent, there have been many studies to investigate the 
same dosage of intravenous NAC in acetaminophen intoxication, in which no life 
threatening adverse events occurred. Beside those studies we refer to the supplied SPC/ 
IB of NAC. 
Study materials will be supplied by the hospital pharmacy or pharmacis.  
 
a. Level of knowledge about mechanism of action 
There is a high level of knowledge of this medicine. It is first choice in acetaminophen 
intoxication and therefore frequently applied in the used dosage. 
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
See references [15, 19, 21] 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
There are several articles which show the effect of NAC on the group-II metabotropic 
glutamate receptors subtypes (mGlu2 and mGlu3 receptors) and the effect of this on pain 
behaviour in animals. [13-15, 17] Pre-emptive NAC can reduce nocifensive behaviour and 
this analgesic effect was abrogated by the Sxc- inhibitor sulphalazaline as well as by 
adding the mGlu2/3 receptor antagonist.[17]  
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
see references [20, 22] 
 
e. Analysis of potential effect 
The potential effect is that through activation of the endogenous mGlu 2/3 receptors via 
the glutamate:cystein antiporter, post operative pain is reduced and therefore the 
necessity for opiates. In animal studies there is a dosage- response curve, were the 
higher the dosage (30 mg/kg, 100 mg/kg or 300 mg/kg) the less pain behaviour was 
observed. [14] This is why we chose to use a higher dosage and intravenous 
administration than previous studies in human did, and this hopefully reduces 
postoperative pain.  
 
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NAC is mainly metabolized in the liver. In plasma NAC can be present in its intact, 
reduced form as well as in various oxidized forms. It can be oxidized to a disulphide and 
form mixed disulphidesby reacting with other low molecular weight thiols such as cysteine 
and glutathione. Based on total NAC concentration, its volume of distribution (Vss) was 
0.47 l·kg-1. The terminal half life was 5.58h after intravenous administration. Elimination is 
renal 
 
g. Study population 
Subjects are scheduled for an elective laparoscopic unilateral inguinal hernia repair. They 
will be screened for contraindications for receiving NAC (see exclusion criteria). 
 
h. Interaction with other products 
In vitro inactivation of antibiotics is seen. Therefore it is not advised to combine antibiotics 
with NAC. Antibiotics are given in the operating room before incision, and therefore no 
interaction is suspected. 
 
i. Predictability of effect 
The evaluation if NAC indeed causes postoperative pain reduction will be measured via 
VAS score, which is a validated measurement to evaluate pain treatment. Values can be 
compared with normals in a database. 
 
j. Can effects be managed? 
Most effects will be monitored in the day clinic. Side effects of the NAC intravenously are 
rare, and if they occur this will be on the ward. Most side effects can be treated with 
tavegyl 1 mg intravenously, since a canula is already in place. Administration of the study 
medication will be done by trained personel to ensure subject safety.  
13.2 Synthesis 
Postoperative pain management is still a challenging manner. Although development in 
surgical techniques has drastically improved chronic pain after inguinal hernia repair, 
acute pain is still not optimized. Due to infiltration with local anesthetics, peripheral nerve 
blockage and analgesics patients leave the hospital with acceptable pain scores. 
However, a day after surgery this no longer provides analgesia and patients report pain 
scores less acceptable.  
With this pilot for pre emptive NAC we hope to improve this patient important outcome. 
The risk for subjects in this study is experiencing side effects of the NAC intravenously, 
which we find an acceptable risk since side effects are never reported to be life 
threatening and there is an extensive history of NAC given intravenously. 
Subjects with an increased risk of NAC side effects are excluded and all subjects are 
monitored during NAC infusion. 
 
 
 
 

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2. Mullins, M.E., R.U. Schmidt, Jr., and T.B. Jang, What is the rate of adverse events with 
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3. Schmidt, L.E., Identification of patients at risk of anaphylactoid reactions to N-
acetylcysteine in the treatment of paracetamol overdose. Clin Toxicol (Phila), 2013. 
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Wagner, R., H.M. Heckman, and R.R. Myers, Wallerian degeneration and 
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