VENLID: A Prospective, Randomized, Double-blind, Controlled Trial on the Application of a 10%-Lidocaine Spray Prior to the Insertion of a Peripheral Intra-venous Catheter in Female Adults
Phase: PHASE4
Conditions: Pain
Sponsor: Lukas Hefler

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 1
 
 
 
 
 
Abteilung für Gynäkologie und Geburtshilfe 
Ordensklinikum Linz 
Seilerstätte 2-4 
4010 Linz 
 
CLINICAL STUDY PROTOCOL 
 
A prospective, randomized, double-blind, controlled trial on the application 
of a 10%-lidocaine spray prior to the insertion of a peripheral intra-venous 
catheter in female adults 
 
Protocol Version and Date: V 3.0, 17May2024 
Previous Version: V 2.0, 07FEB2024 
Previous Version: V 1.0, 23AUG2023 
 
CTIS trial number: 2023-507859-29 
 
Protocol Authors:  
 
 
Lukas Hefler, MD 
 
 
 
 
 
 
Judith Lafleur, MD 
 
 
 
 
 
 
Ulrike Hauer, MD 
 
 
 
 
 
 
Clemens Tempfer, MD 
 
 
 
 
 
 
Laudia Hadjari, BA 
Abteilung für Gynäkologie und Geburtshilfe, Ordensklinikum Linz 
Principal Investigator according to  
Austrian law: 
 
 
 
Lukas Hefler, MD 
Sponsor: 
 Ordensklinikum Linz  
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 2
Inhalt 
 
1. STUDY SYNOPSIS ENGLISH .................................................................................... 5 
TITLE .......................................................................................................................................... 5 
NAME OF MEDICATION ............................................................................................................ 5 
DESCRIPTION OF PROCEDURES .............................................................................................. 5 
OBJECTIVES .............................................................................................................................. 5 
TYPE OF INVESTIGATION......................................................................................................... 6 
NUMBER OF PATIENTS ............................................................................................................. 6 
INCLUSION CRITERIA .............................................................................................................. 6 
EXCLUSION CRITERIA .............................................................................................................. 6 
PRIMARY ENDPOINT ................................................................................................................ 7 
SECONDARY ENDPOINTS ......................................................................................................... 7 
STATISTICS ............................................................................................................................... 7 
NULL HYPOTHESIS .................................................................................................................... 7 
ALTERNATIVE HYPOTHESIS ..................................................................................................... 7 
TABLE 1. VISIT SCHEDULE ..................................................................................................... 8 
2. INTRODUCTION ........................................................................................................... 9 
BACKGROUND INFORMATION CLINICAL ................................................................................. 9 
RATIONALE OF THE INVESTIGATION .................................................................................... 11 
3. OBJECTIVES OF THE CLINICAL INVESTIGATION (HYPOTHESIS) ........ 11 
4. STUDY PROTOCOL AND DESIGN FIGURE 1 .................................................... 12 
5. STUDY POPULATION ................................................................................................ 14 
INCLUSION CRITERIA ............................................................................................................ 14 
EXCLUSION CRITERIA ............................................................................................................ 15 
DURATION OF THE CLINICAL INVESTIGATION .................................................................... 15 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS ............................................................... 15 
CRITERIA FOR WITHDRAWAL .............................................................................................................. 15 
SUBJECTS MUST BE WITHDRAWN UNDER THE FOLLOWING CIRCUMSTANCES: ............................. 16 
FOLLOW-UP OF PATIENTS WITHDRAWN FROM THE CLINICAL INVESTIGATION ............................. 16 
REPLACEMENT POLICY ......................................................................................................................... 16 
PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION ........................................ 16 
6. METHODOLOGY .......................................................................................................... 17 
TREATMENT DURATION AND MODIFICATION ...................................................................... 17 
MEDICATION ........................................................................................................................... 17 
ACCOUNTABILITY OF THE MEDICATION ............................................................................................. 18 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 3
INTENDED USE ..................................................................................................................................... 18 
TYPE I AND II ERRORS .......................................................................................................... 18 
STATISTICS ............................................................................................................................. 18 
SAMPLE SIZE ........................................................................................................................... 19 
CONCOMITANT MEDICATION ......................................................................................................... 20 
THERE IS NO NEED TO CHANGE OF CONCOMITANT MEDICATION. .................................................. 20 
INTERACTIONS, REVERSE REACTIONS AND SIDE EFFECTS .................................................... 20 
BENEFIT AND RISK ASSESSMENT .......................................................................................... 20 
CLINICAL INVESTIGATION PROCEDURES ............................................................................ 21 
 
7. SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ....................... 23 
ADVERSE EVENT (AE): .......................................................................................................... 23 
SUMMARY OF KNOWN AND POTENTIAL RISKS OF THE MEDICAL DEVICE........................................ 23 
DEFINITION OF ADVERSE EVENT AND ADVERSE DEVICE EFFECT .................................................... 23 
SERIOUS ADVERSE EVENT (SAE) ........................................................................................ 25 
HOSPITALIZATION – PROLONGATION OF EXISTING HOSPITALIZATION ........................................ 25 
DEVELOPMET SAFETY UDATE REPORT .................................................................................. 29 
SEVERITY OF ADVERSE EVENTS ............................................................................................ 29 
RELATIONSHIP TO THE STUDY PROCEDURES ...................................................................... 30 
8. FOLLOW UP .................................................................................................................. 32 
9.  STATISTICAL METHODOLOGY AND ANALYSIS ............................................ 32 
INTENTION TO TREAT SET ................................................................................................................... 32 
SAMPLE SIZE ........................................................................................................................... 32 
STATISTICAL ANALYSIS PLAN ............................................................................................... 32 
ENDPOINTS ANALYSIS ........................................................................................................... 33 
PRIMARY ENDPOINT ANALYSIS ........................................................................................................... 33 
SECONDARY ENDPOINT ANALYSIS ...................................................................................................... 33 
INTERIM ANALYSIS ............................................................................................................................... 34 
SOFTWARE PROGRAM(S) .................................................................................................................... 34 
10.  DOCUMENTATION AND DATA MANAGEMENT ............................................... 34 
DOCUMENTATION OF STUDY RESULTS ................................................................................. 34 
CASE REPORT FORM (CRF) ................................................................................................................ 34 
DATA COLLECTION .............................................................................................................................. 35 
SAFEKEEPING .......................................................................................................................... 35 
QUALITY CONTROL AND QUALITY ASSURANCE.................................................................. 36 
MONITORING ........................................................................................................................................ 36 
AUDITS AND INSPECTIONS ................................................................................................................ 36 
REPORTING AND PUBLICATION ............................................................................................ 37 
FINAL REPORT ...................................................................................................................................... 37 
PUBLICATION OF STUDY RESULTS ...................................................................................................... 37 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 4
11.  ETHICAL AND LEGAL ASPECTS ........................................................................... 37 
INFORMED CONSENT OF SUBJECTS ....................................................................................... 37 
INSURANCE ............................................................................................................................. 39 
CONFIDENTIALITY .................................................................................................................. 39 
ETHICS AND LEGAL REQUIREMENTS ..................................................................................... 39 
DECLARATION OF HELSINKI ............................................................................................................... 39 
12. REFERENCES ............................................................................................................... 41 
13.  APPENDIX ................................................................................................................... 47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 5
1. Study Synopsis English 
Title 
A prospective, randomized, double-blind, controlled trial on the application 
of a 10%-lidocaine spray prior to the insertion of a peripheral venous 
catheter in female adults. 
 
Short Title 
VENLID 
Name of Medication 
10% Lidocaine Spray 
Description of procedures 
Volunteers are invited to undergo 4 insertions of a peripheral intra-venous 
18-gauge catheter (PIVC); 2 insertions at the the start of the study on the 
plantar side of the hand/vessel at the dorsum manus, 2 insertions after 2-
10 hours into the forearm/cubita with and without application of a 10-% 
lidocaine spray (5 hubs of xylocaine 10%-pump spray; AstraZeneca BV, 
Zoetermeer, The Netherlands) prior to the insertion of the PIVC. 
Objectives 
Primary objective:  
 To demonstrate a reduction of pain caused by PIVC rated by 
Numerical Rating Scale (NRS), after application of a 10% lidocaine 
spray- Separately measured for the plantar side of the hand/vessel 
at the dorsum manus, and for the forearm/cubita. 
 
Secondary objectives:  
 To measure pain caused by PIVC rated by NRS in the dominant vs. 
non-dominant arm 
 To measure pain caused by PIVC rated by NRS at the plantar side of 
the hand/vessel at the dorsum manus, vs. at the forearm/cubita 
 To measure the correlation between pain caused by PIVC rated by 
NRS and the anticipated pain rated by NRS  

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 6
 To measure the correlation between pain caused by PIVC rated by 
NRS and the anticipated difficulty by the operator to insert the PIVC 
 To measure pain rated by NRS depending on success  
 To describe success rates and compare it 
 To measure the correlation between PCS and pain caused by PIVC 
rated by NRS 
 
Type of investigation 
A prospective, randomized, double-blind, single-center study 
Number of patients 
40 volunteers- 80 upper extremities 
Inclusion criteria  
Female volunteers 18-45 years (we choose female volunteers because 
only femal patients are treated at the department of gynecology and 
obstetrics) 
Personal history of ever having a venipuncture or insertion of PIVC 
Exclusion criteria 
Fractures on the upper extremity resulting in permanent movement 
restriction 
Significant burns on the upper extremity-at the discretion of the principal 
investgator 
Personal history of any thrombosis 
Personal history of chemotherapy 
Potential allergy to a PIVC 
Personal history of surgery in the axilla 
Personal history of any pathologies in the blood coagulation pathway 
Personal history of difficult peripheral venous access 
Personal history of complications with a PIVC 
Any concomitant use of an analgesic within the previous 24 h 
Any concomitant use of anticoagulation 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 7
Primary Endpoint 
Pain caused by PIVC rated by NRS separately for the back of the plantar 
side of the hand/vessel at the dorsum manus, and for the forearm/cubita.  
Secondary Endpoints 
1. Pain caused by PIVC in the dominant vs. non-dominant arm 
2. Pain caused by PIVC at the plantar side of the hand/vessel at the 
dorsum manus, vs. at the forearm/cubita 
3. Correlation between pain caused by PIVC and the anticipated 
pain  
4. Correlation between pain caused by PIVC and the anticipated 
difficulty by the operator to insert the PIVC  
5. Success rate of the venepuncture by descriptive analysis and 
comparison 
6. Pain caused by PIVC broken down by success/failure of insertion 
of PIVC 
7. Correlation between pain caused by PIVC and PCS 
8.  
Statistics 
Primary Endpoint: paired t-test of pain caused by PIVC rated by NRS 
with/without LA separately for the plantar side of the hand/vessel at the 
dorsum manus, and the forearm/cubita.  
 
Null hypothesis 
There is no difference in pain with and without application of LA for the 
plantar side of the hand/vessel at the dorsum manus.  
There is no difference in pain with and without application of LA for the 
forearm/cubita. 
 
Alternative hypothesis 
There is a difference in pain with and without application of LA for the 
plantar side of the hand/vessel at the dorsum manus, and the 
forearm/cubita. 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 
8
 
Table 1. Visit Schedule 
 
Visit 
1 
2 
 
 
 
Name 
Screening 
Treatment Day 
 
 
 
Time 
 
Day 1 
 
 
 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Medical History 
Urine pregnancy test 
X 
X 
 
 
 
 
PIVC vessel at the dorsum 
manus 
 
X 
 
 
 
PIVC forearm/cubita 
 
X 
 
 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 9
2. INTRODUCTION 
Background information 
Insertion of a peripheral intra-venous catheter (PIVC) is one of the most 
common medical procedures worldwide (Webster et al., 2019; Helm et al., 
2015; Zingg et al. 2017; Hadaway et al., 2012; Zingg et al., 2023). While 
many studies focused on potential short and long term complications of 
PIVC such as phlebitis, infiltration/extravasation, occlusion, leakage, and 
dislodgement (Marsh et al., 2020; , Lv et al., 2020; Messika et al., 2015; 
Maki et al., 2006; Worth et al., 2018) and pain in children (Cozzi et al., 
2022), few studies have adressed pain and discomfort in adults. 
Recently, pain caused by the application of PIVC has gained more 
attention in the scientific literature (Bond et al., 2016). It has also been 
stated that causing unnecessary pain during medical procedures - 
including insertion of peripheral PIVC - is doing harm to the patients 
(Bond et al., 2016; Selby et al., 1995). A meta-analysis compared the 
pain after a local anesthetic with the unattenuated pain of PIVC insertion 
and found that all applications of local anaesthetic were less painful than 
PIVC insertion without the local anesthetic (Bond et al., 2016). The 
authors concluded that applying a local anesthetic prior to PIVC insertion 
should become standard practice and should be seen as a surrogate 
marker of high-quality care (Bond et al., 2016). Potentially unnecesary 
pain is uncomfortable for the patient and may also increase fear and 
anxiety about future treatments (Joshi et al., 2005; Moore et al., 2009; 
Pfingsten et al., 2004; Todd et al., 1991). Pain may also trigger an 
autonomic nerve response resulting in vasoconstriction (Calder et al., 
2007; Bamgbade et al., 2007) potentially making PIVC more difficult to 
insert (Collignon et al., 1994; Kagel et al., 2004; Maki et al., 2006). 
Practice patterns concerning the use of local anesthesia prior ro 
insertion ov PVC are differing widely (Sado et al., 2005). .Usually local 
anaesthesia is only provided for children prior to PIVC (Cozzi et al., 2022, 
Bond et al., 2016). Mostly, intradermally injected lidocaine, a eutectic 
cream consisting of a mixture of local anesthetics (EMLA®), or a 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 10 
vapocoolant spray are being used. Local anesthesia is rarely offered to 
adults due to an assumed low grade of pain. Caregivers report various 
reasons for this, including that it was time-consuming (45 %), not 
indicated (35 %), made PIVC more difficult (21 %), not available (13 %), 
logistically difficult (13 %), against peer pressure (4 %), not allowed (4 
%) and practically difficult (4 %) (Norris et al., 2002). 
While many local anesthetic procedures either take a rather long 
preparation time, such as EMLA or cause pain by itself such as intradermal 
injection of lidocaine, lidocaine spray is an easy to use and readily 
available agent, which has been used for various indications and only 
needs a short exposure time. (Kanai et al., 2009; Evans et al., 2006; 
Tanaka et al., 2015; Sunkareni et al., 2011). Its effects reportedly begin 
within 1–2 min, reach maximum efficacy within 5 min, and last for 
approximately 15min (Lee et al., 2016). Studies have shown that 
lidocaine spray is successful in reducing pain from cervical traction during 
intrauterine device placement, endometrial sampling, nasoenteral 
catheterization, and arteriovenous fistula manipulation (Torky et al., 
2017; Karasu et al., 2017; Aksoy et al., 2016; de Oliveira et al., 2020; 
Song et al., 2016). 
Regarding venous punctures, lidocaine spray has been successfully 
tested prior to the insertion of a non-coring needle into a totally 
implantable venous access port (Zhu et al., 2023), in patients 
administered a contrast medium during vein puncture (Oh et al., 2016) 
and in radial arterial puncture (Yildiz et al., 2021). It can be assumed that 
local anesthesia in general and lidocaine spray in particular can reduce 
pain in the range of 10mm on the Visual Analogue Scale or one point in 
the Numeric Rating Scale (NRS). This reduction of pain has also been 
reported to be of clinical relevance (Rüsch et al., 2017)  
Interestingly, only two small randomized study have been published 
on lidocaine spray prior to insertion of a PIVC; one with a relatively low 
number of patients using only a 20 gauge PIVC. It is not unexpected that 
in this scenario the application of lidocaine spray does not reduce pain 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 11 
levels (Datema et al., 2019). The other study reports positive findings 
with the lidocaine spray significantly reducing venipuncture-associated 
pain. Of note, a 20 minute waiting time time prior to the venipuncture was 
used in this study (Van Straten et al., 2018). 
Therefore, the aim of the present study is to provide clinically 
important data on local anesthetic application prior to PIVC insertion with 
a short exposure time. If positive, these data are likely to change clinical 
practice. 
Rationale of the clinical investigation 
Promising data have been reported on local anesthesia prior to PIVC 
insertion. Our treatment plan aims at making local anesthesia application 
prior to PIVC clinically feasible as we test a 2 min exposure time to local 
anesthesia with a readily available and well known local anesthesia 
preparation. 
3. OBJECTIVES OF THE CLINICAL INVESTIGATION 
(HYPOTHESIS) 
Objectives (Hypothesis) 
Primary objective:  
 To demonstrate a reduction of pain caused by PIVC rated by 
Numerical Rating Scale (NRS), after application of a 10% lidocaine 
spray- Separately measured for the plantar side of the hand/vessel 
at the dorsum manus, and for the forearm/cubita. 
 
Secondary objectives:  
 To measure pain caused by PIVC rated by NRS in the dominant vs. 
non-dominant arm 
 To measure pain caused by PIVC rated by NRS at the plantar side of 
the hand/vessel at the dorsum manus vs. at the forearm/cubita 
 To measure the correlation between pain caused by PIVC rated by 
NRS and the anticipated pain rated by NRS  
 To measure the correlation between pain caused by PIVC rated by 
NRS and the anticipated difficulty by the operator to insert the PIVC 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 12 
 To measure pain rated by NRS depending on success 
 To describe success rates and compare it  
 To measure the correlation between PCS and pain caused by PVIC 
rated by NRS 
4. Study protocol and design Figure 1 
 
 
Screening for eligibility 
Study inclusion and 
Randomization  
Day 1 
2-10 hours later 
Exclusion due to ineligibility 
non-dominant/  
LA 
non-dominant/  
placebo 
dominant/  
LA 
dominant/ 
placebo 
dominant/  
LA 
 
 
non-dominant/ 
placebo 
dominant/ 
placebo 
 
 
non-dominant/ 
 LA 
Group A 
PIVC insertion 
Forearm/cubita 
Group D 
PIVC insertion 
 Forearm/cubita 
Group A 
PIVC insertion 
vessel at the dorsum manus 
Group B 
PIVC insertion 
vessel at the dorsum manus 
Group D 
PIVC insertion 
 vessel at the dorsum manus 
Group C 
PIVC insertion 
vessel at the dorsum manus 
non-dominant/ 
LA 
dominant/  
LA 
dominant/ 
placebo 
non-dominant/ 
placebo 
Group B 
PIVC insertion 
Forearm/cubita 
non-dominant/  
placebo 
 
 
dominant/  
LA 
Group C 
PIVC insertion 
Forearm/cubita 
non-dominant/ 
LA 
 
 
dominant/ 
placebo 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 13 
Screening 
All volunteers are screenend for study participation, a medical history is 
taken, inclusion/exclusion criteria are checked, a urine pregnancy test is 
performed. A respective informed consent is signed. 
 
 
Treatment day 1: 
First, volunteers will undergo insertion of PIVC into the vessel at the 
dorsum manus; Volunteers are randomized in 4 groups, volunteers serve 
as there own controls-see Figure 1 
2-10 hours later: 
All volunteers will undergo insertion of PIVC into the forearm/cubita, 
volunteers serve as their own controls. 
 
Description of Randomization. 
 
4 randomization groups are defined per protocol. 
 
"Dominant" refers to the stronger hand/forearm. 
 
o Group A: dominant/Placebo – non-dominant/LA 
o Group B: non-dominant/Placebo – dominant/LA 
o Group C: non-dominant/LA – dominant/Placebo 
o Group D: dominant/LA – non-dominant/Placebo 
 
Four bottles (a,b,c,d) are prepared by the pharmacy. Two bottles are filled 
with placebo and two bottles with the local anesthetic. The content of 
these bottles are only known by the Sponsor and the pharmacy. 
 
Bottle a= local anesthetic (vessel at the dorsum manus) 
Bottle b= placebo (vessel at the dorsum manus) 
Bottle c= placebo (forearm/cubita) 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 14 
Bottle d= local anesthetic (forearm/cubita) 
 
On the treatment day the subinvestigator will obtain a card for each 
subject in which the treatment for each subject is specified. There are 40 
cards and each card specifies the treatment protocol for a single subject. 
See attached document 2023-507859-29 Randomization cards. 
 
Neither the subinvestigator nor the subjects will know what the content of 
the bottles are. 
 
The plantar side of the hand and the forearm/cubita are randomized 
separately into the four groups A,B,C,D. Afterwards hand and arm are 
combined with each other. See attached document 2023-507859-29 
Randomization key. 
 
Randomization lists were generated via two separate block-randomization, 
one for hand and one for forearm.  
Two separate block randomizations are forseen for the plantar side of the 
hand/vessel at the dorsum manus and for forearm/cubita via Software R 
version 4.2.2 (R Core Team, 2022) and Package blockrand version 1.5 
(Snow, 2020). Each 2 blocks with a block length of 20 leading to 40 
subjects randomized with the same amount to 4 groups. 
This resulting list is only accessible for the sponsor. 
Only the principal investigator will be accountable for the medication and 
placebo throughout the study and knows how the numbers are assigned 
to the groups.  
 
5. Study population 
It is planned to include 40 healthy female volunteers into this trial.  
 
Inclusion criteria 
Female probands 18-45 years 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 15 
Personal history of ever having a venipuncture or insertion of PIVC 
 
Exclusion criteria 
Fractures on the upper extremity resulting in permanent movement 
restriction 
Significant burns on the upper extremity-at the dirscretion oft he principal 
investgator 
Personal history of any thrombosis 
Personal history of chemotherapy 
Potential allergy to a PIVC 
Personal history of surgery in the axilla 
Personal history of any pathologies in the blood coagulation pathway 
Personal history of difficult peripheral venous access 
Personal history of complications with a PIVC 
Any concomitant use of an analgesic within the previous 24 h 
Any concomitant use of anticoagulation 
Pregnancy 
 
Females of childbearing potential 
Pregnant or breast-feeding women are excluded form study participation.  
 
Duration of the clinical investigation 
Max. 10 hours 
 
Withdrawal and replacement of subjects 
Criteria for withdrawal 
Subjects may prematurely discontinue from trial participation at any time 
without having to give any reason. Premature discontinuation from trial 
participation is to be understood when the subject did not all 4 insertions 
of PIVC on the same day. 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 16 
Subjects must be withdrawn under the following circumstances: 
• at their own request 
• if the investigator feels it would not be in the best interest of the 
subject to continue 
• if the subject violates conditions laid out in the consent form / 
information sheet or 
• disregards instructions by the clinical investigation personal 
 
In all cases, the reason why subjects are withdrawn must be recorded in 
detail in the CRF and in the subject’s medical records. Should the clinical 
investigation be discontinued prematurely, all clinical investigation 
materials (complete, partially completed and empty CRFs) will be 
retained. 
 
Follow-up of patients withdrawn from the clinical investigation 
No follow-up will be performed. 
 
Replacement policy 
No replacement of volunteers will be performed. 
 
Premature termination of the clinical investigation 
The sponsor has the right to close this clinical investigation at any time. 
The independent ethics committee (IEC) and the competent regulatory 
authority must be informed immediately. 
The clinical investigation will be terminated prematurely in the following 
cases: 
• If adverse event/adverse devise effect occur which are rendered so 
serious that the risk-benefit ratio is inacceptable. 
• If the number of dropouts is so high that proper completion of the 
clinical investigation cannot be expected. 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 17 
6. Methodology  
Treatment duration and modification 
The study duration for each individual volunteer is estimated to be 4-10 
hours. A group of 5 residents working at the department of Obstetrics and 
Gynecology, Ordensklinikum Linz/BHB Linz are selected as potentially 
being responsible for inserting the PIVC; these are numbered in 
alphabetical order; a random number between 1 to 5 is generated by and 
the respectice resident is chosen as being responsible for inserting the 
PIVC. 
 
Medication 
Lidocaine spray 10 % (Xylocaine 10% pump spray; AstraZeneca BV, 
Zoetermeer, The Netherlands) and the placebo, physiological saline 
solution (NaCl 0,9% 250ml Fresenius KABI), are filled in neutral brown 
glass bottles with a dispenser dispensing 0.1ml per pulse of the dispenser 
by the Pharmacy of the Konventhospital Barmherzige Brüder Linz on the 
basis of AMG. 
Lidocaine spray 10 % (Xylocaine 10% pump spray) and the placebo 
(physiological saline solution NaCl 0,9%), are filled in neutral brown glass 
bottles. 2 bottles each are available. 2 bottles with label "a" and "b" for 
plantar side of hand/vessel at the dorsum manus and 2 bottles with label 
"c" and "d" for forearm/cubita. One of the bottles "a" and "b" is a placebo 
and the other one the local anaesthetic. One of the bottles "c" and "d" is a 
placebo and the other one the local anaesthetic. 
 
 
The person responsible for PIVC insertion and the volunteers are unaware 
which bottle contains the 10% lidocaine and which bottle the saline 
solution. Due to the banana like smell of lidocaine the person responsible 
for PIVC insertion and the volunteer will wear nose clips during the 
procedure. 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 18 
Accountability of the medication 
The principle investigator will be accountable for the medication and 
placebo throughout the study. 
 
Intended Use 
Lidocaine spray 10 % is applied with a dispenser dispensing 0.1ml per 
pulse of the dispenser on the area of the skin, where the insertion of the 
PIVC is planned. Exposure time is 2 min, timed with an hour glass; 
validated prior to the study by a stop watch. 0.5 ml (5 pulses) of 10% 
lidocaine spray (equals 50mg of lidocaine) are to be applied before 
insertion of a PIVC 18 Gauge. 
 
Null hypothesis: 
There is no difference in pain with and without application of LA for the 
plantar side of the hand/vessel at the dorsum manus.  
There is no difference in pain with and without application of LA for the 
forearm/cubita. 
 
Alternative hypothesis: 
There is a difference in pain with and without application of LA for the 
plantar side of the hand/vessel at the dorsum manus, and the 
forearm/cubita. 
 
Type I and II errors 
 5% two-sided 
 20% 
 
 
Statistics 
Pain caused by PIVC rated by NRS with/without application of local 
anesthesia will be analyzed by a paired- t-test. NRS is used as a 
continuous measure and we expect the values to be approximately 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 19 
normally distributed and therefore plan a parametric test. Normal 
distribution will be investigated via Shapiro-Wilk-Test. If there is no 
normal distribution, the non-parametric Wilcoxon test for paired samples 
will be used instead of the paired t-test. For descriptive analyses, mean 
values and standard deviations will be reported. For each primary 
outcome (plantar side of the hand/vessel at the dorsum manus and the 
forearm) separate significance tests for separate null hypotheses will be 
calculated and no adaption of the error due to multiple testing is needed. 
The analysis will be performed with the SPSS software (SPSS 32.0, SPSS 
Inc., Chicago, IL). 
For the analysis of the secondary endpoints paired t-test, independent t-
tests and pearson correlation will be used. If the data is not normal 
distributed, wilcoxon test for paired samples, Mann-Whitney-U test for 
independent samples and spearman correlation will be employed instead. 
For analyzing the success rate a chi-squared test will be calculated for 
comparison of groups. 
 
Randomization is performed by a standard randomization program; 
groups are stratified by where (dominant vs. non-dominant extremity) the 
first PIVC will be inserted and whether LA or placebo is used at the first 
PIVC insertion resulting in 4 distinct groups. 
No effect of order of dominant/non-dominant and placebo/LA is 
expected and thus in the main statistical analysis (see above) the 
randomization will not be taken into account. Nevertheless, an additional 
statistical analysis will be run as sensitivity analysis where the both 
randomization factors will be used as control variables in an ANOVA 
model. 
 
Sample size 
Sample size calculation was done using G*Power 3.1 (Faul et al. 2007) 
based on the main statistical analysis, the paired t-test, with a two-sided 
level of significance of 5 % and a power of 80 %. An effect size measure 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 20 
of Cohens d = 0.5 is used as this represents a difference in means of 1 
unit and a standard deviation of 2 and refers to a medium sized effect 
(Cohen 1988). The sample size calculation resulted in a required sample 
size of 36 for the analysis. As a drop out of 10 % is assumed, a sample 
size of 40 for the study is needed. 
An internal survey of 20 doctors at our department revealed an assumed 
drop out rate of 10%. 
 
Specific safety monitoring: Side effects of the treatment will be 
monitored and documented immediately after the treatment and during all 
follow up visits. 
 
Concomitant medication 
There is no need to change of concomitant medication. 
 
Interactions, reverse reactions and side effects 
 
Side effects of Lidocaine 10% on the skin:  
Often (that is, one to ten percent of those treated) temporary skin irritation 
and redness. 
Rarely (in less tahn 0.1 percent of thode treated) allergic reactions, severe 
itching on the skin /with raised lumps. 
Side effects of the treatment will be monitored and documented 
immediately. 
 
Benefit and risk assessment 
Benefits of volunteers 
Volunteers will receive a compensation for missing work for one day and 
compensation for pain and inconvenience, i.e. 140 Euro. 
 
 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 21 
 
Risk of the volunteers 
Volunteers will experience light to moderate pain by the insertion of the 
PIVC. Typical side effects of insertion of a PIVC include hematoma, 
bleeding, arterial punction, phlebitis, thrombosis, infection, abscesses, 
lacerating nerves, pain, etc. As the PIVC is inserted by an experienced 
operator, a standard operating procedure is followed, the PIVC will be 
immediately removed after insertion, all volunteers are monitored by a 
physician, PIVC insertion is performed within a hospital, and all volunteers 
know what to expect; the risk of study participation is regarded as 
minimal. 
 
Clinical investigation procedures 
All study-related measures will be performed at Ordensklinikum Linz 
/Konventhospital der Barmherzigen Brüder Linz. Volunteers are asked to 
lie comfortably horizontally on a bed with the head on a pillow. A 
tourniquet is put around the upper arm, tightened, and the site of the 
venipuncture is identified; the operator rates the anticipated difficulty of 
the PIVC insertion by NRS. The volunteer is asked to rate her anticipated 
pain by NRS and the fill in the Pain Catastrophizing Scale (PCS). 
The PCS is a self-assessment questionnaire to examine 
catastrophizing in clinical and nonclinical populations (Suren et al., 2014). 
Catastrophizing is commonly described as an exaggerated negative 
orientation toward noxious stimuli and plays an important role in 
experiencing and coping with pain. The PCS consists of 13 statements 
containing a number of thoughts and feelings one may experience when 
having pain. The items are divided into the categories of rumination, 
magnification and helplessness, with each item scored on a 5-point scale. 
Wheeler et al. report a mean test–retest reliability of 0.88 (95% CI 5 
0.83-0.93, range 0.73-0.97), representing good reliability. Internal 
consistency as expressed with Cronbach’s alpha was 0.92 (95% CI 5 0.91-
0.93) for the full scale, 0.89 (95% CI 5 0.87-0.91) for the rumination 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 22 
subscale, 0.77 (95% CI 5 0.73-0.82) for the magnification subscale and 
0.88 (95% CI 5 0.86-0.9) for the helplessness subscale. Using a 5-point 
Likert scale, from 0 (not at all) to 4 (always), people are asked to rate 
how often they experience the mentioned thoughts and feelings when 
they are in pain. Along with three subscale scores evaluating rumination, 
magnification, and helplessness, the overall score has a range of 0-52. 
Subscale Scores: Rumination: Items 8,9,10,11; Magnification: Items 
6,7,13; Helplessness: Items 1,2,3,4,5,12 
Higher scores indicate a greater degree of pain catastrophizing. A total 
score of >30 represents a clinically significant level of pain 
catastrophization. 
 
Lidocaine spray 10 % and the placebo, physiological saline solution, are 
filled in neutral brown glas bottles with a dispenser dispensing 0.1ml per 
pulse of the dispenser by the Pharmacy of the Konventhospital 
Bermherzige Brüder Linz, The operator and the volunteers are unaware 
which bottle contains the 10% lidocaine and which bottle the saline 
solution. 5 pulses of either lidocaine 10% or saline are applied to the site 
of the planned venipuncture (plantar side of the hand/vessel at the 
dorsum manus), an hourglass indicating the 2 min time is turned. The 
tourniquet is then loosened. After 2 minutes the tourniquet is tightened 
agained, desinfection is performed, another 30 sec is waited-timed by an 
hourglass-and the insertion of the PIVC is performed. The following PIVC 
will be used: BD Venflon Pro Safety, BD Vialon Material; 18G 1.3 x 32 
mm; (Beckton Dickinson Therapy, Helsingborg, Sweden). To check for 
success of the insertion of the PIVC 5 ml of saline is injected; either way 
(success/failure) the PIVC is to be removed and the pain caused by PIVC 
rated by NRS is recorded. A pressure bandage will be applied and the 
volunteer is checked for well being and discharged at the principal 
investigator’s discretion. Then the same procedure is repeated on the 
other extremity.  

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 23 
After 2-10 hours the next two insertions are performed according to the 
above mentioned protocol on the forearm/or within the cubita. Afterwards 
the volunteers are checked for well-being. 
 
 
General rules for clinical investigation procedures 
All clinical investigation measures (vital parameters, ECG, etc.) have to be 
documented with the current day and time. 
The dates of all procedures should be according to the study protocol. The 
time margins mentioned in the clinical investigation flow chart are 
admissible. If for any reason, a clinical investigation procedure is not 
performed within scheduled margins a protocol deviation should be noted, 
and the procedure should be performed as soon as possible or as 
adequate. 
 
7. Safety definitions and reporting requirements  
Adverse event (AE): 
Summary of known and potential risks of the medical device 
Side effects that might occurr during the approximately three-minute 
insertion process of the PIVC are pain, syncope, bleeding, and allergic 
reaction to lidocaine. 
 
Definition of adverse event and adverse device effect 
An Adverse Event (AE) is any adverse change from the subject's baseline 
condition, i.e. any unfavorable and unintended sign including an abnormal 
laboratory finding, symptom or disease which is considered to be clinically 
relevant by the physician that occurs during the course of the study, 
whether or not considered related to the medical device. 
 
Adverse event includes: 
Exacerbation of a pre-existing disease. 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 24 
Increase in frequency or intensity of a pre-existing episodic disease or 
medical condition. 
Disease or medical condition detected or diagnosed after treatment with 
the medical device even though it may have been present prior to the 
start of the clinical investigation. 
Continuous persistent disease or symptoms present at baseline that 
worsen following the start of the clinical investigation. 
Lack of efficacy in the acute treatment of a life-threatening disease. 
Events considered by the investigator to be related to clinical 
investigation-mandated procedures. 
Abnormal assessments, e.g., ECG and physical examination findings, must 
be reported as AEs if they represent a clinically significant finding that was 
not present at baseline or worsened during the course of the clinical 
investigation. 
Laboratory test abnormalities must be reported as AEs if they represent a 
clinically significant finding, symptomatic or not, which was not present at 
baseline or worsened during the course of the clinical investigation lead to 
interruption or permanent discontinuation of medical device. 
 
Adverse events do not include: 
Pre-planned interventions or occurrence of endpoints specified in the 
study protocol are not considered AEs, if not defined otherwise. 
Medical or surgical procedure, e.g. surgery, endoscopy, tooth extraction, 
transfusion. 
However, the event leading to the procedure is an AE. If this event is 
serious, the procedure must be described in the SAE narrative. 
Pre-existing disease or medical condition that does not worsen. 
Situations in which an adverse change did not occur, e.g., hospitalizations 
for cosmetic elective surgery or for social and/or convenience reasons. 
Misuse of either medical device or concomitant medication without any 
signs or symptoms. However, misuse must be mentioned in the Medical 
Device Inventory/ Treatment Log.   

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 25 
Serious adverse event (SAE) 
A Serious Adverse Event (SAE) is defined as any AE fulfilling at least one 
of the following criteria: 
A) leads to a death, 
B) leads to a serious deterioration in the health of the subject that 
1. resulted in a life-threatening illness or injury, 
2. resulted in a permanent impairment of a body structure or a body 
function, 
3. required in-patient hospitalization or prolongation of existing 
hospitalization, 
C) is an important medical event that may not immediately result in 
death, be life-threatening, or require hospitalization but may be 
considered as SAEs when, based upon appropriate medical 
judgment, it may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the 
definitions above. 
D) shows the occurrence of a malignant tumor (§3 (16) MPG). 
 
Life-threatening refers to an event in which the subject was at risk of 
death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
 
Hospitalization – Prolongation of existing hospitalization 
Hospitalization is defined as an overnight stay in a hospital unit and/or 
emergency room. An additional overnight stay defines a prolongation of 
existing hospitalization. 
The following is not considered an SAE and should be reported as an AE 
only: 
• Treatment on an emergency or out subject basis for an event not 
fulfilling the definition of seriousness given above and not resulting 
in hospitalization. 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 26 
The following reasons for hospitalizations are not considered AEs, and 
therefore not SAEs: 
Hospitalizations for cosmetic elective surgery, social and/or convenience 
reasons. 
Standard monitoring of a pre-existing disease or medical condition that 
did not worsen, e.g., hospitalization for coronary angiography in a subject 
with stable angina pectoris. 
Elective treatment of a pre-existing disease or medical condition that did 
not worsen, e.g., hospitalization for chemotherapy for cancer, elective hip 
replacement for arthrosis. 
 
SAE related to investigational drug 
 
Such SAEs are defined as SAEs that appear to have a reasonable possibility 
of causal relationship. 
 
Reporting procedure of SAEs 
In case of a serious adverse event, the Investigator has to use all supportive 
measures for best patient treatment.  
Reporting needs to follow the rules laid down in Article 41 of Regulation 
(EU) 536/2014 and Annex III. The investigator shall report serious adverse 
events to the sponsor without undue delay but not later than within 
24 hours of obtaining knowledge of the events. 
A written report is also to be prepared and should at least contain the 
following:  
• Patient number  
• Patient sex  
• The suspected investigational medical product (IMP)  
• The adverse event assessed as serious  
• Short description of the event and outcome If applicable, the initial 
report should be followed by the Follow up report, indicating the 
outcome of the SAE.  
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 27 
 
ADR adverse drug reaction is a “response to a drug which in noxious 
and unintended and which occurs at doses normally used in a man for 
prophylaxix, diagnosis, or therapy of disease or for the modification of 
physiologic function”. An ADR is harm directly caused by the drug at 
normal doses, during normal use. An ADR is a special type of AE in which 
a causative relationship can be shown. 
 
 
SUSARS Suspected unexpected Serious Adverse Reaction 
SUSARs are all serious adverse reactions with suspected causal relationship 
to the study drug that is unexpected (not previously described in the 
Summary of Product Characteristics or Investigator’s brochure) and 
serious.  
 
Reporting procedures of SUSARs 
Reporting needs to follow the rules laid down in Article 42 of Regulation 
(EU) 536/2014 and Annex III. 
The period for the reporting of suspected unexpected serious adverse 
reactions by the sponsor to the Agency shall take account of the seriousness 
of the reaction and shall be as follows: 
(a) in the case of fatal or life-threatening suspected unexpected serious 
adverse reactions, as soon as possible and in any event not later than seven 
days after the sponsor became aware of the reaction 
(b) in the case of non-fatal or non-life-threatening suspected unexpected 
serious adverse reactions, not later than 15 days after the sponsor became 
aware of the reaction 
(c) in the case of a suspected unexpected serious adverse reaction which 
was initially considered to be non-fatal or non-life threatening but which 
turns out to be fatal or life-threatening, as soon as possible and in any event 
not later than seven days after the sponsor became aware of the reaction 
being fatal or life-threatening. 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 28 
Where necessary to ensure timely reporting, the sponsor may, in 
accordance with section 2.4 of Annex III, submit an initial incomplete report 
followed up by a complete report. 
Such reports shall be made by the sponsor and should content at least the 
following details: 
• Patient number (study code/screening number)  
• Patient age in years and sex 
• Name of Investigator and investigating site  
• Period of administration  
• The suspected investigational medical product (IMP)  
• The adverse event assessed as serious and unexpected, and for which 
there is a suspected causal relationship to the IMP  
• Concomitant disease and medication  
• Short description of the event:  
• Description  
• Onset and if applicable, end  
• Therapeutic intervention  
• Causal relationship  
• Seriousness criteria or reportable reason  
Electronic reporting to the database referred to in Article 40 (1) of 
Regulation (EU) 536/2014 (“Eudravigilance”) should be the expected 
method for reporting of SUSARs to the competent authority. In that case, 
the format and content as defined by the regulatory requirements should 
be adhered to. The latest version of MedDRA should be applied. Lower level 
terms (LLT) should be used. 
 
The written report is divided into two parts: 
• Initial report: Informs about what has happened (AE assessed as 
serious), if there is a relationship to the medical device, and which 
action was set. 
• Follow up-Report: informs about the outcome 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 29 
The Sponsor is responsible for the classification of adverse events and 
ongoing safety evaluation of the clinical investigation and shall: 
• review the investigators assessment of all adverse events and 
determine and document in writing their seriousness and 
relationship to the investigational device 
• review all devices deficiencies and determine and document in 
writing whether they could have led to a serious adverse device 
effect 
 
Developmet safety udate report 
A Development Safety Update Report (DSUR) will be provided by the 
Sponsor annually in accordance with Article 43 of Regulation (EU) 536/2014 
and the ICH E2F guidance document.  
This report will be submitted to the National Competent Authorities and 
Ethics Committees via the electronic system referred to in Articles 80 of 
Regulation (EU) 536/2014 (“Clinical Trials Information System, CTIS”).  
 
 
Severity of adverse events 
The severity of clinical AEs  is graded on a three-point scale: mild, 
moderate, severe, and reported on specific AE pages of the CRF. 
If the severity of an AE worsens during medical device administration, 
only the worst intensity should be reported on the AE page. If the AE 
lessens in intensity, no change in the severity is required. 
 
Mild 
Event may be noticeable to subject; does not influence daily activities; the 
AE resolves spontaneously or may require minimal therapeutic 
intervention; 
 
 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 30 
Moderate 
Event may make subject uncomfortable; performance of daily activities 
may be influenced; intervention may be needed; the AE produces no 
sequelae. 
 
Severe 
Event may cause noticeable discomfort; usually interferes with daily 
activities; subject may not be able to continue in the study; the AE 
produces sequelae, which require prolonged therapeutic intervention. 
A mild, moderate or severe AE may or may not be serious. These terms 
are used to describe the intensity of a specific event (as in mild, 
moderate, or severe myocardial infarction). However, a severe event may 
be of relatively minor medical significance (such as severe headache) and 
is not necessarily serious. For example, nausea lasting several hours may 
be rated as severe, but may not be clinically serious. Fever of 39°C that is 
not considered severe may become serious if it prolongs hospital 
discharge by a day. Seriousness rather than severity serves as a guide for 
defining regulatory reporting obligations. 
 
Relationship to the study procedures 
For all, the investigator will assess the causal relationship between the 
study procedures and the AE using his/her clinical expertise and judgment 
according to the following algorithm that best fits the circumstances of the  
 
 
AE: 
Unrelated 
May or may not follow a reasonable temporal sequence from 
administration of the study product 
Is biologically implausible and does not follow known response pattern to 
the suspect medical device (if response pattern is previously known) 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 31 
Can be explained by the known characteristics of the subject’s clinical 
state or other modes of therapy administered to the subject. 
 
Unlikely 
There is a reasonable temporal relation between the AE and the medical 
device, but there is a plausible other explanation for the occurrence of the 
AE. 
 
Possibly 
Follows a reasonable temporal sequence from administration of the 
medical device. 
The AE may equally be explained by the study subject’s clinically state, 
environmental ortoxic factors, or concomitant therapy administered to the 
studsubject. 
• The relationship between the medical device and AE may also be 
clinically plausible. 
 
Probably 
Follows a reasonable temporal sequence from administration of the 
medical device, and plausible reasons point to a causal relation with the 
medical device. 
 
Related 
Follows a reasonable temporal sequence form administration of the 
medical device. 
Follows a known response pattern to the medical device (if response 
pattern is previously known). 
No other reasonable cause is present. 
 
Not assessable 
The causal relationship between the medical device and the AE cannot be 
judged. 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 32 
 
• report or ensure the reporting of all SAEs, wheter or not related to 
the medical device, to the EC and regulatory authorities (AGES)! 
 
8. Follow Up 
Follow-up of clinical investigation participants including follow-up 
of adverse events 
No follow up will be performed. 
 
9. 
STATISTICAL METHODOLOGY AND ANALYSIS 
Intention to treat set 
The statistical analysis of the primary and secondary endpoint is 
based on the intention-to-treat principles i.e. all patients included in the 
study will be analyzed.  
 
Sample size 
Sample size see section 7. Methodology 
 
Relevant protocol deviations 
All study protocol deviations will be listed in the study report. No 
deviations from the study protocol of any type will be made without 
complying with all IRB/EC established procedures and in accordance with 
applicable regulations. 
 
Statistical analysis plan 
A statistical analysis plan (SAP) will be completed before closure of the 
database. The SAP will include precise information on the statistical tests 
and the descriptive calculations for primary and secondary endpoints that 
will be used, the exact specification of the method for calculating the 95% 
confidence intervals, the exact definition of the analysis set that will be 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 33 
used, and additional explorative analysis as well as information of the 
statistical software. 
95 % confidence intervals will be reported for effect size measures Cohens 
d (comparison of difference in means) and correlation coefficients 
(correlation analysis). 
 
Endpoints analysis 
Primary endpoint analysis 
Primary endpoint analysis: The statistical analysis is based on calculating 
a paired t-test regarding pain caused by PIVC rated by NRS with and 
without 10% lidocaine spray separately for the plantar side of the 
hand/vessel at the dorsum manus and the forearm/cubita.  
 
Secondary endpoint analysis 
1. A paired t-test regarding pain caused by PIVC rated by NRS in the 
dominant vs. non-dominant arm, separately analyzed for 
placebo/LDA and hand/forearm. 95% confidence interval will be 
reported for the effect size measure Cohens d for this difference in 
means. 
2. A paired t-test regarding pain caused by PIVC rated by NRS at the 
plantar side of the hand/vessel at the dorsum manus vs. at the 
forearm/cubita, separately analyzed for placebo/LDA. 95% 
confidence interval will be reported for the effect size measure 
Cohens d for this difference in means. 
3. The sample Pearson correlation coefficient between pain caused by 
PIVC rated by NRS and the anticipated pain rated by NRS, 
separately analyzed for placebo/LDA and hand/forearm as well as 
95% confidence interval for correlation coefficient will be computed.  
4. The sample Pearson correlation coefficient between pain caused by 
PIVC rated by NRS and the anticipated difficulty by the operator to 
insert the PIVC rated, separately analyzed for placebo/LDA and 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 34 
hand/forearm as well as 95% confidence interval for the correlation 
coefficient will be computed. 
5. Success rate of the venipuncture by descriptive analysis and chi-
square test for comparing success rate between hand and forearm. 
6. A t-test for independent samples comparing pain caused by PIVC 
rated by NRS between success and failure of insertion of PIVC. This 
analysis will be calculated separately for placebo/LDA and 
hand/forearm. 95% confidence interval will be reported for the 
effect size measure Cohens d for this difference in means. 
7. The sample Pearson correlation coefficient between PCS Score (total 
sum score of 13 items ranging from 0-4) and pain caused by PIVC, 
separately analyzed for placebo/LDA and hand/forearm as well as 
95% confidence interval for the correlation coefficient will be 
computed. 
 
Interim analysis 
No interim analysis with possible consequence of stopping the trial for 
futility or efficacy will be performed. 
 
Software program(s) 
All statistical analysis were performed with the help of IBM SPSS Statistics 
Version 23. 
10. Documentation and data management 
Documentation of study results 
A subject screening and enrollment Log will be completed for all eligible or 
non-eligible subjects with the reasons for exclusion. 
 
Case report form (CRF) 
For each subject enrolled, a CRF will be completed and signed by the 
Investigator or a designated sub-Investigator. This also applies to those 
subjects who fail to complete the study. If a subject withdraws from the 
study, the reason will be noted in the CRF. Case report forms are to be 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 35 
completed on an ongoing basis. CRF entries and corrections will only be 
performed by study site staff, authorized by the Investigator. The entries 
will be checked by trained personnel and any errors or inconsistencies will 
be checked immediately. 
 
Data Collection 
Data collected at all visits are entered into a CRF. The CRFs will be source 
documents verified following guidelines established before study onset. All 
data that is collected in the course of study visits (screening, treatment,), 
will be entered into a CRF.  
 
Safekeeping 
The investigator will maintain adequate and accurate records to enable 
the conduct of the study to be fully documented and the study data to be 
subsequently verified. These documents will be classified into two different 
categories: investigator's file with all essential study documents, and 
subject clinical source documents. 
 
The investigator's file will contain the study protocol/amendments, CRFs, 
data clarification and query forms, EC/IRB and Regulatory Authority 
approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, screening and enrollment logs, 
and other appropriate documents/correspondence as per European 
Standard of EN ISO 14155 and regulatory requirements. 
Subject clinical source documents include, but are not limited to 
subject hospital/clinic records, physician’s notes, appointment book, 
original laboratory reports, pathology and special assessment reports, 
consultant letters, etc. 
These two categories of documents must be kept on file by the 
investigator for as long as needed to comply with national regulations. If 
source documents are not durable as long as needed (e.g. ECG printouts) 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 36 
they must be preserved as a copy. No study document should be 
destroyed without prior written approval from the sponsor of the study. 
When source documents are required for the continued care of the 
subject, appropriate copies should be made for storing outside of the site. 
All patient data will be pseudonymised with an identification number 
when entered into the eCRF and are only assignable to specific individuals 
with a number code. Only the study investigator of the particular center or 
authorized persons are able to make a connection between the number 
code and the individual patient. 
 
Quality Control and Quality Assurance 
Monitoring 
No formal monitoring will be performed by an external monitoring 
company. The files and the conduct of the study will be internally checked 
by GCP experienced scientific personel not directly involved in the study. 
It will be the responsibility of the monitoring personel to inspect the CRFs 
at regular intervals throughout the study, to verify the adherence to the 
study protocol and the completeness, consistency and accuracy of the 
data being entered on them. The monitoring standards require full 
verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs/SADEs and the 
recording of the main outcome measures.  
 
 
Audits and Inspections 
Upon request, the investigator will make all study-related source data and 
records available to a qualified quality assurance auditor mandated by the 
sponsor or to regulatory authority inspectors. The main purpose of an 
audit or inspection is to confirm that the rights and welfare of the subjects 
have been adequately protected, and that all data relevant for assessment 
of safety and efficacy of the investigational product have appropriately 
been reported to the sponsor.  

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 37 
 
The study investigator Prim. Univ.-Prof. Dr. Lukas Hefler, MBA has access 
to all study data and statistics at any time. 
 
Reporting and Publication 
Final report 
Within one year after the final completion of the study, a full Final Report 
will be written by the principal investigator. The Investigators will be 
asked to review and sign the Final Report. 
 
Publication of study results 
The findings of this study will be published by the sponsor (investigators) 
in a scientific journal and presented at scientific meetings. The manuscript 
will be circulated to all co-investigators before submission. Confidentiality 
of subjects in reports/publications will be guaranteed. 
 
11. Ethical and legal aspects  
Informed consent of subjects 
Following comprehensive instruction regarding the nature, 
significance, impact and risks of this clinical investigation, the patient 
must give written consent to participation in the study. During the 
instruction the patients are to be made aware of the fact that they can 
with-draw their consent – without giving reasons – at any time without 
their further medical care being influenced in any way. 
In addition to the comprehensive instructions given to the patients 
by the investigator, the patients also receive a written patient information 
sheet in comprehensible language, explaining the nature and purpose of 
the study and its progress. The patients must agree to the possibility of 
study-related data being passed on to relevant authorities. 
The patients must be informed in detail of their obligations in 
relation to the proband insurance in order not to jeopardize insurance 
cover. 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 38 
Acknowledgement / approval of the clinical investigation 
The investigator will submit this study protocol and any related document 
provided to the subject (such as subject information used to obtain 
informed consent) to an Ethics Committee (EC) or Institutional Review 
Board (IRB). Approval from the committee must be obtained before 
starting the clinical investigation, and should be documented in a dated 
letter to the investigator. 
The clinical investigation shall be performed in full compliance with the 
valid legal regulations of the Republic of Austria.  
The study must be notified to the Austrian Agency for Health and Food 
Safety (AGES) and Ethics Committee. 
 
Changes in the Conduct of the Clinical Investigation Plan 
Amendments of the clinical investigation plan 
Proposed amendments must be submitted to the ECs. Substantial 
amendments may be implemented only after EC approval has been 
obtained. Amendments that are intended to eliminate an apparent 
immediate hazard to subjects may be implemented prior to receiving EC 
approval. However, in this case, approval must be obtained as soon as 
possible after implementation. 
 
 
Termination of the clinical investigation 
If the sponsor or the investigator decides to terminate the clinical 
investigation before it is completed, they will notify each other in writing 
stating the reasons of early termination. In terminating the study, the 
sponsor and the investigator will ensure the adequate consideration is 
given to the protection of the subject interests. The investigator or 
sponsor will notify the relevant regulatory authorities and EC. 
Documentation will be filled in the Trial Master (Clinical Investigation) 
clinical investigation and Investigator Files. 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 39 
Insurance 
During their participation in the clinical investigation the patients will be 
insured as defined by legal requirements. The investigator of the clinical 
investigation will receive a copy of the insurance conditions of the 
'patients insurance'. The sponsor is providing insurance in order to 
indemnify (legal and financial coverage) the investigator/center against 
claims arising from the clinical investigation, except for claims that arise 
from malpractice and/or negligence. The compensation of the subject in 
the event of clinical investigation-related injuries will comply with the 
applicable regulations. Details on the existing patients insurance are given 
in the patient information sheet. 
 
Confidentiality 
The information contained in this document, especially unpublished data, 
is the property of the sponsor. It is therefore provided to you in 
confidence as an investigator, potential investigator, or consultant, for 
review by you, your staff, and an Ethics Committee or Institutional Review 
Board. It is understood that this information will not be disclosed to others 
without written authorization from the sponsor, except to the extent 
necessary to obtain informed consent from those persons to whom the 
medical device may be treated with. 
 
Ethics and legal requirements 
Declaration of Helsinki 
The investigator will ensure that this study is conducted in full 
conformance with the principles of the "Declaration of Helsinki" (as 
amended at the 56th WMA General Assembly, Tokyo, Japan, 2008). 
 
ICH: E6 (R2): Guideline for good clinical practice 
This document addresses the good clinical practice, an international 
ethical and scientific quality standard for designing, conducting, recording 
and reporting trials that involve the participation of human subjects.  

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 40 
 
It specifies general requirements intended to: 
• protect the rights, safety and well-being of human subjects, 
• ensure the scientific conduct of the clinical investigation and the 
credibility of the clinical 
 investigation results, 
• assist sponsors, monitors, investigators, ethics committees, 
regulatory authorities and other 
• bodies involved in the conformity assessment of medical devices. 
 
The investigator of the clinical investigation shall guarantee that only 
appropriately trained personnel will be involved in this. All clinical 
investigations must follow the European Standard of ICH E6 (R2) and the 
regulatory requirements. 
 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 41 
12. References 
 
Aksoy H, Aksoy U, Ozyurt S, Acmaz G, Babayigit MA, Yücel B, et al. Effect 
of lidocaine spray in painmanagement during office-based endometrial 
sampling: a randomised placebo-controlled trial. J Obstet Gynaecol. 2016; 
36(2):246–50.  
 
Bamgbade OA. Severe needle phobia in the perianesthesia setting. J 
Perianesth Nurs. 2007; 22:322–9. 
 
Bond M, Crathorne L, Peters J,Coelho H, Haasova M, Cooper C, Milner Q, 
Shawyer V, Hyde C, Powell R. First do no harm: pain relief for the 
peripheral venous cannulation of adults, a systematic review and network 
meta-analysis. BMC Anesthesiol. 2016 Oct 1;16(1):81. 
 
Calder I. The pain of venous cannulation. J R Soc Med. 2005; 98(8):388.  
 
Cohen, J. (1988).Statistical power analysis for the behavioral sciences (2. 
Auflage). Hillsdale, NJ: Erlbaum. 
 
Collignon PJ. Intravascular catheter associated sepsis: a common 
problem. The Australian Study on Intravascular Catheter Associated 
Sepsis. Med J Aust. 1994; 161(6):374–8. 
 
Cozzi G, Cognigni M, Busatto R, Grigoletto V, Giangreco M, Conte M, Barbi 
E. Adolescents' pain and distress during peripheral intravenous 
cannulation in a paediatric emergency setting. Eur J Pediatr. 2022; 
181(1):125-131. 
 
Datema J, Veldhuis J, Bekhof J. Lidocaine spray as a local analgesic for 
intravenous cannulation: a randomized clinical trial. Eur J Emerg Med. 
2019 Feb; 26(1):24-28. 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 42 
de Oliveira AS, Ribeiro CJN, Oliveira ALC, Correia VOS, Pinto JS, Santos-
Júnior E, et al. Analgesic efficacy of 10% lidocaine spray during 
nasoenteral catheterization: randomized triple-blind trial. Eur J Pain. 
2020; 24(3):536–43.  
 
Evans LT, Saberi S, Kim HM, Elta GH, Schoenfeld P. Pharyngeal anesthesia 
during sedated EGDs: is ‘the spray’ beneficial? a meta-analysis and 
systematic review. Gastrointest Endosc. 2006; 63:761–766. 
 
Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A. (2007). G*Power 3: A 
flexible statistical power analysis program for the social, behavioral, and 
biomedical sciences. Behavior Research Methods, 39, 175-191. 
 
Hadaway L. Short peripheral intravenous catheters and infections. Journal 
of Infusion Nursing. 2012; 35(4):230-40. 
 
Helm RE, Klausner JD, Klemperer JD, Flint LM, Huang E. Accepted but 
unacceptable: peripheral IV catheter failure. J Infusion Nurs. 2015; 
38(3):189e203.  
 
Joshi GP, Ogunnaike BO. Consequences of inadequate postoperative pain 
relief and chronic persistent postoperative pain. Anesthesiol Clin North 
Am. 2005; 23:21–36. 
 
Kagel EM, Rayan GM. Intravenous catheter complications in the hand and 
forearm. J Trauma. 2004; 56(1):123–7. 
 
Kanai A, Kumaki C, Niki Y, Suzuki A, Tazawa T, Okamoto H. Efficacy of a 
metered-dose 8% lidocaine pump spray for patients with post-herpetic 
neuralgia. Pain Med. 2009; 10:902–909. 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 43 
Karasu Y, Cömert DK, Karadağ B, Ergün Y. Lidocaine for pain control 
during intrauterine device insertion. J Obstet Gynaecol Res. 2017; 
43(6):1061–6. 
 
Lee HS. Recent advances in topical anesthesia. J Dent Anesth Pain Med. 
2016;16(4): 237–44.  
 
Lv L, Zhang J. The incidence and risk of infusion phlebitis with peripheral 
intravenous catheters: A meta-analysis. J Vasc Access. 2020; 
21(3):342e9. 
 
Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in adults 
with different intravascular devices: A systematic review of 200 published 
prospective studies. Mayo Clin Proc. 2006; 81(9):1159e71.  
 
Marsh N, Webster J, Ullman AJ, Mihala G, Cooke M, Chopra V, et al. 
Peripheral intravenous catheter non-infectious complications in adults: A 
systematic review and meta-analysis. J Adv Nurs. 2020; 76(12):3346e62.  
 
Messika J, Roux D, Dreyfuss D, Ricard JD. Voies veineuses périphériques 
et risque d’infections acquises en réanimation. Médecine Intensive 
Réanimation. 2015; 24(3), 310–317. 
 
Moore A, Straube S, McQuay H. Minimising pain during intravenous 
cannulation. BMJ. 2009; 338:a2993. 
 
Norris WD. The use of local anaesthesia in peripheral venous cannulation: 
current practice of junior doctors. J R Nav Med Serv. 2002; 88(2):62–4. 
 
Oh YM, Jeong HC. Effects of Lidocaine Spray on Pain and Anxiety in 
Patients Administered a Contrast Medium during Vein Puncture. 
International Journal of Bio-Science and Bio-Technology. 2016; 8, 73-82. 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 44 
 
Pfingsten M, et al. Fear-avoidance behavior and anticipation of pain in 
patients with chronic low back pain: a randomized controlled study. Pain 
Med. 2004; 2:259–66. 
R Core Team (2022). R: A language and environment for statistical 
computing. R Foundation for Statistical Computing, Vienna, Austria. URL 
https://www.R-project.org/. 
 
Rüsch D, Koch T, Spies M, Eberhart LHJ: Pain during venous cannulation - 
a randomized controlled study of the efficacy of local anesthetics. Dtsch 
Arz-tebl Int. 2017; 114: 605–11. DOI: 10.3238/arztebl.2017.0605. 
 
Sado DM, Deakin CD. Local anaesthesia for venous cannulation and 
arterial blood gas sampling: are doctors using it? J R Soc Med. 2005; 
98(4):158–60. 
 
Selby I, Bowles B. Analgesia for venous cannulation: a comparison of 
EMLA (5 minute application), lignocaine, ethyl chloride and nothing. J R 
Soc Med. 1995; 88(5):264–7. 
 
Snow G (2020). _blockrand: Randomization for Block Random Clinical 
Trials_. R package version 1.5, https://CRAN.R-
project.org/package=blockrand. 
 
Song JM, Park HJ. Effects of 10% lidocaine spray and aroma hand 
massage on pain, anxiety, blood pressure, and pulse during arteriovenous 
fistula needling in hemodialysis patients. Korean J Rehab Nurs. 2016; 
19(1):1–11. 
 
Sunkaraneni VS, Jones SE. Topical anaesthetic or vasoconstrictor 
preparations for flexible fibre-optic nasal pharyngoscopy and 
laryngoscopy. Cochrane Database Syst Rev 2011; 3:CD005606.  

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 45 
 
Suren M, Kaya Z, Gokbakan M, Okan I, Arici S, Karaman S, M Comlekci M, 
Balta MG, Dogru S. The role of pain catastrophizing score in the prediction 
of venipuncture pain severity. Pain Pract 2014;14(3):245-51. 
 
Tanaka Y, Nakayama T, Nishimori M, Tsujimura Y, Kawaguchi M, Sato Y. 
Lidocaine for preventing postoperative sore throat. Cochrane Database 
Syst Rev. 2015; 7:CD004081. 
 
Todd JE, Lader D. Adult dental health. London: HMSO; 1991. 
Torky H, Moussa A, El-Desouky ES, Dief O, Ahmed A. Lidocaine gel vs 
lidocaine spray in reducing pain during insertion of the intrauterine 
contraceptive device. Eur J Contracept Reprod Health Care. 2017; 
22(2):159–61.  
 
Van Straten A, Murray AA, Levin AI. Xylocaine® 10% pump spray as 
topical anaesthetic for venepuncture pain. S Afr J Anaesth Analg. 2018; 
24(3):75–8. 
 
Webster J, Osborne S, Rickard CM, Marsh N. Clinically indicated 
replacement versus routine replacement of peripheral venous catheters. 
Cochrane Database Syst Rev. 2019; Jan 23;1(1):CD007798. 
 
Wheeler CHB, Amanda C de C Williams A, Morley SJ.  
Meta-analysis of the psychometric properties of the Pain Catastrophizing 
Scale and associations with participant characteristics. Pain 
2019;160(9):1946-1953. 
 
Worth LJ, Daley AJ, Spelman T, Bull AL, Brett JA, Richards MJ. Central and 
peripheral line-associated bloodstream infections in Australian neonatal 
and paediatric intensive care units: findings from a comprehensive 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 46 
Victorian surveillance network, 2008-2016. J Hosp Infect. 2018; 
99(1):55e61.  
 
Yildiz IU, Yildirim C, Özhasenekler A, Sener A, Gökhan S. Effectiveness of 
lidocaine spray on radial arterial puncture pain: A randomized double-
blind placebo controlled trial. Am J Emerg Med. 2021; 50:724-728. 
 
Zhu Y, Niu S, Zhang Y, Zhang H, Chang J, Ye L. Effect of lidocaine spray 
on relieving non‑coring needle puncture‑related pain in patients with 
totally implantable venous access port: a randomized controlled trial. 
Supportive Care in Cancer. 2023; 31:452. 
 
Zingg W, Barton A, Bitmead J, Eggimann P, Pujol M, Simon A, Tatzel J. 
Best practice in the use of peripheral venous catheters: A scoping review 
and expert consensus. Infect Prev Pract. 2023; 5(2):100271. 
 
Zingg W, Metsini A, Balmelli C, Neofytos D, Behnke M, Gardiol C,et al. 
National point prevalence survey on healthcare-associated infections in 
acute care hospitals, Switzerland, 2017. Euro Surveill. 2019;24(32).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 47 
 
13.  Appendix 
 
    13.1 Appendix 1 - Numeric Pain Rating Scale  
 
The NRPS is a segmented numeric version of the visual analog scale in 
which a respondent selects a whole number (0-10 integers) that best 
reflects the intensity of his/her pain. 
 The common format is a horizontal bar or line 
 Similar to the VAS, the NPRS is anchored by terms describing pain 
severity extremes. 
The 11-point numeric scale ranges from ‚0‘ representing one pain extreme 
(e.g.“no pain“) to ‚10‘ representing the other pain extreme (e.g. „pain as 
bad as you can imagine“ or „worst pain imaginable“) 
 
                           
 
 
 
 
 
 
 
 
 
 
 
 
 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 48 
 
14.2  Appendix 2 - Pain Catastrophizing Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

VENLID 
 
Version 3.0 
 
 
Date: 17.05.2024 
 
 
 49 
 
 
 
 
DECLARATION OF SPONSOR 
 
 
 
VENLID: A prospective, randomized, double-blind, controlled trial on the application 
of a 10%-lidocaine spray prior to the insertion of a peripheral intra-venous catheter in 
female adults 
 
 
I have read this trial protocol and agree that it contains all the information required to 
conduct the trial. I agree to conduct the trial as set out in this protocol. In particular, I 
agree to adhere to the moral, ethical and scientific principles governing clinical 
research as set out in the current version of the Declaration of Helsinki, the ICH 
Guideline on Good Clinical Practice E6 (R2) and the appropriate national laws and 
regulations. 
 
 
 
I agree to handle all information concerning the trial confidentially. 
 
 
 
 
 
 
_________________________                   __________________________ 
Place, Date  
 
 
 
      Printed Name 
 
 
 
 
 
_________________________                    __________________________ 
Address 
 
 
 
 
      Signature