A Study of the Use of Microneedle Patches to Deliver Topical Lidocaine in the Oral Cavity
Phase: PHASE1
Conditions: Topical Anaesthesia
Sponsor: Innoture Ltd

Final Clinical Investigation Plan 
Version 4.0, 11th April 2018  
 
Confidential 
 
Page 1 of 34 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
A STUDY OF THE USE OF MICRONEEDLE PATCHES TO DELIVER 
TOPICAL LIDOCAINE IN THE ORAL CAVITY 
 
Clinical Investigation Plan Number: Innoture/NW-01 
 
Version 4.0 – 11th April 2018  
 
 
 
Principal Investigator: 
Professor N West  
 
Co-Investigator: 
Dr. N Claydon  
 
Study Site: 
Rhiwbina Dental Surgery 
 
25-27 Heol Y Deri 
 
Cardiff 
 
CF14 6HB 
 
 
 
 
Sponsor: 
 
 
Innoture Limited 
 
 
 
 
2nd Floor, 58 Davies Street 
 
 
 
 
Mayfair 
 
 
 
 
London 
 
 
 
 
W1K 5FJ 
 
 
 
 
 
 
 
 

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Clinical Investigation Plan Agreement 
 
A STUDY OF THE USE OF MICRONEEDLE PATCHES TO DELIVER TOPICAL 
LIDOCAINE IN THE ORAL CAVITY 
 
Clinical Investigation Plan Number: Innoture/NW-01 
 
 
 
 
 

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Page 3 of 34 
 
Clinical Investigation Plan Agreement 
 
 
A STUDY OF THE USE OF MICRONEEDLE PATCHES TO DELIVER TOPICAL 
LIDOCAINE IN THE ORAL CAVITY 
 
Clinical Investigation Plan Number: Innoture/NW-01 
 
 
 
 
 

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Table of Contents 
 
Section Number Section 
Page Number 
1.0 
SUMMARY OF STUDY 
6 
2.0 
STUDY FLOW CHART 
8 
2.1  
Study Timelines 
8 
3.0 
INTRODUCTION AND RATIONALE 
8 
4.0 
METHODS AND MATERIALS 
9 
4.1 
Participant Recruitment 
9 
4.2 
Study Design 
10 
4.3 
Study Population 
11 
4.4 
Assessment Methods 
11 
5.0 
OBJECTIVES 
11 
5.1 
Primary Objectives 
11 
5.2 
Secondary objective 
11 
6.0 
STUDY PERSONNEL AND 
RESPONSIBILITIES 
12 
7.0 
INCLUSION & EXCLUSION CRITERIA FOR 
SELECTION OF PARTICIPANTS  
13 
7.1 
Inclusion Criteria 
13 
7.2 
Exclusion Criteria 
13 
7.3 
Withdrawal of Subjects from the Clinical Trial 
13 
7.4 
Participant Remuneration 
13 
8.0 
TREATMENT PLAN & METHODS 
13 
8.1 
Study Schedule and Administration 
13 
8.2 
Allocation of Treatments and Randomisation 
Procedures 
14 
8.3 
Participant Restrictions/Concurrent Treatments 
14 
8.4 
Screening and Enrolment Procedures 
14 
8.5 
Assessments for Efficacy 
14 
8.6 
Assessments for Safety 
15 
8.7 
Compliance Checks 
15 
9.0 
STUDY MATERIALS 
15 
9.1 
Test Products and Dosage 
15 
9.2 
Storage and Disposition of Test Products 
16 
9.3 
Precautions/Overdosage  
16 
9.4 
Other Study Supplies 
16 
10.0 
ADVERSE EVENTS 
16 
10.1 
Adverse Event and Medical Device Adverse 
Effects 
16 
10.1.1 
Exceptions 
16 
10.2 
Serious Adverse Event 
17 
10.3 
Severity and Relatedness of Adverse Events 
17 
10.4 
Reporting of Adverse Events 
18 
10.5 
Follow-up of Adverse Events 
18 
10.6 
Pregnancy Testing 
18 
10.7 
Serious Adverse Event Reporting 
18 
11.0 
DATA MANAGEMENT AND STATISTICAL 
ANALYSES 
19 
11.1 
Rationale for Sample Size 
19 
11.2 
Data Capture and Data Management 
19 

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11.3 
Statistical Analyses 
19 
12.0 
ETHICAL CONSIDERATIONS 
20 
13.0 
REGULATORY REQUIREMENTS AND 
INVESTIGATOR OBLIGATIONS 
21 
13.1 
GCP Statement 
21 
13.2 
Premature Termination of the Study  
21 
13.3 
Clinical Study Report  
21 
13.4 
Monitoring  
21 
13.5 
Compensation for Medicine-Induced Injury and 
Indemnification Requirements 
21 
13.6 
Publication Policy 
21 
14.0 
REFERENCES 
21 
Appendix 1 
Investigator/Designee Instructions for VAS 
Training Exercise 
23 
Appendix 2 
Participant Instructions for VAS Training 
exercise 
25 
Appendix 3a 
Topical Anaesthetic Information 
27 
Appendix 3b 
Infiltration Anaesthetic Information 
31 
 
 
 
 
 
 

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1.0 SUMMARY OF STUDY 
 
OBJECTIVES 
To look at the effect on patient perceived pain resulting from infiltration injection with local anaesthetic 
in a dental syringe with prior application of topical anaesthetic to the oral mucosa on a microneedle 
patch compared to a patch with no microneedles. 
 
To look at the safety of the patches when applied to the oral mucosa. 
 
STUDY DESIGN 
This is a randomised, 2 treatment, double blind design, with respect to the clinical assessor and subject, 
split mouth, crossover design with a negative control (patch with no microneedles).  
 
Prior to the start of the study, ethical approval by an independent research ethics committee and MHRA 
approval will be obtained. Potential participants will be invited to attend a screening visit. At this visit 
participants will be asked to read and sign a Participant Information Sheet and Consent Form prior to 
any study procedures being performed. They will be given ample time to decide if they wish to participate 
in the study. All participants will be private dental patients of Rhiwbina Dental. 
 
A dentally qualified clinician will record the participant’s demographics, medical history, 
current/concomitant medications, perform an oral soft tissue examination and ensure the participant 
fulfils the inclusion and exclusion criteria for the study. Two areas of the mouth will be identified for 
assessment during the study. The areas of the mouth will be identified as S1 or S2. Site S1 will be left 
or right palatal mucosa adjacent to the premolar area and S2 will be left or right upper buccal mucosa 
adjacent to the upper lateral incisor area. Only palatal or buccal aspect will be treated per treatment 
visit.  
 
Participants who successfully fulfil all the necessary entrance criteria will be provided with training by 
study staff on how to use a Visual Analogue Scale (VAS) record sheet and randomised to the study to 
receive treatment combination A or B in a random order. For eligible subjects, the screening visit and 
first treatment visit will occur at the same visit. The treatment possibilities are outlined below: 
 
Treatment A The application of a 5% topical lidocaine gel to one of the identified area within the 
participants mouth using a microneedle patch. The microneedle patch will be applied to the oral mucosa 
of the identified site for 3 minutes, followed by infiltration with a local anaesthetic to one of the identified 
areas within the participants mouth.  
 
Treatment B The application of a 5% topical lidocaine gel to one of the identified sites within the 
participants mouth using a patch with no microneedles. The patch with no microneedles will be applied 
to the oral mucosa of the identified site for 3 minutes, followed by infiltration with a local anaesthetic to 
one of the identified areas within the participants mouth.  
 
The chosen sites will be: S1; left and right palatal mucosa adjacent to the premolar area or S2; left and 
right upper buccal mucosa adjacent to the upper lateral incisor area. Each participant at the first visit 
will have either S1 or S2 sites allocated for treatment. For example, Treatment A will be allocated to S1 
left side and Treatment B to S1 right side or vice versa. At the second visit, 2 weeks (+/- 3 days) after 
the first visit, Treatment B will be allocated to S2 left side and Treatment A to S2 right side.  After 

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each treatment to each site participants will be asked to make pain assessments relating to the giving 
of the local infiltration anaesthetic. 
 
The study consists of 2 visits. At each visit, participants will be assigned to one of the treatment 
procedures (A or B) according to a predetermined randomisation schedule supplied by the study 
statistician, see section 8.2.  
 
Pain Assessment. 
Pain assessments will be performed after application of the topical anaesthetic for 3 minutes. Each test 
will be performed sequentially i.e. 3 separate needle insertions, with pain assessments recorded by the 
participant using a Visual Analogue Scale (VAS) and a verbal pain grading after each test. The level of 
pain at S1 or S2 will be assessed as follows: 
 
Test I. A short dental needle, mounted on a dental syringe containing a cartridge of 2% lidocaine 
hydrochloride and 1:80,000 adrenaline, will be used to penetrate the oral mucosa at the treated site and 
the patient asked to score the pain using a VAS rating scale and by verbal grading of zero, mild, 
moderate or severe. 
 
Test 2.  The same needle will be inserted through the oral mucosa and down to contact bone. Pain will 
be assessed as in Test 1. 
 
Test 3. The same needle will be again inserted through the oral mucosa and the cartridge of local 
anaesthetic will be injected into the site. Pain will be again assessed as in Test I. 
 
Following enrolment on to the study, participants will be given written and verbal instructions on the VAS 
and how to complete it. They will be given a test sheet to practice scoring which will be measured and 
checked by the clinician to ensure the participant understands how to complete the VAS form, see 
appendix 1. 
 
STUDY POPULATION 
Healthy participants of either gender aged 18 and over, with no medical or pharmacotherapy history 
which could compromise the conduct of the study will be recruited. It is envisaged that a sufficient 
number of healthy subjects will be screened by the study site so that a maximum of 16 who fulfil all the 
entry criteria will be randomised. 
 
 
 
 
 

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2.0 - STUDY FLOW CHART 
 
Obtain NHS Ethical and MHRA Approval 
I 
Screen Participants 
Informed Consent, Medical History, Oral Screening 
| 
Procedure A or B with pain assessment (Visit 1) 
I 
Procedure A or B with pain assessment (Visit 2) 
I 
Analysis of data 
I 
Final Report written 
 
2.1 – STUDY TIMELINES 
Start date June 2018 
End date December 2018 
Study duration 7 months 
 
3.0 INTRODUCTION AND RATIONALE 
Topical anaesthetic agents are often applied to skin and mucosae to reduce the discomfort of the patient 
to the subsequent use of a needle to inject the same or other drug. In dentistry, the most common use 
of topical anaesthetics is prior to the injection of a local anaesthetic. Topical lidocaine is perhaps the 
best known and most frequently used topical anaesthetic in dentistry, which dates back several 
decades. The British National Formulary (BNF) (1) states that lidocaine applied topically is absorbed 
through the oral mucosae and can be used up to a concentration of 10%. Side effects, including drug 
interactions are stated to be much less likely when lidocaine is applied topically (2), appendix 3. 
 
From clinical experience, the benefits of topical anaesthetics in dentistry to reduce pain associated with 
the subsequent injection is variable and dependent on several factors ranging from the apprehension 
of the patient to the site of the planned injection. What is generally accepted is that, topical anaesthetics 
alone do not provide sufficient anaesthesia for most operative procedures to the gingivae, oral mucosa, 
bone and teeth. These limitations in part must be related to the amount of lidocaine absorbed through 
the stratified squamous cell epithelium of the oral mucosa into the underlying connective tissues.  
 
Microneedle patches consist of a 2cm by 2 cm array of 625 needles of 400µm height and diameter of 
(200-250µm) printed using a UV cure resin onto a flexible backing material.  The advantage of these 
patches is that the needles are designed to puncture the outer surface of the epithelium (approximately 
150-250µm penetration under normal pressure when tested in vitro on pig skin), thus creating minute 
channels through which a topically applied drug can pass.  This method allows a wider range of drugs 
to be introduced to the site of action while still providing the benefit of by passing first-pass metabolism 
and thereby improving bioavailability.  One key advantage for patients is that use of the microneedle 
patches does not induce a pain response because they do not penetrate to the dermal layer of the skin 
which is where the nerve cells and capillaries are located.  
 

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a = 400µm, b = 800µm, c = ~450/500µm, d = ~250-350µm 
 
 
 
 
Preliminary in vitro studies using human skin of the rate of permeation of two medicinal products 
(lidocaine and inulin) with microneedle patches showed that microneedle treatment increased the skin 
permeation of both compounds assessed.  In addition, the permeation of lidocaine also showed a large 
reduction in lag time which would hasten the onset of local anaesthesia (Ref 3-4). Based on the 
biological principles of microneedles, they offer the possibility, if not potential, of improving the degree 
and depth of anaesthesia of topically applied anaesthetics in dentistry.  
 
The aim of this study is to look at the effect on patient perceived pain resulting from infiltration injection 
with local anaesthetic in a dental syringe with prior application of topical anaesthetic to the oral mucosa 
on microneedle patch compared to a patch with no microneedles. The oral sites chosen for the study 
are the upper palatal area and the upper anterior buccal sulcus. These sites represent two areas, which 
from clinical experience, are difficult to provide pain free dental injections even with prior application of 
topical anaesthetics. In addition, the safety of the microneedle needle patches will also be considered 
through the visual oral soft tissue examination performed by the dentist at each visit and the recording 
of adverse events. 
 
Current standard clinical practice for the application of oral topical anaesthetic is to extrude the gel 
directly onto a cotton wool roll then rub into the oral mucosa to be treated. For this study, the topical 
anaesthetic gel will be dispensed onto patches, with or without microneedles, then applied directly to 
the oral mucosa to be tested. The topical anaesthetic application method being investigated in this 
study is the patch containing microneedles. It was decided that the most relevant clinical 
comparator/control application method was to use a patch again, but with no microneedles. The use of 
cotton wool was not deemed a relevant control as the amount of topical anaesthetic applied to the oral 
mucosa could not be easily controlled. This is due to a degree of absorption of the gel into the cotton 
wool thus reducing the amount available for application to the mucosa. This does not happen with the 
use of the patch thus all topical anaesthetic dispensed is applied to the treatment area.  
 
 
4.0 METHOD AND MATERIALS 
 
4.1 PARTICIPANT RECRUITMENT 
Prior to the study NHS Ethics and MHRA approvals will be obtained. Potential participants will be sought 
from private dental patients of Rhiwbina Dental Surgery. 

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4.2 STUDY DESIGN 
This is a randomised, 2 treatment, double blind design, with respect to the clinical assessor and subject, 
split mouth, crossover design with a negative control (patch with no microneedles).  
 
Potential participants will be invited to attend a screening visit. At this visit participants will be asked to 
read and sign a Participant Information Sheet and Consent Form prior to any study procedures being 
performed. They will be given ample time to decide if they wish to participate in the study. All participants 
will be private dental patients of Rhiwbina Dental. 
 
A dentally qualified clinician will record the participant’s demographics, medical history, 
current/concomitant medications, perform an oral soft tissue examination and ensure the participant 
fulfils the inclusion and exclusion criteria for the study. Two areas of the mouth will be identified for 
assessment during the study. The areas of the mouth will be identified as S1 or S2. Site S1 will be left 
or right palatal mucosa adjacent to the premolar area and S2 will be left or right upper buccal mucosa 
adjacent to the upper lateral incisor area.  
 
Participants who successfully fulfil all the necessary entrance criteria will be provided with training by 
study staff on how to use a VAS record sheet and randomised on to the study to receive treatment 
combination A or B at in a random order according to a predetermined randomisation schedule supplied 
by the study statistician. The screening visit and first treatment visit will occur at the same visit.  The 
treatment possibilities are outlined below: 
 
Treatment A The application of a 5% topical lidocaine gel to one of the identified areas within the 
participants mouth using a microneedle patch. The microneedle patch will be applied to the oral mucosa 
of the identified site for 3 minutes, followed by infiltration with local anaesthetic to one of the identified 
areas within the participants mouth.  
 
Treatment B The application of a 5% topical lidocaine gel to one of the identified sites within the 
participants mouth using a patch with no microneedles. The patch with no microneedles will be applied 
to the oral mucosa of the identified site for 3 minutes, followed by infiltration with local anaesthetic to 
one of the identified areas within the participants mouth.  
The chosen sites will be: S1; left and right palatal mucosa adjacent to the premolar area or S2; left and 
right upper buccal mucosa adjacent to the upper lateral incisor area. Each participant at the first visit 
will have either S1 or S2 sites allocated for treatment. For example, Treatment A will be allocated to S1 
left side and Treatment B to S1 right side or vice versa. At the second visit, 2 weeks (+/- 3 days) after 
the first visit, Treatment B will be allocated to S2 left side and Treatment A to S2 right side.  Both 
sides of the mouth for S1 or S2 will be treated at the same. After each treatment participants will be 
asked to make pain assessments relating to needle insertion into the oral mucosa and the giving of the 
local infiltration anaesthetic.  
 
 
 

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4.3 STUDY POPULATION 
It is envisaged that a sufficient number of potential participants will be screened in order to randomise 
16 onto the study. The dental practice will display a poster informing private patients of Rhiwbina Dental 
Surgery that a new trial is taking place and details of the study coordinator if they require more details. 
 
4.4 ASSESSMENT METHODS 
 
Three minutes post-topical anaesthetic application: 
Pain Assessment. 
Pain assessments will be performed after application of the topical anaesthetic for 3 minutes. Each test 
will be performed sequentially i.e. 3 separate needle insertions, with pain assessments recorded by the 
participant using a Visual Analogue Scale (VAS) and a verbal pain grading after each test. The level of 
pain at S1 or S2 will be assessed as follows: 
 
Test I. A short dental needle, mounted on a dental syringe containing a cartridge of 2% lidocaine 
hydrochloride and 1:80,000 adrenaline, will be used to penetrate the oral mucosa at the treated site and 
the patient asked to score the pain using a VAS rating scale and by verbal grading of zero, mild, 
moderate or severe. 
 
Test 2.  The same needle will be inserted through the oral mucosa and down to contact bone. Pain will 
be assessed as in Test 1. 
 
Test 3. The same needle will be again inserted through the oral mucosa and the cartridge of local 
anaesthetic will be injected into the site. Pain will be again assessed as in Test I. 
 
Following enrolment on to the study, participants will be given written and verbal instructions on the VAS 
and how to complete it. They will be given a test sheet to practice scoring which will be measured and 
checked by the clinician to ensure the participant understands how to complete the VAS form, see 
appendix 1. 
 
5.0 OBJECTIVES 
 
5.1 PRIMARY OBJECTIVE 
To compare the level of perceived pain in healthy participants, when a proprietary topical 5% lidocaine 
dental gel is applied to the oral mucosa with a microneedle patch and a patch with no microneedles, 
prior to infiltration with local anaesthesia. 
 
5.2 SECONDARY OBJECTIVE 
To assess the safety of the patches when applied to the oral mucosa. 
 
 

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6.0 STUDY PERSONNEL AND RESPONSIBILITIES 
 
PRINCIPAL INVESTIGATOR: 
Name:  
 
 
Prof N West  
Address: 
 
 
Department of Oral and Dental Science 
 
  
 
 
University of Bristol Dental School 
 
  
 
 
Lower Maudlin Street 
 
  
 
 
Bristol BS1 2LY 
Tel:    
 
 
0117 342 9368 
Fax: 
0117 342 4100 
  
 
CO-INVESTIGATOR: 
Name: 
Dr N. Claydon 
Address: 
 
 
    Rhiwbina Dental 
    25 Heol-Y-Deri 
    Rhiwbina 
    Cardiff 
    South Glamorgan 
    CF14 6HB 
 
 
CLINICIAN / STUDY DENTIST: 
Name:  
 
 
Dr N. Claydon/Dr S Daley 
 
STUDY MEDICAL STATISTICIAN: 
Name: 
 
 
 
Robert G. Newcombe PhD CStat FFPH 
 
 
 
 
Emeritus Professor of Biostatistics 
 
 
 
 
Cardiff University 
Address:  
 
 
21 King George V Drive West 
 
 
 
 
Cardiff 
 
 
 
 
CF14 4EE 
Tel: 
 
 
 
029 2075 6723 
STUDY SPONSOR: 
Name:  
 
   Innoture Limited 
Address 
 
         2nd Floor, 58 Davies Street, Mayfair, London, W1K 5FJ 
 
STUDY SITE:  
 
Rhiwbina Dental  
25 Heol-Y-Deri 
Rhiwbina 
Cardiff 
South Glamorgan 
CF14 6HB 
 
 

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7.0 INCLUSION AND EXCLUSION CRITERIA FOR SELECTION OF PARTICIPANTS 
 
7.1 Inclusion Criteria 
To be included in the study, subjects must: 
1. 
be aged 18 years and over, of either gender and in good health; 
2. 
be willing and physically able to carry out all study procedures; 
3. 
be willing and able to give Informed Consent and provide details of any medical history; 
4. 
be available for all of the study dates 
5. 
have a good standard of oral hygiene and gingival health 
6. 
must have 1 premolar or canine in each quadrant that has no/minimal restorations 
 
7.2 Exclusion Criteria 
Individuals with the following conditions will not be eligible for participation in the study: 
 
 
1. presence of soft tissue oral pathology; 
2. presence of advanced periodontal disease; 
3. Individuals with any serious health conditions, that would preclude participation, in the professional 
judgement of the Study Dentist; 
4. individuals with known allergies or sensitivities to local anaesthetics 
5. have participated in another clinical trial in the last 30 days 
6. in the opinion of the investigator unable to comply fully with the trial requirements. 
7. the subject is an employee of the Sponsor or the site conducting the study. 
 
7.3 Withdrawal of Participants from the Clinical Trial 
Participants will be advised at the start of the study that they may withdraw from the study at any time, 
without giving a reason.  Participants will be told that they may be removed from the study by the Study 
Dentist without prior notice for medical reasons (see above), and also if the participant fails to report to 
the study site when scheduled, unless suitable alternative arrangements can be made (subject to the 
discretion of the Investigator). 
The Investigator will be responsible for documenting all cases of withdrawals. The Investigator will also 
make every reasonable effort to ascertain the reason for withdrawal. 
 
7.4 Participant Remuneration 
The participants that complete the study will receive £50 which relates to £25 per visit completed.  If for 
any reason, the study should be terminated before its expected completion date, participants will be 
reimbursed in full as will participants who are withdrawn due to an adverse event. If participants do not 
complete the whole study, they will be paid on a pro rata basis at the discretion of the Investigator. 
 
8.0 TREATMENT PLAN AND METHODS 
8.1 Study Schedule and Administration 
The 2 treatment procedures to be undertaken over 2 visits are: 
A. Microneedle patches with topical anaesthetic to assess patient perceived pain at chosen buccal 
and palatal oral mucosa sites and following insertion of a needle into the oral mucosa and 
administration local anaesthetic using infiltration injection. 

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B. Patches with no microneedles with topical anaesthetic to assess patient perceived pain at 
chosen buccal and palatal oral mucosa sites and following insertion of a needle into the oral 
mucosa and administration of local anaesthetic using infiltration injection. 
0.5g of the topical anaesthetic gel will be dispensed to the microneedle patch and patch with no 
microneedles prior to application of the patch to the oral mucosa. The topical anaesthetic gel will contain 
5% lidocaine with 0.15 g of cetrimide/100g.  
 
 
8.2 Allocation of Treatments and Randomisation Procedures 
Eligible, consenting participants will be randomised equally to one of four possible treatment groups (1-
4) for the 2 treatment procedures being assessed as shown below: 
 
Visit 1 
2 weeks ± 3 days 
Visit 2 
 
Left Side 
Right Side 
Left Side 
Right Side 
Treatment 
group 
Palatal 
mucosa 
Buccal 
mucosa 
Palatal 
mucosa 
Buccal 
mucosa 
Palatal 
mucosa 
Buccal 
mucosa 
Palatal 
mucosa 
Buccal 
mucosa 
1 
A 
 
B 
 
 
B 
 
A 
2 
B 
 
A 
 
 
A 
 
B 
3 
 
A 
 
B 
B 
 
A 
 
4 
 
B 
 
A 
A 
 
B 
 
 
8.3 Participant Restrictions/Concurrent Treatments 
There are no restrictions placed on the participants during this study, other than those stated in the 
exclusion criteria. 
 
8.4 Screening and Enrolment Procedures 
At the first visit to the study site, participants will be given time to read the Informed Consent 
Form/Information Sheet and given the opportunity to ask questions about the study. They will then be 
asked to sign the form and to complete a Medical History Questionnaire.  
The clinician will check the documents to assess if all the Medical History eligibility criteria are met.  
They will then carry out an oral examination and check that all the other eligibility criteria are met.  
Participants who are suitable for the study will be invited to participate in the study and the first 
procedure will commence. 
The participants GDP (dentist) will be notified of their participation in the study (participant consent 
given). Study Staff will treat all study documentation as strictly confidential. 
 
8.5 Assessments for Efficacy 
Data recorded at the screening visit will be recorded into paper CRFs. The clinician and Scribes will 
initial and date the CRFs. All data must be recorded directly, promptly and legibly in black ink.  Any 
corrections must be made in such a way that the correction does not obscure the original entry.  
Data will be transcribed into an excel spreadsheet and transferred to the study statistician in this form. 
Mandatory cross-infection control procedures and GCP will be followed. 
 

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8.6 Assessments for Safety 
The clinician will carry out an oral soft tissue examination at the screening visit and at all the assessment 
visits, both before and after treatment with the patches. Any findings (deviations from normal) will be 
recorded as adverse events on the Case Report Form provided and will be signed and dated by the 
clinician.  In addition, participants will be asked to report any observations made in connection with 
using the study regimen (see also Adverse Events). 
 
8.7 Compliance Checks 
All participants will be asked at each visit as to their adherence to the clinical investigation plan. All 
answers will be recorded in their Case Report Form. 
 
9.0 STUDY MATERIALS 
 
9.1 Test Products and Dosage 
The products used in the study will be as follows: 
 
1. Microneedle patch  
(Innoture Ltd, London) 
 
2. Patch with no microneedles  
(Innoture Ltd, London) 
 
3. Lidocaine topical dental gel: 5% lidocaine with 0.15 g of cetrimide/100 g 
(Septodont Ltd, Maidstone, Kent, ME16 0JZ) 
 
4. Infiltration anesthesia - 2% lidocaine hydrochloride + 1 in 80,000 adrenaline 
(Septodont Ltd, Maidstone, Kent, ME16 0JZ). 
 
Microneedle Patch  
A 2.4x2.4cm square patch containing a microneedle array of 2x2cm to the center, 400 microns height 
with an 800 micron pitch. 
This will be provided in its standard packaging to the study site by the sponsor. It will be labeled 
appropriately, with clinical investigation plan number, expiry date, manufacture date and lot number. 
 
Patch with no Microneedles  
2.4x2.4cm square patch with no microneedles to the centre. 
This will be provided in its standard packaging to the study site by the sponsor. It will be labeled 
appropriately, with clinical investigation plan number, expiry date, manufacture date and lot number. 
 
The manufacturer’s expiry dates for the test products, as appears on each product, will be documented 
in the study file. 
 
Lidocaine topical dental gel: 
This will be provided in its standard packaging by the study site. 0.5g of lidocaine gel will be dispensed 
directly to the centre of either the microneedle patch or patch with no microneedles (this will be 

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confirmed by weighing the lidocaine and patch). The patches will then be applied directly to the area of 
the mouth to be tested. The patches should be pressed to the area, then released slightly and then 
pressed again and held in place for 3 minutes, so that the whole patch area receives pressure. After 
this time, the patches will be removed, and the pain assessments will be conducted.  
 
Infiltration anesthesia: 
This will be provided in its standard packaging by the study site. A standard dental syringe and short 
needle will be used. Infiltration anesthesia will be injected down to the bone of the area of the mouth 
being tested following the pain assessment tests 1-2. 
 
 
9.2 Storage and Disposition of Test Products 
The microneedle patches, patches with no microneedles, lidocaine topical gel and the infiltration 
anaesthetic will be stored at room temperature in a locked area in the clinical unit at the study site which 
is not accessible to people outside the study team. Following use, the products will be disposed of as 
sharps clinical waste. Patches not used after completion of the study will be accounted for and returned 
to Innoture Ltd. Lidocaine topical gel and the infiltration anaesthetic not used after completion of the 
study will be accounted for and disposed of. 
 
9.3 Precautions/Overdosage 
The test products will only be used in the clinical unit under the supervision of study staff.  
 
9.4 Other Study Supplies 
The Informed Consent forms, Medical History, CRF's, Subject Withdrawal and Adverse Event forms 
will be supplied by the Study Site Team. 
 
10.0 ADVERSE EVENTS 
10.1 Adverse Event and Medical Device Adverse Effects 
An adverse event (AE) is any untoward medical occurrence in a subject whether or not related to study 
product or the study procedures. Adverse events include any occurrence that is new in onset, an 
exacerbation of a pre-existing condition and clinically significant laboratory values. 
A Medical Device Adverse Effect (MDAE) is any untoward medical occurrence in a subject which is 
related to the study product.  Medical Device Adverse Effects also include any adverse events resulting 
from insufficient or inadequate instructions for use (IFUs) and any event resulting from use error or from 
intentional misuse of the medical device.  
No significant adverse effects or medical device adverse effects are expected during the study. AEs and 
MDAEs will be monitored and recorded throughout the study. 
10.1.1 Exceptions 
The following medical occurrences will not be reported as AEs in any study sponsored by Innoture; 
• Pre-treatment Adverse Events; Any medical occurrence that occurs after informed consent, but 
before first administration of study product or first study procedure is considered as medical history 
and only recorded as an AE if it worsens during the study. 

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• Pre-existing medical condition; Events that occur with comparable frequency and severity to the 
subject’s baseline condition are reported as medical history, not AEs.  
• Pregnancy; This is not an AE however the PI must report any pregnancies to Innoture for advice 
regarding the appropriate course of action.  
• Overdose; If the amount of study product that is taken or applied is higher than that stated in this 
clinical investigation plan, this is not an AE. However, any clinical sequalae (signs or symptoms) 
of the overdose must be reported as an AE. A MDAE must be recorded if the subject is assigned 
to the investigational product. 
10.2 Serious Adverse Event 
A serious adverse event (SAE) is an AE that results in any of the following outcomes: death; a life-
threatening event; in-patient hospitalisation; prolongation of existing hospitalisation; a persistent or 
significant disability/incapacity; a congenital anomaly or birth defect.  Any other important medical event 
may be considered a SAE when the event may jeopardise the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed previously.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, or 
convulsions that do not result in in-patient hospitalisation. Just as a stable pre-existing condition is not 
an AE, hospitalisation for elective treatment (e.g. cosmetic or dental procedure) of a pre-existing 
condition that did not worsen from baseline is not an SAE. 
10.3 Severity and Relatedness of Adverse Events 
An AE will be recorded only once, with the most extreme severity. Severities are defined as: 
Mild 
Awareness of symptoms which require minimal or no treatment and do not 
interfere with daily activity 
Moderate 
Discomfort or low level of interference which is enough to interfere with but not 
prevent daily activity 
Severe 
Interrupted or unable to perform usual daily activity and usually requires 
treatment. 
 
The likelihood that the AE was related to the study product or study procedure is defined as; 
Not Related The AE is clearly due to an alternative cause, even if this cannot be definitely 
identified. Alternative causes include disease or environmental factors. 
Unlikely 
A connection between the AE and the study product or procedure is unlikely.  
• 
The AE has a relationship in time to the study product or procedure  
• 
An alternative cause (e.g. disease or environmental factors) is the most 
likely explanation, even if this cannot be identified. 
Possibly 
A connection between the AE and the study product or procedure cannot be 
ruled out with certainty.  
• 
The AE has a relationship in time to the study product or procedure 
• 
An alternative cause (e.g. disease or environmental factors) seems likely 
or possible or there is significant uncertainty about the cause of the AE. 

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Probably 
There is a high degree of certainty that the AE is related to the study product or 
procedure. 
• 
The AE has a relationship in time to the study product or procedure  
• 
A possible alternative cause may be present. 
• 
AE disappears or decreases on withdrawal or reduction of study product 
or procedure (if performed). 
Definitely 
The AE is clearly related to the study product or procedure. 
• 
There is a strong relationship in time  
• 
An alternative cause is unlikely 
• 
AE disappears or decreases on withdrawal or reduction of study product 
or procedure (if performed) 
10.4 Reporting of Adverse Events 
All minor adverse events (AEs) will be recorded in the Case Report Form (CRF) and submitted to 
Innoture.  The site staff must maintain source documents to fully record all AEs.  
Additionally, Serious Adverse Events (SAEs) and AEs that may affect the safety or continued 
participation of subjects on the study must be reported immediately.  A SAE must be reported to Innoture 
within 24 hours of the site staff becoming aware of the event.  The contact details for reporting any 
expedited AE are given in the Contacts section of this clinical investigation plan.  
10.5 Follow-up of Adverse Events 
If an AE is ongoing at the end of the study, follow-up will be performed until the AE has resolved, unless 
the PI and the Innoture contact named in the clinical investigation plan agree that no further follow up is 
necessary.  Follow-up may take the form of subject visits, a referral to another specialist, site telephone 
calls to the subject or letters from the treating physician. For expedited AEs, if applicable, the PI will 
submit follow up reports on additional expedited report forms.  
The PI or designee must comply with the specific reporting requirement(s) of the ethics committee, 
reporting as a minimum any Serious Unexpected Suspected Adverse Reaction (SUSAR) which is an 
unexpected SAE that may be related to study product or procedure.  
10.6 Pregnancy Testing 
There is no known risk to the foetus associated with the use of the study products and/or procedures in 
this study. It is not required to take any additional contraceptive precautions or perform any pregnancy 
testing prior to inclusion of females of child bearing potential into this study. 
 
10.7 Serious Adverse Event Reporting 
 
The investigator shall immediately after awareness (and in any event, not later than 24 hours) inform 
the sponsor of all SAE’s occurring in the study using the following contact details: 
 
SAEreporting@innoture.co 
 
At the end of the study, the investigator has to inform the sponsor details of all adverse events 
that occurred. 

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11.0 DATA MANAGEMENT AND STATISTICAL ANALYSES 
 
11.1 Rationale for Sample Size 
This study with 16 volunteers has 80% power to detect a difference in analgesia efficacy between 
microneedle administration and administration without microneedles at the conventional 5% two-sided 
alpha level provided this difference is at least 0.7 times the standard deviation representing the variation 
of this difference between different volunteers.    
 
11.2 Data Capture and Data Management 
There will be a CRF for each subject randomised into the study. It is the responsibility of the PI to ensure 
the completeness and accuracy of the CRF and to authorise only trained members of staff to complete 
the CRF.  
The CRF will include: 
• 
Demographics 
• 
Inclusion/Exclusion criteria assessment 
• 
Soft tissue pathology CRF 
• 
VAS training 
• 
VAS pain assessment 
• 
Adverse events 
The CRF must be completed legibly, using a black ballpoint pen. Erroneous values and/or text must not 
be obliterated. Instead, the error must be crossed out with a single line, the correct value/text added, 
and the correction signed or initialled and dated.  
There will be study specific records to record the identification of any data to be recorded directly on the 
CRFs or other written or electronic record of data, and to be considered to be source data.  
All site staff must ensure that the subject's anonymity will be maintained. On all documents that are to 
be submitted to Innoture, subjects must be identified only by an identification code and not by their 
names. The PI or designee must keep a separate confidential enrolment log that matches identifying 
codes with the subject's names and addresses. The PI or designee must maintain these documents at 
the site.  
It is the responsibility of the PI or designee to maintain adequate clinical study records. Copies of all 
clinical study material must be archived for a period of at least 15 years after the end of the study (or 
more as legally required) or until informed by Innoture that the documents can be destroyed. All 
documents must be archived in a secure place and treated as confidential material. 
 
The Investigator will keep the CRF’s securely in a lockable cupboard or filing cabinet. All CRF’s will be 
maintained in an up-to-date condition at all times. 
 
11.3 Statistical Analyses 
Two sites per subject will be studied, so the 16 subjects will provide 32 treatment site analysis points. 
Separate statistical analyses will be performed for each outcome measure for the results from palatal 
sites and the results from buccal sites, for the three challenges (tests 1, 2 & 3) described in section 4.4. 
Summary statistics, based on all 16 volunteers, will be calculated for each outcome measure for scores 

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immediately post-treatment, for administration to the mucosa and to the bone, for each of the following 
series of results: 
 
Sites with microneedle use. 
Sites with no microneedle use. 
 
Paired differences in scores, microneedle minus no microneedle use. 
 
The statistical significance of the microneedle minus comparator differences will be assessed by the 
Hills-Armitage method: right minus left differences will be calculated for each subject, and compared 
between subjects who have microneedles used on the right side of the mouth and those who have 
microneedles used on the left side using a 2-sample t-test. Estimated differences between treatments 
will be reported, with 95% confidence intervals, in addition to p-values. In the event of substantial 
departure from Gaussian distributional form, analogous non-parametric analyses will also be 
considered. 
 
All adverse events will be listed in the Clinical Investigation Report.  
 
12.0 ETHICAL CONSIDERATIONS 
 Ethics Committee Review 
NHS ethical approval and MHRA approval will be obtained prior to the start of the study. 
The PI or designee must submit a copy of the clinical investigation plan, subject information sheet and 
consent form to an Independent Ethics Committee or Institutional Review Board who must provide 
written approval before study specific procedures commence. The IEC/IRB must also approve any other 
information that is given to subjects such as advertisements and may require other documents such as 
study product documentation.   
Any modification to the agreed clinical investigation plan must be agreed by both Innoture and the PI 
and approved in writing by the IEC/IRB. Written approval must be obtained from the IEC/IRB before any 
amendment is implemented, unless immediate change is required to eliminate hazards to the subjects 
or when the change(s) involves only logistical or administrative aspects of the study (e.g., change of 
monitor(s), telephone number(s)).   
The PI or designee must obtain informed consent from each subject participating in the study, after 
explanation of the aims, methods, benefits and potential hazards of the study. The consent must be 
obtained before any study-specific procedures are performed. It must be made completely and 
unambiguously clear to each subject that they are free to refuse to participate in the study, or that they 
can withdraw their consent at any time and for any reason, without incurring any penalty or withholding 
of treatment. The subject must be given their own copy of the information sheet and signed consent 
form. The original signed informed consent must be kept on file by the PI or designee. 
 
 

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13.0 REGULATORY REQUIREMENTS AND INVESTIGATOR OBLIGATIONS 
 
13.1 GCP Statement 
It is the responsibility of the PI to ensure that the study is conducted in accordance with the principles 
of Good Clinical Practice, the latest ratified version of the Declaration of Helsinki and according to 
applicable local laws and regulations concerning studies conducted on human subjects which are 
outside of the definition of a medicinal product or medical device. 
Quality assurance audits may be performed by the University, the sponsor or any ethics committee or 
regulatory authority during the course of the study or after study completion. 
 
13.2 Premature Termination of the Study 
If the study must be terminated before the scheduled end (e.g. because of serious adverse events) the 
Investigator will notify the Ethics Committee in writing. 
 
13.3 Clinical Study Report 
The Investigator will provide a final study report. This must include:  
 
-the number of subjects enrolled into and completing the study, 
 
-subjects dropped out or withdrawn (stating reasons) 
 
-a report of all adverse events 
 
- clinical investigation plan deviations or violations 
 
-results and conclusions 
 
The Statistician will be responsible for the provision of the statistical analysis for the final report.  
 
13.4 Monitoring 
The study monitoring will be done by the sponsor according to the sponsors internal SOP’s. 
Given adequate supervision and guarantee of confidentiality, the investigator will allow the monitor to 
check the CRFs for completeness and consistency and to check the informed consent forms in order 
to verify observance to the clinical investigation plan. 
 
13.5 Compensation for Medicine-Induced Injury and Indemnification Requirements 
All participants will be insured against any injury caused by the study products by the sponsor according 
to legal requirements. The participants will be informed about the insurance and requirements on their 
part. 
 
13.6 Publication Policy 
The results of this study will be published externally in a peer reviewed scientific journal subject to the 
contractual arrangements agreed with the sponsor. 
 
14.0 REFERENCES 
(1). Lidocaine in: British National Formulary (BNF); pp714-715 
BMJ Group and RPS publishing, London  
 
(2). Lidocaine (interactions) in: British National Formulary (BNF); p766 

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BMJ Group and RPS publishing, London 
 
(3) Dabboue H, Builles N, Frouin E, Scott D, Ramos J, Marti-Mestres G. Assessing the impact of 
mechanical damage on full thickness porcine and human skin using an in vitro approach. BioMed 
Research International 2015; 434623, 10 pages  
 
(4). Assessment of the performance of prototype microneedles 1: evaluation of permeation of 
radiolabelled lidocaine and inulin through human skin in vitro with and without microneedles and 
pressure. (Study report No: F01/01/05) 
 
 
 

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Appendix 1: Investigator/Designee Instructions for VAS Training Exercise  
Participants will be given instructions for using the VAS and asked to complete the VAS line 
scale training exercise form.  The investigator or designee should read the instructions aloud 
while the participant reads along.  Participants will be permitted to ask questions.  However, 
most questions should be answered by rereading the appropriate section of the instructions.  
The investigator, or designee, will then determine whether the participant understands how to 
use the VAS based on the line scale training exercise answers and the criteria below. 
Interpretation of the VAS Training Exercise 
The objective of this exercise is not to determine whether the participant can get the exact 
answers, but to determine whether they understand the concept.  Therefore, the following 
general criteria are suggested: 
• Are the majority of the marks within ±10 mm of the correct value? 
• Are the marks generally toward the correct side of the scale?  In particular, is the first 
mark toward the left end, the second toward the right end and the third in the middle?  
Do the last three responses form a monotonically increasing sequence across the middle 
of the scale?  Is item 4 ≥ item 1?  Is item 5 ≥ item 8? 
If participants appear unable to interpret the level of shading, the investigator or designee 
should talk them through the first three figures using questions such as, “is it more or less than 
half shaded?” and “is it a lot more or a lot less than half shaded?”  If the marks are generally 
correctly ordered, but far from their true positions, the investigator or designee should try to get 
the participant to verbalize why they placed the marks as they did.  However, the investigator 
or designee should be careful not to pressure the participant to change their responses.  One 
approach would be for the investigator or designee to start with an item that the participant did 
well, ask about that and then continue by asking about one that seems off. 
If participants are not able to deal with the concept of proportions as presented in the exercise, 
it is unlikely that they will provide useful responses on the subjective and clinical response 
questionnaires.  These participants should be disqualified.

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Answer Key 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No  
Shading 
Complete 
Shading 
10 
No 
Shading 
Complete 
Shading 
90 
No 
 Shading 
Complete 
Shading 
50 
No 
Shading 
Complete 
Shading 
13 
No 
Shading 
Complete 
Shading 
75 
No 
Shading 
Complete 
Shading 
25 
No  
Shading 
Complete 
Shading 
38 
No  
Shading 
Complete 
Shading 
67 

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Appendix 2: Participant Instructions for VAS Training Exercise 
 
We will be asking you to rate your oral health using a line scale such as the one 
below.  You should respond by making a single vertical mark on the line. 
 
 
If you experience no pain or discomfort, you should make your mark at the left end 
of the line (“No Pain”).  If you couldn’t imagine the pain being any worse, you should 
make your mark at the right end of the line (“Worst Pain Imaginable”).  If your 
discomfort pain falls somewhere between these two extremes, you should mark a 
point on the line that represents how bad the pain is relative to these to end-points.  
If you think that it is half-way between No Pain and the Worst Pain Imaginable, then 
you would mark the middle of the line. 
When we test your teeth, it is important to distinguish between sensation (“I feel 
something”) and discomfort or pain (“It hurts”).  A sensation that does not hurt should 
be rated as “No pain.” 
In all the evaluations, there are no right or wrong answers; only your opinion counts.  
Answer carefully, but keep in mind that first impressions are often the most accurate. 
In order to give you some practice with this scale, we would like you to complete the 
exercise on the next page.  In this exercise you will be estimating how much of the 
total area of a series of shapes has been shaded.  If none of the figure has been 
shaded, you should mark the left end of the line.  If the figure has been completely 
shaded, you should mark the right end of the line.  If only part of the figure has been 
shaded, you should make a vertical mark at the appropriate point on the line.  For 
example, if half of the figure has been shaded, you should make your mark in middle 
of the line.  If a quarter of the figure has been shaded, you should make your mark 
one quarter of the distance from the left end of the scale, etc.  Please remember, we 
are asking you to estimate the area shaded and then to estimate the position of your 
mark on the line.   
 
 
 
 
Please make a single vertical mark at the point on the line that best represents the 
degree to which the figure is shaded. 
NO 
PAIN 
WORST PAIN 
IMAGINABLE 

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No 
Shading 
Complete 
Shading 
No 
Shading 
Complete 
Shading 
No 
Shading 
Complete 
Shading 
No 
Shading 
Complete 
Shading 
No 
Shading 
Complete 
Shading 
No 
Shading 
Complete 
Shading 
No 
Shading 
Complete 
Shading 
No 
Shading 
Complete 
Shading 

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APPENDIX 3a – Topical Anaesthetic 
 

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Appendix 3b – Infiltration Anaesthetic 
 
 
 

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