Document Name Clinical Protocol 204930 Type Version Document Identifier Effective Date eldo_clinical_doc 6.0; Most-Recent; Effective; CURRENT 090032d580c189ed 12-Sep-2016 05:12:55 Reason For Issue Auto Issue
The Clinical Protocol
204930
Copy ri ght: Gl axoSmit hKlin e. An unpublished work subject to trade secret protecti on. Thi s work contains confident ial and propri etary i nformat io n of Gl axoSmi th Kline and should not be copied, circulated, or distributed to persons not em pl oy ed by GlaxoSmi th Kline unless specifically authori zed. Unauthorized di scl osure of this work is expressly prohibi ted.
Page 1 of 108 Document Name Clinical Protocol 204930 Type Version Document Identifier Effective Date eldo_clinical_doc 6.0; Most-Recent; Effective; CURRENT 090032d580c189ed 12-Sep-2016 05:12:55 Reason For Issue Auto Issue
CONFIDENTIAL
SUMMARY INFORMATION
Title: Study to Investigate the Impact on Oral Health Related Quality of Life of Managing Dentine Hypersensitivity with a Daily Use Anti -Sensitivity Tooth paste
Protocol Number: 204930 Sponsor: GlaxoSmithKline Consumer Healthcare (GSKCH) UK Trading Limited St Georges Avenue, Weybridge, Surrey, KT13 0DE, United Kingdom (UK) Tel: PPD
Product Name: Dentifrice containing 0.454% w/w stannous fluo ride (1100ppm fluoride) Development Phase: N/A
Tel: PPD Expert Advice Outside of Normal Working Hours:
PRIMARY CONTACT PPD BSC HONS Clinical Study Manager : PPD BSC, MSC
Protocol Authors: Clinical Research: PPD , MSC Tel: PPD Biostatistician: PPD PPD , B.Sc, M.Sc
Clinical Supplies: PPD
Principal Investigator: Robert M aclure , BSc, BDS Study Site Name & Address: SITE 1. Intertek Clinical Research Services (CRS), 2Frederick Street, Wid nes, Cheshire, WA8 6PG
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SITE 2. INTERTEK CLINICAL RESEARCH SERVICES (CRS), 119 STATION ROAD, ELLESMERE PORT, CHESHIRE, CH65 4BW, UK Study Site Telephone Number: + PPD
Study Examiner : PPD , BSc, BDS
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
I confirm agreement to conduct the study i n co mp liance wit h the protocol and any amendments and according to the current ICH GCP guidelines.
I acknowl edge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study.
I agree to ensure that all associates, colleagues and emplo yees assist ing in the conduct of the study are inform ed about thei r obligati ons. Mechanisms are in pl ace to en sure si te staff receives all appropriate informat io n throughout the study .
I agree to conduct this study i n full conformance wit h the l aws and regulations of the country i n which the research is conducted and the Declaration of Helsinki.
Invest igator Name: Dr Robert Maclure
Invest igator Qualificat io ns: BSc, BDS
Invest igator Signature: PPD
Date of Si gnature/ Agreement:
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Table of Content
SUMMARY INFORMATION ...... 2 PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT
PAGE ...... 3
Table of Content ...... 4 PROCESS FOR AMENDING TH E PROTOCOL ...... 8 PROTOCOL AMENDMENT PAGE ...... 9 PROTOCOL SYNOPSIS FOR STUDY 204930 ...... 15 1. INTRODUCTION ...... 19 2. OBJECTIVES AND ENDPOINTS ...... 21 3. STUDY PLAN ...... 21 3.1. Study Design ...... 21 3.2. Subject Restrictions ...... 23 3.3. Type and Planned Number of Subjects ...... 24 3.4. Study Design and Dose Justification ...... 25 4. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA ...... 26 4.1. Inclusion Criteria ...... 26 4.2. Exclusion Criteria ...... 28 4.3. Screening/ Baseline Failures ...... 29 4.4. Withdrawal/ Stopping Criteria ...... 30 4.5. Subject Replacement ...... 32 4.6. Subject and Study Completion ...... 32 5. PRODUCT INFORMATION ...... 32 5.1. Study Product ...... 32 5.2. Dose Schedule ...... 33
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5.3. Dose Modification ...... 33
5.4. Product Compliance ...... 33
5.5. Precautions ...... 33
5.6. Overdose ...... 33 5.7. Rescue Therapy ...... 34
5.8. Product Assignment ...... 34
5.8.1 Randomisation ...... 34 5.8.2 Blinding ...... 34 5.9. Pack aging and Labelling ...... 34
5.9.1. Accountability of Product ...... 35 5.9.2. Storage of Product ...... 35
6. STUDY ASSESSMENTS AND PROCEDURES ...... 35
6.1. Visit 1 -Screening Visit ...... 35 6.1 .1 Telephone Screening ...... 35 6.1.2. Informed Consent ...... 36 6.1.3. Demographics ...... 36 6.1.4. Medical History and Concomitant Medication ...... 36 6.1.5. Oral Hard Tissue (OHT) Examination ...... 36 6.1.6. Oral Soft T issue (OST) Examination ...... 36 6.1.7. Eligible Tooth Assessment ...... 37 6.2. Visit 2 to Visit 8 ...... 38 6.2.1. Dentine Hyersensitivity Experience Questionnaire (DHEQ) ...... 38 6.2.2 Labelled Magnitude Scales (LMS) Training Exercise ...... 39 6.2.3. Oral Soft Tissue (OST) Examination ...... 39 6.2.4. Evaporative Air Sensitivity Assessments ...... 39 6.2.5. Stu dy Conclusion ...... 41 7. SAFETY ASSESSMENTS ...... 41 7.1. Definitions of an Adverse Event and Serious Adverse Event ...... 41
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7.1.1. Adverse Events ...... 41
7.1.2. Serious Adverse Events ...... 42 7.2. Recording Adverse Eve nts and Serious Adverse Events ...... 43
7.3. Evaluating Adverse Events and Serious Adverse Events ..... 44
7.4. Reporting Adverse Events and Serious Adverse Events ...... 45 7.5. Follow -up of Adverse Events and Serious Adverse Events .. 46 7.6. Definition of and Procedure for Reporting Medical Device Incidents ...... 47 7.6.1. Definition of an Incident ...... 48
7.6.2. Reporting of Incidents and Malfunctions ...... 48 7.6.3. Follow -up of Incidents ...... 49 7.7. Collection of Pregnancy Information ...... 50
7.7.1. Time Period for Collecting of Pregnancy Information ...... 50 7.7.2. Action to be Taken if Pregnancy Occurs ...... 50
8. DATA M ANAGEMENT ...... 51 8.1. Source Documents/ Data ...... 51 8.2. Electronic Case Report Form ...... 51 8.3. Data Handling ...... 52 8.3.1. Data Queries ...... 52 8.4. Processing Patient Reported Outcomes ...... 53 9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES ...... 53 9.1 Sample Size Determination ...... 53 9. 2. General Considerations ...... 53 9.2.1. Definition of Analysis Populations ...... 53 9.2.2. Exclusion of Data from Analysis ...... 54 9.2.3. Criteria for Evaluation ...... 54 9.2.4. Criteria for Assessing Efficacy ...... 55 9.2.5. Criteria for Assessing Tolerability ...... 55
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9.2.6. Handling of Dropouts and Missing Data ...... 55
9.2.7. Other Issues ...... 55 9.3. Statistical Methods and Analytical Plan ...... 55
9.3.1. Demographic and Baseline Characteristics ...... 55 9.3.2. Primary Analysis ...... 55 9.3.3. Exploratory Analyses ...... 57 9.3.4. Safety Analyses ...... 57
9.3.5. Other Analyses ...... 58 10. STUDY GOVERNANCE CONSIDERATIONS ...... 58 10.1. Posting of Inf ormation on Publicly Available Clinical Trials Registers ...... 58 10.2. Regulatory and Ethical Considerations, Including the
Informed Consent ...... 58 10.3. Quality Control (Study Monitoring) ...... 58 10.4. Quality Assurance ...... 59 10.5. Conditions for Terminating the Study ...... 59 10.6. Records Retention ...... 60 10.7. Provision of Study Results to Investigators, posting of Information on Publicly Available Clini cal Trials Registers and Publication ...... 61 11. REFERENCES ...... 62 12. APPENDICES ...... 64 12.1. Appendix 1 -Abbreviations ...... 64 12.2. Appendix 2 –DHEQ ...... 66 12.3. APPENDIX 3 -SUBJECT INSTRUCTIONS FOR LMS TRAININ G EXERCISE ...... 89 12.4. APPENDIX 4 -LMS SUBJECT ASSESSMENT FORM (EXAMPLE) ...... 107
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PROCESS FOR AMENDING THE PROTOCOL
Protocol m odificati ons to ongoing studies which could potentially adversely affect the safet y of subjects or which alter the scope of the investigation, the scientific qualit y of th e study , the experimental design, dosages, duration of t herapy, assessment variables, the number of subjects treated, or subject select io n cri teri a are considered major/substant ia l amendments and must be made only af ter appropri ate consul tati on between an appropriate representative of GSKCH and the invest igator .
Details o f amendments to the protocols should be recorded on the fo llo wing page. Protocol m odificati ons m ust be prepared by a representative of GSKCH. All changes must be just ified in the Reason for Amendment section of the fo llo wing Protocol Amendment Page. Approval of amendments will be made by the original protocol si gnatori es or thei r appropri ate desi gnees.
All major/substant ial protocol m odificat io ns must be reviewed and approved by the appropriate IEC in accordance wit h lo cal requi rements, before t he revised edit io n can be implemented.
All non-substant ia l/ minor/ administrative amendments should be submitted to the IEC as per country specific requi rements. In som e countri es pre -approval of a minor am endment i s not requi red and will just be held on file by the sponsor and investigator.
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PROTOCOL AMENDMENT PAGE
Details o f all amendments should be recorded in the table below. Affected sec ti ons shoul d be listed in the table; the actual amendment/ change should be made in the rel evant secti on of the m ai n protocol . To hi ghlight the change, the fo llo wing features will be used:
To add text: Use of CAPITAL LETTERS, BOLD AND UNDERLINE To delete text: Use of Stri kethrough e.g. strikethrough
Amendme Type of Amendment Reason f or Other Section(s) PI nt No. & Amendment Doc uments Amended Amendmen New Requiring t Protocol Amendmen Agreement Version t Signature
No. & Date Amendme Non - This is Protocol Inform ed Page 2 - Si gnature: nt No.: Substant ia l/Minor am endment 1 Consent Personnel 1 (Protocol Ye s changes Protocol Substant ia l/ Major versio n 4.0) as No Date: Version previous Saf et y 6.2.1 - No.: am endments Statem ent Cl ari ficat io n 4 (2.0 and 3. 0) Ye s text added were m ade No pri or to Ethics CRF Replace submissio n. Ye s Appendix 12.3 No and 12.4 Change the ori entati on of th e LMS scales fro m hori zontal to verti cal. This will allow all 4 scales o f th e LMS Form to fi t on one page making it easier for subjects to com plete the scales.
Personnel changes
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Cl arif icat io n text added
Amendme Non - Personnel Inform ed Page 2 - Si gnature: nt No.: Substant ia l/Minor changes - Consent Personnel 2 change to Ye s ch anges Study Manager No Date: Protocol Substant ia l/ Major Due to Page 3 - Version recrui tment Summary No.: issues at Saf et y Inform at io n 5 Intertek Statem ent Widnes site, a Ye s
second site is No being init iated CRF at Ellesmere Ye s Port to recruit No th e rem aining subject numbers. Addit io n of 2 nd si te address Page14 -Brief Summary Change of text fro m “single Page 14 - centre” to Overall Design “mult i- si te” Page 20 - Secti on 3.1 Study Design
Cl arify act io ns Page 29 -4.4 to be taken i f Wit hdrawal/ Stopping subject is cri teria prescribed ant ibiot ics during the course of the study
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Change of text Page 39 regarding how Secti on 6.2.4.2
LMS scales Labelled Magnitude will be Scal es (LMS) measured. Change text fro m “left to
ri ght” to “bottom to top” Page 55 Secti on 9.3 .2 Cl arificat io n of Primary Analysis addi ti onal statist ical Page 55 analysis that Secti on 9.3.3 will be carried Expl oratory out to p rovi de Analysis endpo int summaries by si te Amendme Non - Personnel Inform ed Page 2 - Si gnature: nt No.: Substant ia l/Minor Consent Personnel 3 changes - change to Ye s changes No Study Protocol Substant ia l/ Major Date: Version Stati st ic ian and No.: clinical 6 supplies lead Saf et y Page 55,56 - Statem ent Secti on 9.3.2 Due to mo ving Ye s Primary fro m single site No Analysis CRF to a mult isite Ye s Secti on 9. 3.3 study , the No Expl oratory primary and Analysis exploratory analysis has been changed fro m pai red t test to mixed effect AN OVA
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fo raccount ing effects by si te .
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SCHEDULE OF EVENTS Baseline Visit3 Visit4 Visit5 Visit 6 Visit7 Visit8 Screening Visit 2 Procedure Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Visit1 Week 0 (Day 28 ±3) (Day 56 ± 3) (Day 84 ±3) (Day 112 ±3) (Day 140 ±3) (Day 168 ±3) (Day 0) Informed Consent X Demographics, Medical X Histor y Curren t/Co ncomitant X X X X X X X X Medications Inclusion/Exclusion X X
Subject Eligibility X X Subject Continuance X X X X X X X Oral Soft Tissue (OST) and X X X X X X X X Oral Hard Tissue (OHT) Assessment Eligible Teeth Assessments X (Dent itio n Exclusio ns, EAR, MGI, Tooth Mobility) Qualifying Evaporative Air X Sensitivity (Y/N) Dispense Acclimatisation X Toothpaste, Toothbrush, Diary and Timer Supervised Brushing with X Acclimatisation Toothpaste Return Acclimatisation X Toothpaste , Toothbrush and Diary AcclimatisationPeriod -Minimum 3 weeks –Maximum 6 weeks 6 –Maximum weeks 3 -Minimum AcclimatisationPeriod DHEQ completion 1,5 X X X X X X X LMS 5training X
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Baseline Visit3 Visit4 Visit5 Visit 6 Visit7 Visit8 Screening Visit 2 Procedure Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Visit1 Week 0 (Day 28 ±3) (Day 56 ± 3) (Day 84 ±3) (Day 112 ±3) (Day 140 ±3) (Day 168 ±3) (Day 0) Evaporative A ir Assessment (Schiff Sensitivity Score, X LMS 5)on all Eligible Teeth from Screening
weeks Selection of 2 ‘Test Teeth’ X Evaporative A ir Assessment (Schiff Sensitivity Score, X X X X X X 5 LMS )on 2 ‘Test Teeth’ Evaporative A ir Assessment (Schiff Sensitivity Score )on X X X X X X Remaining Eligible Teeth fro m Screening Dispense Study Product X2 X X X2 X X Supervised Brushing X X3 X3 X3 X3 X3 Return Study Product and X X X X X X Diary Compliance checks X X X X X X X Adverse Events X4 X X X X X X X
Acclimatisation Period -Minimum 3 weeks –Maximum 6 6 Incidents –Maximum weeks 3 -Minimum Period Acclimatisation X X X X X X X Study Conclusion X 1. To be completed prior to OST examination and any clinical assessments 2. Dispense a new toothbrush at this visit also 3. Subject instructed to bring all supplies back to all subsequent visits 4. After first supervised brushing with acc limatisation product 5. To be completed by subjects
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PROTOCOL SYNOPSIS FOR STUDY 204930
Brief Summary
This single centre MULTI- SITE , non -co mparati ve design study will be used to mo nit or th e impact of lo ng term m anag ement of dent ine hypersensit ivit y(DH) wi th daily u se of a sensi ti vit y toothpaste on the qualit y of life of a popul at io n of sensit ivit y sufferers . Changes in oral h eal th rel ated quali ty of life will be m oni tored using the Dent ine Hypersensit ivit y Experience Quest io nnaire (DHEQ) . The study will b e conducted in subjects in good general heal th , wi th pre -exist ing self -reported and clinically diagnosed tooth sensit ivit y at screening.
Objectives and Endpoints
Objective s Endpoint s Primary
To m oni tor the impact of l ong term Change from baseline in DHEQ management of DH over a 24 week endpo int s over time . peri od, wi th twi ce daily use of a
sensit ivit y toothpaste, on th e oral healt h rel ated quali ty of life in sensi ti vit y sufferers, as m easured by the DHEQ .
Exploratory To evaluate changes in dent ine Mean Schiff Sensit ivit y Score fo r all hypersensit ivit y over the 24 week timepo int s. treatm ent peri od, including the nu mber of Change from baseline in Schiff sensit ive teeth, as measured by Schiff sensit ivit y score (two test teeth ) f or all Sensit ivit y Score to assess examiner timepo int s. perform ance on this m easure. Change from baseline in Schiff sensit ivit y score ( all qualifying teeth) fo r all t imepo int s. To evaluate changes in dent ine Mean LMS ( of each of 4 VAS scales) hypersensit ivit y over the 24 week and change fro m baseline (for the two treatm ent peri od, as m easured by test teeth) at each time point. Labelled Magnitude Scales (LMS).
Study Design Overall Design A sing le centre MULTI- SITE , non -co mparat ive design study will be used to monitor th e impact of lo ng term m anag ement of DH wit h daily u se of a sensi ti vit y toothpaste
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on the qualit y of l ife of a populati on of sensi ti vi ty s ufferers . Changes in oral h eal th rel ated qualit y of life will be m oni tored using the DHEQ. The study will b e conducted in subjects in good general heal th , wi th pre -exist ing self -reported and clinically diagnosed tooth sensit ivit y at screening. Visit 1 -Screening Visit
The fo llo wing assessments will be conducted in the order written: Wr it ten inform ed consent. Review of the oral care products th e subject is current ly using to confirm they do not con tain any ingredients intended for treating sensit ive teeth. Dem ographics, concomitant medicat io ns and medical history . Oral examinat io n including an oral soft tissue (OST) examinat io n and oral hard ti ssue (OHT) assessments to determine eligible teeth. Qualifying evaporative air sensit ivit y.
Inclusio n/exclusio n cri teria review. Confirmation o f subjec t eligibilit y. Di spensat io n of acclimat is ati on toothpaste, toothbrush, diary and timer. Supervised brushing with acclimat isat io n toothpaste. Ad verse Events (AEs) will be docum ented from complet io n of the supervised
brushing with acclimat isation toothpaste. Visit 2 -Baseline Visit (Day 0) The fo llo wing assessments will be conducted in the order written: Review of conco mit an t m edicat io ns and AEs . Return of acclimat is ati on toothpaste, toothbrush and diary . Review of completed diary to determine usage comp liance. Inclusio n/exclusio n cri teria review. Confirmation o f subject eligibilit y and cont inuance. Co mp let io n of DHEQ Secti on 1 and Sect io n 2. LMS Training Exercise OST and OHT examinat io ns. Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale , LMS) on all eligible teeth from Visit 1. Sel ect io n of two test teeth . Di spensat io n of study toothpaste , toothbrush and diary . Supervised brushing with study treatm ent. AEs and Incidents from supervised brushing with study treatm ent Visit 3 -Week 4 (Day 28 ± 3) Visit 4 –Week 8 (Day 56 ± 3) Visit 5 – Week 12 (Day 84 ± 3) Visit 6 – Week 16 (Day 112 ± 3) Visit 7 –Week 20 (Day 140 ± 3)
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The fo llo wing assessments will be conducted in the order written: Review of conco mit ant m edicat io ns, AEs and incidents.
Return of study toothpaste and diary. New toothbrush at Week 12. Review of completed diary to determine usage compliance. Inclusio n/exclusio n cri teria review. Confirmation o f subject continuance. Co mp let io n of DHEQ Section 1 (Q7 -9) & Section 2 .
OST and OHT examinat io ns. Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale, LMS) on tw o test teeth. Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale) on rem aining eligible teeth from Visit 1. Di spensat io n of study toothpaste and di ary (and toothbrush at Visit 5) . Supervised brushing with study treatm ent. AEs and Incidents from supervised brushing with study treatm ent
Visit 8 –Week 24 (Day 1 68 ± 3) The fo llo wing assessments will be conducted in the order written: Review of conco mit ant m edicat io ns, AEs and incidents. Return of study toothpaste , toothbrush and diary . Review of completed diary to determine usage compliance. Confirmation o f subject continuance. Co mp let io n of DHEQ Section 1 (Q7 -9) & Section 2. OST and OHT examinat io n. Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale, LMS) on tw o selected test t eeth . Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale) on rem aining eligible teeth from Visit 1. AEs and incidents will be recorded for 5 day s a ft er last treatm ent.
Type and Planned Number of Subjects Sufficient subjects will be screened to ensure approximately 112 sui table subjects enter the accli mat isat io nphase. Approximately 75 eligible subjects will be allocated th e study toothpaste in order to ensure that approximately 60 subjects complete the study .
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Diagnosis and Main Criteria for Inclusion
Subjects aged 18 -55 y ears of age, with a minimum of 20 natural teeth and in good general healt h who suffer from tooth sensit ivit y. At Screening, subjects must have a minimum o f tw o accessible non adjacent teeth (incisors, canines, or pre -mo lars) with si gns of erosi on or abrasio n or facial/cervical gingiva l recessio n (EAR), with a mo dified gingival index (MGI) =0 adjacent to the test area and a clinical mo bilit y of ≤1, and with signs of sensit ivit y measured by qualifying evaporative air assessment. At Baseline subjects must have a minimum o f tw o, non -adj acent accessible teeth (i ncisors, canines or p re -mo lars), with signs of sensit ivit y, m easured by an evaporative air assessment (Schiff Sensit ivit y Score ≥ 2).
Product Information
Treatment Study Product Group Dent ifr ice containing 0.454% w/w stannous fluoride (1100ppm f luori de)
Sensodyne Repair and Protect Daily Repair Toothpaste.
Germ an marketpl ace CCI MFC Commercial Product Route of Topi cal oral use administration Dosing Subjects will brush wit ha full brush head of toothpaste for 1 timed Instructions minute (in their usual manner ), twi ce daily (m orning and evening) fro m Visi t 2 -8
Statistical Methods
Mean values and changes fro m baseline wit h 95% confidence intervals will be pl otted fo r all m easures of DH (DHEQ, Schiff Sensi ti vi ty ,and LMS (Intensit y, Durati on, Tol erabilit y, Descri pt io n) over time. Statistical significance of changes from baseline at each timepo int EFFECT OVER TIME will be assessed USING MIXED EFFECT ANOVA WITH VI SIT AND SITE AS FIXE D EFFECT, SUBJECT AS RANDOM EFFECT .
AEs, incidents and OST abnormalit ies will be listed by treatm ent .
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1. INTRODUCTION
Dent in al hypersensi ti vit y (DH) is described as ‘pain derived from exposed dent ine in
response to chemical, thermal, tactile, or osmotic stimuli which can’t be explained as ari sing fro m any other dental defect or pathology’ [Addy , 1985, 2000] . The definit io n was l ater revised to replace the word ‘pathology ’ wi th ‘disease’ to avoid confusio n wi th pain ori ginat ing fro m other dental condi ti ons [Canadian Advisory Board, 2003] . D H ori ginates fro m aeti ol ogi c fact ors such as gingival recessio n, erosi on and/or abrasi on, which result in loss of enamel or cementum and subsequent exposure of the underlying dent ine with patent dentinal tubules [Orchardson, 1987] . Brännström’s hydrodynamic theory of DH hypothesizes that the movement of fluid wi thi n the tubules when a stimulus is applied to the dent ine, stimulates the nerve processes in the pulpal area of the dent ine to transmit a pain impulse [Brannstrom , 1964; Hall, 2000] .
Current ly there are two approaches to the management of DH ; nerve depo lar isat io n (physio lo gical act io n) ;
dent inal tubule occlusio n (physical act io n).
Nerve depo lar ising agents, such as potassium nitrate, generally require a period of use (for example, 14 to 28 days) before their benefit is established . The delivery o f pota ssium io ns to the dent ine -pulp j unct io n (odontoblastic layer) via dent inal tubules is believed to result in depolarisat io n of the afferent nerve membrane thereby blocking the pain response [Orchardson, 1975] . The second approach uses tubule occl uding agents which physically blo ck the exposed ends of the dentinal tubules, th us reducing dent inal fluid mo vement and pulpal irritation . Tubul e occl uding agents such as strontium salts, stannous salts, bioglasses or silicas serve to seal or block the dent ine tubules ,and thereby reduce the effect of external st imu li . Tubul ar occl usi on can be favoured over n erve depo lar isat io n primarily due to the more rapid onset of relief fro m DH which can be associated with the occlusio n approach [Gillam, 2006] .
Stannous fluoride has been incorporated into oral hygiene products indicated for the reducti on of DH since the 1960s [Schiff, 2006a] . Its long- term efficacy has been reported in a number of published s tudi es [Schiff, 2000a, 2000b, 20 06b; Sharma, 2010, 2012; Chaknis, 2011; Du, 2011; Ni, 2011; Parkinson, 2013] wit h a few studi es report ing short term efficacy also [He, 2011; Sharma, 2011].
Wit h the growing acknowledgment of the value of the informat io n gl eaned di rect ly fro m th e subject, self -reported outcom e m easures have becom e increasingly important barom eters of the benefit of clinical int ervent io ns . These are increasingly
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used in dentistry to capture the psy chosoci al experiences of, f or exam ple ,pain, di scomfort and m alfuncti oning [Jokovi c, 2002] . Broad, mult id imensi on al quali ty of life measures such as the Oral Healt h Im pact Profile ( OHIP) are commo nly used [Slade, 1994, 1997] . Use of the OHIP in a study amo ng patients diagnosed with DH attending a group of general pract ices in Germany reported considerably more impaired oral healt h rel ated qualit y of l ife (OH RQo L) than subjects in the general popul at io n indicat ing that DH is significant ly associ ated wi th i mpaired OHRQoL
[Bekes, 2009] . Research on OHRQoL commo nly uses instruments like the OHIP th at are generic for a number of oral health condit io ns. They cover a broad spectrum of limitations and dy sfunct io ns and may not detect th e nuances of a specific condit io n. The dent ine hypersensit ivit y experience quest io nnai re (DHEQ )is a validated, condi ti on specific m easure of OH RQo L in relat io n to DH [Boi ko, 2010; Baker, 2014;
Robinson, 2015] . It has been shown to have good psychom etri c properti es in both the general population and in a clinical sample of DH sufferers . In a pooled analysis o f clinical studies conducted by GSK [GSKCH Study RH02026] , the DHEQ has shown th e si gnificant impact that DH can have on th e every day life of the sufferer (for example, 70.4% of suffere rs reported “Having sensations in my teeth takes a lot of the pl easure out of eat ing and drinking” ). The data included in th epool ed analysis were primarily generated from studies of 8 week duration . The current st udy will explore th e impact of lo ng term manag ement of DH by daily u se of a sensit ivit y toothpaste on th eoral healt h rel ated qualit y of life of a popul at io n of sensit ivit y s ufferers , over six mo nt hs, using the DHEQ. The long term clinical efficacy o f th e study product (a marketed, sensit ivit y toothpaste co nt aining 0.454% w/w stannous fluoride) for the relief o f DH has been previously dem onstrated in two, 8 week randomised, controlled clinical studies [GSKCH Study RH01685; Parkinson, 2013] .
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2. O BJECTIVES AND ENDPOINT S
Objectives Endpoints Primary To m oni tor the impact of l ong term Change from baseline in DHEQ endpo int s over time . management of DH over a 2 4 week peri od, wi th twi ce daily use of a sensit ivit y toothpaste, on the oral healt h rel ated quali ty of life in sensi ti vit y sufferers, as m easured by the DHEQ . Exploratory To evaluate changes in dent ine Mean Schiff Sensit ivit y Score for all
hypersensit ivit y over the 24 week timepo int s. treatm ent peri od, including the number of Change from baseline in Schiff sensit ive teeth, as measured by Schiff sensit ivit y score (two test teeth) for all
Sensit ivit y Score to assess examiner timepo int s. perform ance on this m easure.
Change from baseline in Schiff sensit ivit y score (all qualifying teeth) for all t imepo int s. To evaluate changes in dent ine At each time po int the m ean LMS (of hypersensit ivit y over the 24 week each of 4 VAS scales) and change fro m treatm ent peri od, as m easured by baseline (for the two test teeth) and will be calculated. Labelled Magnitude Scales (LMS).
3. STUDY PLAN 3.1. Study Design
Overall Design This single -centre MULTI- SITE , non -co mparat ive design study will be used to mo nit or th e impact of lo ng term m anag ement of dent ine hypersensit ivit ywi th daily use of a sensit ivit y toot hpaste on the qualit y of life of a popul at io n of sensit ivit y sufferers . Changes in oral h eal th rel ated quali ty of life will be m oni tored using the Dent ine Hypersensit ivit y Experience Quest io nnaire. The study will be conducted in subjects in good general heal th , wi th pre -exist ing self -reported and clinically di agnosed tooth sensit ivit y at screening. Visit 1 -Screening Visit
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The fo llo wing assessments will be conducted in the order written: Wr it ten inform ed consent.
Review of the oral care products th e sub ject is current ly using to confirm they do not con tain any ingredients intended for treating sensit ive teeth. Dem ographics, concomitant medicat io ns and medical history . Oral examinat io n including an oral soft tissue (OST) examinat io n and assessments to de te rmine eligible teeth.
Qualifying evaporative air sensit ivit y. Inclusio n/exclusio n cri teria review. Confirmation o f subject eligibilit y. Di spensat io n of acclimat is ati on toothpaste, toothbrush, diary ,and t imer. Supervised brushing with acclimat isat io n to othpaste. Ad verse Events (AEs) and incidents will be documented fro m co mp letion of the supervised brushing wit h acclimat isat io n toothpaste. Visit 2 -Baseline Visit (Day 0)
The fo llo wing assessments will be conducted in the order written: Re view of conco mit ant m edicat io ns and AEs . Return of acclimat is ati on toothpaste, toothbrush and diary . Review of completed diary to determine usage compliance. Inclusio n/exclusio n cri teria review. Confirmation o f subject eligibilit y and cont inuance. Com plet io n of DHE Q Secti on 1 and Sect io n 2. LMS Training Exercise OST examinat io n. Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale, LMS) on all eligible teeth from Visit 1. Sel ect io n of two test teeth. Di spensat io n of study toothpaste , toothbrush and diary . Supervised brushing with study treatm ent. Incidents fro m supervised brushing with study treatm ent
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Visit 3 -Week 4 (Day 28 ± 3) Visit 4 –Week 8 (Day 56 ± 3)
Visit 5 –Week 12 (Day 84 ± 3) Visit 6 –Week 16 (Day 112 ± 3) Visit 7 –Week 20 (Day 140 ± 3 ) The fo llo wing assessments will be conducted in the order written: Review of conco mit ant m edicat io ns, AEs and incidents.
Return of study toothpaste and diary . New toothbrush at Week 12. Review of completed diary to determine usage compliance. Confirmati on of subject continuance. Com plet io n of DHEQ Section 1 (Q7 -9) & Section 2. OST examinat io n. Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale, LMS) on two test teeth. Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale) on rem aining eligible teeth from Visit 1. Di spensat io n of study toothpaste and diar y(and toothbrush at Visit 5) . Supervised brushing with study treatm ent. Incidents fro m supervised brushing with study treatm ent Visit 8 – Week 24 (Day 168 ± 3) The fo llo wing assessments will be conducted in the order written: Review of conco mit ant m edicat io ns, AEs and incidents. Return of study toothpaste, toothbrush and diary . Review of completed diary to determine usage compliance. Confirmation o f subject continuance. Com plet io n of DHEQ Section 1 (Q7 -9) & Section 2. OST examinat io n. Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale, LMS) on two selected test t eeth . Evaporative air sensit ivit y assessment (Schiff Sensit ivit y Scale) on rem aining eligible teeth f rom Visi t 1. AEs and incidents will be recorded for 5 day s after last treatm ent.
3.2. Subject Restrictions
Lifestyle/ Dietary For the duration of the study (S creening –Week 24 ): Eligible subjects will be asked to stop using their regular oral care products from Screening for the duration of the study . Subjects will not be permitted to use any other oral care products (i.e., oral rins es, tongue cleaners, whitening/bleaching
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products) than those provided to them. Subjects will not be permitted to use any dental products, including home remedies, intended for treating sensit ive teeth.
Subjects will be per mit ted to use dental f lo ss f or the rem oval of i mpacted food only . Subjects will not be permitted to chew gum. Pri or to study visi ts: (Baseline -Week 24) In order to standardize oral hygiene practices , s ubjects will be asked to refrain
fro m all oral hygieneprocedures for at least 8 hours , and from eat ing and drinking for at least 4 hours , pri or to thei r scheduled Baseline and Wee k 4 to Week 24 visits. Wit hin fo ur hours of the visit (but not within one hour of the visit), small sips o f room -tem perature wate r will be permitted to take med icat io ns and relieve thirst . Subjects will be requested to refrain fro m excessive al coho l consumpt io n for 24 hours pri or to the Baseline and all subsequent visit s. If, in the opinio n of the Invest igator, the subject has cons umed an excessive am ount of alcohol prior to a visit, every effort will be made to reappoint them to the next day . If thi s is not possible, the subject should be treated as per section 4.4. Medications and Treatments For the duration of the study (scree ning –la st visi t): If conco mit ant m edicat io ns and tradi ti onal h erbal ingredients/treatments are used during the study , thei r i dent it y, as well as their dosage and frequency, start and stop dates must be recorded in the CRF . Shoul d a subject take an anal gesic within 8 hours of a scheduled visit, every effort will be made to reappoint them to the next day . If this is not possible, the subject should be treated as per section 4.4. Subjects who enter the study will be requested to delay having any n on - em erg ency, elect ive dental treatment until after study co mp letion (including dental prophylaxis).
3.3. Type and Planned Number of Subjects
Approximately 200 subjects will be screened to ensure approximately 112 sui ta ble subjects enter the acclimat isat io nphase. Approximately 75 eligible subjects will be allocated the study toothpaste in order to ensure that approximately 60 subjects com plete the study .
Subjects will be recruited by the CRO , primarily f rom thei r vo lu nteer database. Subjects m ay al so be recrui ted vi a advert isements placed in the local press, by use o f leaflets and posters or by word of m outh.
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3.4. Study Design and Dose Justification
The current study will explore the impact of lo ng term m anag ement of DH wi th daily use of a sensit ivit y toothpaste on the qualit y of life of a popul at io n of sensit ivit y sufferers , using the DHEQ. Changes in DH will also be mo nit ored clinically over th e 24 week treatm ent peri od.
A non- com parat ive, monadic study design has been selected as appropri ate to achi eve th e aims of this research. The inclusio n of a control or com parator treatment is not
considered necessary to m eet the objectives of the study (which i s to m oni tor To mo nit or the imp act of l ong term m anagement of DH over a 24 week period, with twi ce daily use of a sensit ivit y toothpaste, on the oral health related qualit y of life in sensit ivit y sufferers, as m easured by the DHEQ ). All subjects will use the same sensit ivit y toothpaste (a clinically proven 0.454% w/w stannous fluoride formulat io n
[GSKCH Study RH01685; Parkinson, 2013] fo r the duration of the 24 week study peri od.
The ant i- sensi ti vit y efficacy of toothpaste s containing 0.454 % w/w st annous fluoride has been established in a number of published studies [fo r example Schiff, 2000a,
2000b, 2006a; Pradeep, 2010; Sharma, 2010; Chaknis, 2011; Du, 2011; Ni , 2011; Parkinson, 2013]; and will not be investigated further here. The study toothpaste contains 0.454% stannous fluoride and will be provided in co mmercial tubes, overwrapped to mask its identit y. The dosage regimen of twice daily brushing (m ornin g and evening) will be the same for all subjects, and has been selected based on dental heal th care professio nals (DHCP) recommended pract ice.
It i s ant ic ipated that DH symptoms will decrease over the 24 week study peri od wi th daily use of a clinically p roven, sensit ivit y toothpaste. A validated, condit io n specific measure of oral healt h- rel ated quali ty of l ife for DH (Dentine Hy persensi ti vi ty Experi ence Quest io nnaire (DHEQ) [Boiko, 2010; Baker, 2014] will be co mp leted by th e subjects at Baseline and 4, 8, 12, 16, 20 and 24 weeks to mo nit or the im pact of a reducti on in DH on everyday life . The DHEQ (48 item) has been shown to have good psy cho met ri c p roperti es in both the general popul at io n, and in DH sufferers [Boi ko, 2010; Baker, 2014] .
An evaporative air st imulus will be administered using a d ental ai r sy ri nge. Response to this stimulus will be evaluated using
Schiff Sensit ivit y Scale [Schiff, 1994] : This i s an examiner assessment of the subject ’s response to an evaporative air st imulus . It is scored immediately fo llo wing the st imulus and focuses on a combinat ion of specific, observable, physical, behavioural and verbal responses from the subject as a result of the
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stimulat io n of exposed dent ine, rather than so le ly an oral request from the subject to discont inue st imulation and may facilitate discrimination.
Lab elled Magnitude Scales (LMS) [Heaton, 2013] : These are completed by
th e subject fo llo wing the evaporative st imulus (on a tooth by tooth basis) and apply psychophysical procedures (magnitude est imat io n and cross -mo dalit y magnitude matching) to condit io n specific descriptive words relevant to the subject’s response. The descriptive wor ds are then aligned alo ng a Vi sual Analogue Scale (VAS) at di stances th at reflect the psychological distances between words. These scales have been piloted and validated in a previously reported dentine hypersensit ivit y tri al .
The select io n of two ‘test t eeth ’to evaluate changes in DH is co mmo n practice in sensit ivit y studi es [Docimo, 2009] . The sensit ivit y of the remaining teeth th at qualified fo llo wing assessments of EAR, MGI and tooth mobilit y at Screening will also be assessed at Baseline and 4, 8, 12, 16, 20 and 24 weeks.
The dosage regimen of twice daily usage (m or ning and evening) for 1 timed minute will be the same for all subjects, and has been selected based on widely reco mmended oral hygiene pract ice, and t yp ical consumer habit.
4. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA
Specific information rega rding warnings, precautions, contraindications, adverse events, and other pertinent informat io n on the GSK invest igat io nal product or other study treatm ent that m ay impact subject eligibilit y is provided in the Saf et y Statem ent.
Deviat io ns from i nclusio n a nd exclusio n cri teri a are not allowed as th ey can potenti ally j eopardi ze the scient ific integrit y of the study , regul atory acceptabilit y or subject safety . Therefore, adherence to the criteria as specified in the protocol is essent ia l. 4.1. Inclusion Criteria
A subject will be eligible for inclu si on i n this study only if all of the f ol lo wing criteria apply:
1. CONSENT Dem onstrates understanding of the study and willingness to participate as evidenced
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by vo lu nt ary wri tten inform ed consent and has received a signed and dated copy of th e informed consent form.
2. AGE
Aged 18 -55 y ears.
3. GENERAL HEALTH Good general and mental healt h wi th , in the o pinio n of the invest igator or m edically qualified designee : a) No clinically significant and relevant abnormalit ies of m edical history or oral examinat io n. b) Absence of any condi ti on that woul d impact on the subject ’s safet y or wellbeing or affect the individual’s abilit y to understand and fo llo w study procedures and requirements.
4. COMPLIANCE
Understands and is willing, able and likely to comply wit h all study procedures and restri ct io ns.
5. DENT AL HEALTH At Visit 1 (Screening) : a) Self -reported history of dent inal hypersensit ivit y (DH) l asting m ore than six mo nt hs but not more than 10 y ears. b) Minimum o f 20 natural teeth. c)Minimum o f 2 accessible non -adjacent teeth (incisors, canines, pre -mo lar s), pre ferably in different quadrants, that meet all of the fo llo wing cri teri a: - Si gns of facial/cervical gingival recessio n and/or signs o f erosi on or abrasi on (EAR). - Tooth wi th MGI score =0 adj acent to the test area (exposed dent ine) only [Lobene, 1986] and a clinical mo bilit y of ≤1 - Tooth wi th signs of sensit ivit y measured by qualifying evaporative air assessment (Y/N response) At Visit 2 (Baseline) : d) Minimum o f two, non -adjacent accessible teeth (incisors, canines, pre - mo lars), that meet all o f th e f ol lo wing criteria: - wi th signs of sensit ivit y, m easured by a qualifying evaporative air assessment (Schiff Sensit ivit y Score ≥2)
Note: All teeth which meet the EAR, GI and mobilit y inclusio n cri teria and none of the dentit io n exclusio n cri teri a at Screening should be assessed by
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evaporative air st imulus at Baseline. Test Teeth shoul d not be adj acent to each other and preferab ly in different quadrants.
4.2. Exclusion Criteria
A subject will not be eligible for inclusio n in this study i f any of the fo llo wing cri teri a apply:
1. PREGNANCY Wo me n who are known to be pregnan t or who are intending to become pregnant over
th e duration of the study .
2. BREAST -FEEDING Wo me n who are breast -feeding
3. ALLERGY/ INTOLERANCE Known or suspected intolerance or hy persensi ti vi ty to the study m ateri als (or cl osely rel ated com pounds) or any of thei r stated ingredients.
4. CLINICAL STUDY/ EXPERMENTAL PRODUCT a) Parti ci pati on in another clinical study (including cosmetic studies) or receipt of an invest igat io nal drug wi thin 30days of the screening visit. b) Previous participat io n in this study .
5. SUBSTANCE ABUSE Recent history (wi thin the l ast y ear) of alcohol or other substance abuse.
6. PERSONNEL An emplo yee of the sponsor or the study si te or m embers of their immediate family .
7. DISEASE a) Presence of chronic debilitating disease which, in the opinion o f th e investigator, could affect study outcom es. b) Any condi ti on which, in the opinio n of the investigator, causes xerostomia.
8. GENERAL DENTITION EXCLUSIONS a) Dental prophylaxis wit hin 4 weeks of Screening. b) Tongue or lip piercing or presence of dental implants. c) Desensit izing treatment within 8 weeks of Scre ening (professional sensit ivit y treatm ents and non -dent ifr ice sensit ivit y treatm ents). d) Gross periodontal disease, treatment of periodontal disease (including surgery )
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wi thin 12 m on th s of Screening, scaling or root planning within 3 months of Screening.
e) Tee th bl eaching wi thin 8 weeks of Screening.
9. SPECIFIC DENTITION EXCLUSIONS FOR TEST TEETH a) Tooth wi th evidence of current or recent caries, or reported treatment of decay wi thin 12 m on th s of Screening. b) Tooth wi th exposed dent ine but with deep, defective or f acial restorati ons,
teeth used as abut me nt s f or fixed or rem ovable parti al dentures, teeth wi th f ull crowns or veneers, orthodontic bands or cracked enamel. Sensit ive teeth with contributing aet iolo gi es other than erosion, abrasio n or recessio n of exp osed dent ine. c) Sensit ive tooth not expected to respond to treatment with an over -th e- counter dent ifr ice in the opinio n of the invest igator.
10. PRODUCT USE
Use of an oral care product indicated for the relief of dent ine hypersensit ivit y wi th in 8 weeks o f screening (subjects will be required to bring their current oral care products to the site in order to verify the absence of known ant i- sensi ti vit y ingredients).
11. CONCOMITANT MEDICATION a) Daily doses of medication/treatments which, in the opinio n of th e invest igator, coul d interfere wi th the percepti on of pain. Examples of such medications include analgesics, ant ico nvulsants, antihistamines that cause marked or mo derate sedati on, sedat ives, tranquilisers, anti -depressants, m ood -alt ering and ant i- infl ammatory drugs. b) Current ly taking ant ibiotics or has taken antibiot ic s wi thin 2 weeks of Baseline. c) Daily dose of a medicat io n which, in the opinio n of the invest igator, is causing xerostomia.
12. OTHER Any subject who, in the judgment of the invest igator , should not participate in the study .
4.3. Screening/ Baseline Failures
Screen failures are defined as subjects who consent to participate in the study but are never subsequent ly provided wi th study product at the Baseline visit . In order to
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ensure transparent reporting of screen failure subjects, a minimal set of screen failure inform at io n is required including Demography, Screen Failure details, Eligibilit y
Cri teria, and any Seri ous Adverse Events. Re -screening of subject s will not be allowed in this study .
4.4. Withdrawal/ Stopping Criteria
A subject m ay wi th draw from the study at any ti me at his/her own request, or may be wi th drawn at any time at the di screti on of the investi gator for safet y, behavioral or administrative reasons . Where applicable, i f a subject wi th draws or i s wi th drawn fro m th e study , all h uman bi ol ogi cal samples collected before they exi ted the study will be analysed and repor ted unless the subject requests otherwise. A subject may request for their human bio lo gical samples to be destroy ed. In these cases, the investigator must document this in the site study records and the samples should not be used for any f urther research.
If the reason for removal o f a subject fro m th e study is an AE or an abnormal laboratory test resul t, the principal specific event or test will be recorded on the el ectroni c case report form (CRF). If a subject is withdrawn from the study because of a pr oduct limit ing AE, thorough efforts should be clearly made to document the outcom e. Any AEs ongoing at the final visit will be fo llo wed up unt il reso lved, the condi ti on stabilizes, is otherwise explained, or the subject is lost to follow -up.
Shoul d a subje ct take an analgesic medicat io n wi thin 8 hours of a treatment visit, or shoul d any other factor, in the opinio n of the investigator, be thought to affect study outcom es (e.g. excessive alcohol consumption), the fo llo wing act io ns must be taken Baseline visi t: every attem pt will be m ade to reschedul e the subject, if they cannot be reappointed they will be wi th drawn from the study . No clinical efficacy m easures will b e perform ed. Week 4, Week 8, Week 12, Week 16, Week 20 visit: every attem pt will be made to reschedule the subject. I f th ey cannot be reappointed they will continue in the study wi th all procedures other than clinical efficacy measures com pleted. The subject will not be withdrawn. Week 24 visit: every attem pt will b e made to reschedul e the subje ct, if they cannot be reappointed they achieve study conclusion with all procedures other th an clinical efficacy measures com pleted. The subject shoul d not be repl aced.
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SHOULD A SUBJECT TAKE ANTIBIOTIC MEDICATION TWO WEEKS PRIOR TO A TREATMENT VISIT, THE FOLLOWING ACTIONS MUST BE TAKEN
BASELINE VISIT: EVERY ATTEMPT WILL BE MADE TO RESCHEDULE THE SUBJECT, IF THEY CANNOT BE REAPPOINTED THEY WILL BE WITHDRAWN FROM THE STUDY. NO CLINICAL EFFICACY MEASURES WILL BE PERFORMED.
WEEK 4, WEEK 8, WEEK 12, WEEK 16, WEEK 20 VISIT: EVERY ATTEMPT WILL BE MADE TO RESCHEDULE THE SUBJECT WITHIN THE 3 DAY VISIT WINDOW. IF THEY CANNOT BE REAPPOINTED THEY WILL CONTINUE IN THE STUDY WITH ALL PROCEDURES OTHER THAN CLINICAL EFFICACY MEASURES COMPLETED. THE SUBJECT WILL NOT BE WITHDRAWN.
WEEK 24 VISIT: EVERY ATTEMPT WILL BE MADE TO RESCHEDULE THE SUBJECT, IF THEY CANNOT BE REAPPOINTED WITHIN THE 3 DAY VISIT WINDOW THEY ACHIEVE STUDY CONCLUSION WITH ALL PROCEDURES OTHER THAN CLINICAL EFFICACY MEASURES COMPLETED. THE SUBJECT S HOULD NOT BE REPLACED.
The fo llo wing acti ons m ust be taken in relation to a subject who fails to attend the clinic for a required study visi t:
The site must attempt to contact the subject and re -schedule the missed visit as soon as possible. The site mu st counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wishes to and/or shoul d continue in the study . In cases where the subject is deemed ‘lost to follo w up’, the investigator or desig nee must make every effort to regain contact with the subject (where possible, at least 2 telephone calls). The contact attempt should be docum ented in the subject’s record. Shoul d the subject continue to be unreachable, only then will he/she be considere d to have withdrawn fro m th e study wi th a primary reason of “Lost to Follow -up”.
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4.5. Subject Replacement
Subjects who withdraw fro m th e study post all ocati on of study product will not be repl aced .
4.6. Subject and Study Completion
A co mp leted subject is one wh o has com pleted all phases of the study . The end of the study i s defined as the date of the last subject’s last visit.
5. PRODUCT INFORMATION
5.1. Study Product
The fo llo wing study products will be supplied by the Clinical Supplies Department, GSKCH:
Treatment Study Produ ct Dent ifr ice containing 0.454% w/w stannous fluoride Group (1100ppm f luori de)
Sensodyne Repair and Protect Daily Repair Toothpaste. Germ an marketpl ace MFC Commercial Product CCI Route of Topi cal oral use administration Dosing Subje cts will brush wit ha full brush head of toothpaste for 1 timed Instructions minute (in their usual manner ), twi ce daily (m orning and evening) fro m Visi t 2 -8
Other items to be supplied by the Clinical Supplies Department, GSKCH: Name of Item Purpose Si gnal ®Family P rotecti on toothpaste Acclimat isat io n product -t o s tandardi se containing 1450 ppm fluoride as sodium oral hygiene pract ice pri or to Visit 2 mo no fluorophosphate (SMFP) , (UK market place product) Aquafresh Clean Control (Every day Toothpaste applicat io n by tooth brushing Cl ean) toothbrushes (UK m arket pl ace product)
® Signal is a registered trademark of Unilever plc.
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Countdown timers To ensure accurate brushing duration
The subject diary will be supplied by th e clinical site.
5.2. Dose Schedule
For both the acclimat isat io n and study toothpaste, the s ubjec ts will apply a f ull brush head o f th e toothpaste and brush for one timed minute in their usual manner twice daily (m orning and evening) .
5.3 . Dose Modification
No dose m odificat io n is permitted in this study .
5.4. Product Compliance
Di aries will b e used throughout the study to a) allo w the subject to familiarize th em selves wi th thei r com plet io n during the acclimat isat io nphase and b) prom ote com pliance during the treatment phase. Subjects will not be excluded due to missed brushings but will be reminded to use the products supplied as per the instructions provi ded and to complete the diary af ter each product usage to encourage compliance.
Study si te staff will review the diaries at the start of each visit for compliance and any reports of changes/new medicat io ns. 5.5 . Precautions
No special precaut io ns are necessary provided the study i s carri ed out in accordance wi th this protocol . 5.6. Overdose
An overdose is a deliberate or inadvertent administration of a product at a dose higher th an specified in the protocol.
Overdose is not likely to occur in this study . Limit ed quant it ies of the product will be supplied, and closely m oni tored by the si te f or each subject.
Overdose per se is not an AE. However, any clinical sequelae of an overdose should be reported as an AE (and serious adverse event (SAE), if appropria te). For reporting, fo llo w the AE and SAE reporting instructions.
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5.7. Rescue Therapy
No rescue therapy i s requi red in this study . 5.8 . Product Assignment
All eligible subjects at Visit 2 will be provided with the same study product.
5.8.1 Randomisation
There i s no randomisation in this study . All subjects eligible at Vi si t 2 will be provi ded wi th the same study product.
5.8 .2 Blinding
The subject is blinded to the identit y of the study toothpaste (they will not be aware of th e brand name of the toothpaste they are using). The packaging will be overwrapped as d etailed below. Neither the study sta ff nor the sponsor are blinded. 5.9. Pack aging and Labelling
The acclimat is at io n product ( Si gn al F amily Protectio nToothpaste ) will be sourced fro m th e UK market and supplied in its co mmercial tube (no overwrapping) with a study l abel affixed. Each subject will receive a sufficient number of tubes to c over usage during the acclimat is at io n phase.
The study toothpaste will be sourced from the German market. The tubes will be overwrapped in white vinyl to obscure any branding on the commercial tube pack. Each subject will receive a carton containing sufficient number of tubes to cover usage during e ach 4 week visit. Each tube and carton will have a study l abel affixed. The contents of the label will be in accordance with all applicable regulatory requi rements (including the device precaut io nary sta tem ent ‘Exclusively For Clinical Invest igat io n)’ and will be the responsibilit y of the Clinical Supplies Depart me nt , GSKCH . Re -dispensing o f product will occur at each treatment visit (Visi t 3 – Vi si t7). At Visit 2 and 5 a new toothbrush will be dispensed to each subject.
All sundry i tems will b e supplied in their commercial packaging.
Care should be taken with the supplied products and their labels so that they are maintained in good condition. It is important that all labels remain intact and legible fo r the durati on of the study . Subj ects shoul d be ins tructed not to remove or deface any part of the study l abel .
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5.9.1. Accountability of Product
All products supplied are for use only in this clinical study and shoul d not be used for any other purpose.
The invest igator or designee will maintain a full record of study product accountabilit y. A Product Dispensing Log must be kept current and will contain the fo llo wing informat io n:
The i dent ificat io n of the subject to whom the study product was dispensed. Th e date(s) and quantit y of the study product di spensed to the subject. The date(s) and quantit y of the study product returned by the subject (if applicable).
The inventory m ust be available for inspect io n by the study m oni tor during the study .
At the end o f th e study , study product supplies will be verified by the monitor. Study product supplies will then be either collected by the study m oni tor or returned by the investigator or designee to the GSKCH Clinical Supplies Depart me nt or designated vendor.
5.9. 2. Storage of Product Study product supplies must be stored in compliance with the label requirement s in a secure place with limited or controlled access. 6. STUDY ASSESSMENTS AND PROCEDURES
This sect io n lists the procedures and parameters of each planned study assessment. The exact timing of each assessment is listed in the Schedule of Events sect io n.
Ad herence to the study design requi rements, including all assessments and procedures are essential and required for study conduct. 6.1. Visit 1 -Screening Visit
6.1.1 Telephone Screening Pri or to the screening visit, telephone screening of interested subjects will be conducted using a tele phone script. This will be conducted by the si te recrui tm ent staff or designee.
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6.1.2. Informed Consent
The invest igator, or designee, must obtain written (signed and dated by th e subject) inform ed consent from each subject parti ci pating in this study af ter adequate explanat io n of the aims, methods, objectives, and potential hazards of the study .
The invest igator, or designee, must also explain to the subjects that they are com pletely free to refuse to enter the study or to wi th draw from i t at any time. Appropriate forms for document ing a written consent will be provided by the investigator or by GSKCH. The invest igator, or designee, should sign and date the consent form to con fir m th at the consent process was completed correctly . The subject will be provided with a copy of thei r signed and dated consent form and any other wri tten information which they sh oul d be instructed to retain.
If, during a subject’s participat io n in the study , any new information beco me s available that may affect the subject’s willingness to participate in the study , each ongoing subject should receive a copy of this new inform at io n and be re -consented int o the study . Subjects should be provided wit h a c opy of the signed and dated am ended consent form. The date of consent will be recorded on the CRF.
6.1.3 . Demographics The fo llo wing dem ographic parameters will be captured by the Investi gator or designee and recorded on the CRF: year of birth, gender , ethnicit yand race.
6.1.4 . Medical Histor y and Concomitant Medication Medical history will be assessed as related to the inclusion/exclusio n cri teri a by the Invest igator or medically qualified designee. Details of any relevant medical or surgi cal history (wi thin the last y ear) , including allergies or drug sensit ivit y, will be recorded on the CRF. Any conco mit ant therapy taken in the 30 days pri or to the Screening Visit and throughout the study will al so be recorded.
6.1.5. Oral Hard T issue (OHT) Examination The dent ist will perf orm a visual ex aminat io n of the oral hard tissue to co nfir m that th e subject has a minimum o f 20 natural teeth and to evaluate the dent itio n fo r exclusio ns.
6.1. 6.O ral Soft Tissue (OST) Examination Where possib le, this procedure should be conducted by a single trained dental examiner. The examinat io n will b e acco mp lished by direct observat io n and palpat io n wi th retracti on ai ds as appropri ate. The examiner will include examinat io n of the Labial Mucosa (including lips), Buccal Mucosa, Mucogingival fo ld s, Gingival
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Mucosa, Hard Palate, Soft Palate, Tonsilar Area, Pharyngeal Area, Tongue, Sublingual Area, Submandibular Area and Salivary Glands. The results of the
examinat io n will be recorded in the CRF as eit her norm al or abnorm al wi th details of any abnormalit ies. A br ief description o f any abnorm ali ty observed by the examiner or reported by the subject at the applicat io n site fo llo wing the administration of the acclimat isat io n or treatment toothpaste s will be recorde d as an AE.
An OST examinat io n will be conducted at every study visi t pri or to any clinical assessments. While it is preferable to use the same OST examiner throughout the study , to f acilitate subject flow, OST examinat io ns may be carried out by different examiners.
6.1. 7.Eligible Tooth Assessment
Eligible tooth assessment will include an oral hard tissue examination (visual assessment only to evaluate denti ti on exclusio ns -see Exclusio n Cri teri a 8 and 9 ); erosi on, abrasi on and/or gingival recessio n; mo dified gingival index; tooth mobilit y and qualifying evaporative air assessment. Assessments will be carried out by the Invest igator or medically qualified designee against the inclusio n/excl usi on cri teri a and recorded in the CRF.
6.1. 7.1 . Erosion, Abrasi on and Recession (EAR) assessment The presence of cervical erosion, abrasio n and/or gingival recessio n[A ddy , 2000] will be determined on the facial surfaces of individual teeth. Teeth exhibit ing EAR will be assessed to ensure they do not meet any o f th e general dent itio n exclusio n cri teria and the specific dent itio n exclusio n cri teri a f or test teeth (see Exclusio n Cri teria 8 and 9 ).
6.1. 7.2 .Modified Gingival Index ( MGI) Assessmen t The MGI i s a non -invasive visual evaluation of gingival healt h[Lobene, 198 6] scored on a scal e of 0 -4. MGI will be assessed for the facial gingiva adjacent to the test area (exposed dent ine) only of teeth exhibit ing facial cervical erosion, abrasio n and/or recessio n at the Screening visit. MGI = 0 is required for eligible teeth .
Score Description
0 Absence of inflammat io n mild inflammat io n; slight change in co lo r, li ttl e change in co lo r; litt le 1 change in texture of any portion of the marginal or papillary gingival unit. mild inflammat io n; criteria as above but invo lving t he ent ir e m arginal or 2 papillar gingival unit.
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mo derate inflammat io n; gl azing, redness, edema, and/or hy pertrophy of 3 th e marginal or papillary gingival uni t.
severe inflammat io n; marked redness, edema and/or hy pertrophy of the 4 marginal or papillary gi ngival unit, spontaneous bleeding, congest io n, or ul cerat io n.
6.1. 7.3 .Tooth Mobility Assessment
The clinical mo bilit y assessment will only b e perform ed on teeth exhibit ing facial cervical erosion, abrasio n and/or recession and that have a MGI = 0. Clin ical mo bilit y will be classified in the fo llo wing way (based on a modificat io n to the Miller Index)
[Laster, 1975] and the degree of mobilit y will b e recorded. A clinical mo bilit yof ≤1 is required for eligible teeth.
Degree 0 No m ovement or mobilit y of the crown of the tooth < 0.2mm in a hori zontal di rect io n.
Degree 1 Mobilit y of the crown of the tooth 0.2 –1mm in a hori zontal di rect io n Degree 2 Mobilit y of the crown of the toot h exceeding 1mm in a horizontal di rect io n Degree 3 Mobilit y of the crown of the tooth in a vertical direction as well.
6.1.7 .4. Qualifying Evaporative air Sensitivity The screening dent ist will assess sensit ivit y by a simple air blast on the facial surf ace of all teeth that m eet the EAR, MGI and mobilit y cri teri a. This assessment is made by di rect ing a one second applicat io n of air fro m a standard dental sy ri nge perpendicular to the tooth surface approximately 1 -2 mm coronal to the free gingival margin and fro m a distance of approximately 1cm. Foll owing the ai r blast, the dent ist will ask the subject if they experienced sensit ivit y. In order to qualify , the subject shoul d confirm th ey experienced sensit ivit y and a simple “yes/no” response will be recorde d. 6.2. Visit 2 to Visit 8
6.2.1 . Dentine Hyersensitivity Experience Questionnaire (DHEQ) The DHEQ (Appendix 2) will be co mp leted by the subjects at Vi si t 2 (Baseline) and Vi si ts3 -8( Week 24 ), pri or to any clinical assessments (including OST assessment). Secti on 1 asks quest io ns about “y our sensi ti ve teeth and the impact it has on y our everyday life”. Section 2 asks questions about “the way s in which the sensations in yo ur teeth affec t y ou in y our daily life”, and is grouped into domains as fo llo ws. Restrictions (Section 2, Q 1-4) Adaptation (Section 2, Q 5-16)
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Soci al Impact (Secti on 2, Q 17-21) Em oti onal Im pact (Section 2, Q 22-29 ) Ident it y (Sect io n 2, Q30 -34)
Vi si t DHEQ questions to be answered by subjects
Vi si t 2 Secti on 1: Secti on 2: All quest io ns, Q1 -9 All quest io ns, Q1 -39 Vi si t 3 -8 Secti on 1: Secti on 2: Q7 -9 All quest io ns Q1 -39
THE SITE WILL CHECK AND CROSS REFERENCE THE SUBJECT’S RESPONSE TO DHEQ SECTION 1 QUESTION 2, AT VISIT 2 (BASELINE), WITH THE INCLUSION CRITERIA 5(A) BEFORE THE SUBJECT LEAVES
THE STUDY SITE, AND CLARIFY ANY DISCREPANCY WITH THE SUBJECT IF NECESSARY.
6.2.2 Labelled Magnitude Scales (LMS) Training Exercise
At Baseline (V isit 2) , e ligible subjects will be g iven instructions on how to use the LMS and asked to complete the LMS training exercise. The invest igator or designee will determine whether or not the subject understands how to use the LMS. Invest igator instructions fo r administrating and int erpreti ng th e LMS training exercise can be found in Appendix 3. Subject instructions for complet ing the LMS training exercise can also be fo und in Appendix 3. The data fro m this exercise are for training purposes only and will not be recorded in the CRF.
6.2.3 . Oral Soft Tissue (OST) Examination Com plete as described in Section 6.1. 6.
6.2. 4. Evaporative Air Sensitivity Assessments This assessment will be conducted by a single examiner fo r all subjects at each visit by direct ing a maximum one second applicat io n of ai rfro m adental air sy ri nge to the exposed dentine surface fro m a distance of approximately 1 cm. The examiner should take appropriate measures to iso lat e the test tooth surface in order to prevent stimulus exposure to adjacent tooth or surrounding so ft tis sue.
At B aseline, the examiner w ill assess the evaporative air sensi ti vi ty of all clinically eligible teeth ident ified at S creening (teeth that qualified on EAR, MGI and tooth mo bilit y cri teria, and had none of the dentit io n exclusio ns), using the Schiff
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Sensi ti vi ty Scale and LMS (Appendix 4 ). Two test teeth will be selected according to specific eligibilit ycri teria in an individual subject .
At Week 4, 8, 12, 16, 20 and 24 visits th e examiner will first assess the evaporative ai rsensit ivit y of th e two i dentified test teeth from the Baseline visit using the Schiff Sensit ivit y Scale and LMS . The examiner will then assess the evaporative air sensit ivit yof the rem aining Eligible Teeth from Screening (teeth that qualified on EAR, MGI and tooth mobilit y cri teri a, and had none of the dentit io n exclusio ns), using the Schiff Sensit ivit y Scale .
6.2. 4.1. Schiff Sensitivity Scale This is an examiner based index [Schiff, 1994] , scored immediately fo llo wing administration of th e evaporative air st imulus. This scale focuses on a combin at io n of specific, observable, physical, behavioural and verbal responses fro m th e subject as a resul t of the stimulat io n of exposed dent ine, rather than so le ly an oral request from th e subject to discontinue stimulat io n and m ay facili tate discriminat io n. The examiner will indicate the subject’s response to the evaporative air st imulus, after the stimulat io n of each individual tooth, using the Schiff Sensi ti vi ty Scale as foll ows.
0 Subject does not respond to air st imulation Subject responds to air st imu lus but does not request 1 di scontinuati on of st imulus Subject responds to air st imu lus and requests discont inuat io n or 2 mo ves from st imulus Subject responds to stimulus, considers st imulus to be painful, 3 and requests discontinuation of the st imulus
6.2. 4.2. Labelled Magnitude Scales (LMS) The LMS score should be co mp le ted af ter the Schiff Sensit ivit y score assessment to avo id examiner bias. The examiner should not use the subjects response to the LMS to gui de their Schiff assessment score. These are com pleted by the subject immediately f oll owing the evaporative st imulus and apply psychophysical procedures (m agni tude estimati on and cross -mo dalit y magnitude m atching) to condit io n specific descript ive words relevant to the subject ’s response [Gracely , 1978] . The descript ive words are then aligned alo ng a VAS at di stan ces that reflect the psy cho lo gi cal di stances between words. These scales have been piloted and validated in a previously reported dentine hypersensit ivit y tri al [Heaton, 2013] . Subjects will use LMS (see Appendix 3and 4) to rate the i nt ensi ty , durati on, tolerabilit y and descript ive qualit y of thei r response to the evaporative air s ti mulus ,af ter the
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stimulat io n of each individual tooth, using 100 millimetre (mm) LMS. The study staff will measure the line segment marked -off in mm from le ft to ri ght BOTTOM TO
TOP al ong th e line and record this measurement.
6.2.5 . Study Conclusion Subjects w ill be evaluated to determine if they completed all study procedures or if th ey were discontinued from the study early. If the subject discont inued at any po int during the study , the primary reason for wi th drawal sh oul d be recorded on the Study Concl usi on page of the CRF by select ing one of the options below.
Subject did not meet study cri teri a Ad verse Event Lost to Follow Up Protocol Vi ol at io n Wit hdrawal o f Consent Other
7. SAFETY ASSESSMENTS
7.1. Definitions of an Adverse Event and Serious Adverse Event
7.1.1. Adverse Events The invest igator or site staff will be responsible for detecting, documenting and reporting events that meet the definit io n of an AE or SAE.
Adverse Event Definition: An AE i s any untoward m ed ical occurrence in a patient or clinical investigat io n subject, temporally associ ated wi th the use of an invest igat io nal or washout product, whether or not considered related to the invest igat io nal or washout product. NOTE: An AE can therefore be any unfav orable and unintended sign (i ncluding an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of an invest igat io nal or washout product.
Events meeting AE definition include: Any abnormal laboratory te st resul ts (if applicable) or other safet y assessments, including those that worsen from baseline, and felt to be clinically significant in the medical and scient ific judgm ent of the investigator. Exacerbat io n of a chronic or intermittent pre -exist ing cond itio n including ei th er an increase in frequency and/or intensit y of the condi ti on . New condit io n(s) detected or diagnosed after study product administration
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even though it may h ave been present prior to the start of the study . Si gns, symptoms, or the clini cal sequelae of a suspected interaction.
Si gns, symptoms, or the clinical sequelae of a suspected overdose of either study product or a concomitant medicat io n (overdose per se will not be reported as an AE/SAE).
Events NOT meeting definition of an AE inc lude: Any clinically si gnificant abnormal laboratory f indings (if applicable) or other abnorm al safety assessments which are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condit io n. The disease/disorder/ condit io n being studied or expected progression, signs,
or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condit io n.. Medical or surgical procedure (e.g., endoscopy , appendect omy): the condit io n th at leads to the procedure is an AE. Si tuati ons where an untoward medical occurrence did not occur (social and/or
convenience admissio n to a hospital). Ant ic ipated day -to -day fluctuations of pre -exist ing disease(s) or condit io n(s) pres ent or detected at the start of the study that do not worsen.
7.1.2. Serious Adverse Events Serious Adverse Event is defined as any untoward medical occurrence that, at any dose: A. Results in death B. Is life -threatening NOTE: The term 'life -th reatening' in the definit io n of 'serious' 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, whi ch hypotheti cally might have caused death, if it were mo re severe. C. Requires hospitalization or prolongation of existing hospitalization NOTE: In general, hospitalizat io n signifies that the subject has been detained (usually invo lving at least an overnight stay ) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in th e physician’s office or out -pati ent setti ng. Com plicat io ns that occur during hospi talizati on are AEs. If a com plicati on prol ongs hospi tali zati on or f ulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalizat io n” occurred or was necessary , the AE shoul d be considered seri ous.
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Hospitalization for elect ive treatment of a pre -existing condit io n that di dnot worsen from baseline is not considered an AE.
D. Results in disability/incapacity NOTE: The term disabilit y means a substant ia l disrupti on of a person’s abilit y to conduct normal life funct io ns.
This definit io n is not intended to include experiences of rel at ively minor
medical significance such as unco mp licated headache, nausea, vo mit ing, di arrhea, influenza, and accidental trauma (e.g. sprained ankle) which may int erf ere or prevent every day life funct io ns but do not constitute a substant ial di srupt io n. E. Is a congenital anomaly/birth defect F. Other Situations Medical or scient ific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important
medical events that may not be immediately life -threatening or r esul t in death or hospitalizat io n but may jeopardize the subject or may requi re m edical or surgi cal intervent io n to prevent one of the other outcom es listed in the above definit io n. These should also be considered serious. Examples of such events are invas ive or m alignant cancers, intensive treatm ent in an emergency room or at hom e f or allergi c bronchospasm, blood dyscrasias or convulsio ns that do not result in hospitalizat io n or development of drug dependency or drug abuse or reports of spontaneous abortio n.
7.2 . Recording Adverse Event sand Serious Adverse Event s
Recording of adverse events and serious adverse events: The invest igator or site staff will be responsible for detecting, doc umenting and reporting events that meet the definit io n of an AE or SAE. The invest igator or site staff will then record all relevant informat io n regarding an AE/SAE in the CRF. There m ay be instances when copies of medical records for certain cases are re quested by GSK. In thi s instance, all subject ident ifier s, wi th the except io n of the subject number, will be blinded on the copies of the medical records pri or to submissio n of to GSK. The invest igator will attempt to establish a diagnosis of the event ba sed on si gns, symptom s, and/or other clinical information. In such cases, the di agnosis will be documented as the AE/SAE and not the individual
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si gns/symptom s. Clinical A Es will be described by diagnosis and not by symptoms when possible (e.g., upper resp ir atory tract infection, seasonal
allergy , etc. instead of runny n ose). AEs will be co llected fro m th e start of the investigational product and until 5 days fo llo wing l ast administrati on of the study product. SAEs will be collected over the same time perio d as stated above for AEs. However, any SAEs assessed as related to study parti cipat io n (e.g.,
investigat io nal product, protocol mandated procedures, invasive tests, or change in exist ing therapy) or related to a GSK conco mit ant m edicat io n will be recorde d from the time a subject consents to participate in the study up to and including any fo llo w- up contact. Medical condit io ns reported prior to the time period for reporting AEs/SAEs shoul d be recorded as part of the subject’s medical history .
7.3 . Eval uating Adverse Event sand Serious Adverse Event s
Assessment of Intensity: The invest igator or designee will make an assessment of intensit y fo r each AE and SAE reported during the study and will assign i t to one of the following c ategori es: Mild: An event that is easily tolerated by the subject, causing minimal di scomfort and not interfering wit h everyday act ivities. Moderate: An event that is sufficient ly disco mfo rting to interfere with normal everyday act ivit ies Severe: An eve nt that prevents normal everyday activit ies. -an AE that is assessed as severe will not be confused with an SAE. Severit y is a category utilized for rating the intensit y of an event; and both AEs and SAEs can be assessed as severe. Note: An event is defin ed as ‘seri ous’ when i t m eets at l east one of the pre -defined outcom es as described in the definit io n of an SAE.
Assessment of Causality: The invest igator is obligated to assess the relationship between study product and the occurrence of each AE/SAE. A"reasonable possibilit y" is me ant to convey that there are facts/evidence or argum ents to suggest a causal relationship, rather than a relat io nshi p cannot be rul ed out. The invest igator will use clinical judgment to determine the relat io nship. Alt ernat ive causes, such as natural history of the underlying diseases, concomitant therapy , other risk factors, and the temporal relat io nship of the event to the study product will b e considered and investigated.
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The invest igator will also consult the Invest igator B rochure (IB) and/or Product Informat io n, for marketed products, in the determinat io n of his/her
assessment. For each AE/SAE the investigator must document in the medical notes (source document) or CRF that he/she has reviewed the AE/SAE and has provi ded an assessment of causalit y. There m ay be si tuati ons when an SAE has occurred and the invest igator has
minimal informat io n to include in the init ial report to GSK. However, it is very important that the investigator always make an assessment of causality for every event prior to the initial transmission of the SAE data to GSK. The invest igator may change his/her opinio n of causalit y in light of fo llo w-up inform at io n, am ending the SAE data collect io n tool accordingly. The causalit y assessment is one of the cri teri a used when determining regul atory reporting requi rements.
7.4 . Reporting Adverse Event sand Serious Adverse Event s
AE Reporting to GSKCH: AEs will be recorded in the AE sect io n of the CRF. Medical condit io ns recorded by the subject on a diary card or similar docum ent that m eet the definit io n of an AE must also be recorded in the AE sect io n of the CRF, if not previously well -characteri zed by the invest igator in th e subject’s medical history . AEs elicited by the investigator in a standard manner at the study visits should also be recorded i n the AE sect io n of the CRF. The invest igator or designee must ask the subject the fo llo wing question during each visit including any fo llo w- up visits: “Have you felt unwell, experienced any symptoms or taken any medication (since your last visit) (today ) (since your last dose) (since the last session)?” The m edically qualified investigator should review adverse events in a timely manner; this review should be documented in writ ing in the source document or in the CRF. After the study i s com pleted at a g iven site, and the site has received their study data on Com pact Discs (CDs), the el ectroni c data collection tool will be rem oved from the internet to prevent the entry of new data or changes to exist ing data.
SAE Reporting to GSKCH: A paper copy of the SAE form provi ded in the investigator study m aster file should
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be co mp leted as fully as possible. It i s essent ia l to enter the following informat io n:
Protocol and subject i dent ifiers Subject’s demography Descript io n of events, with diagnosis if availabl e Invest igator opinio n of relationship to study product (see section 8.3) Cri teri on f or seri ousness.
The fo llo wing are desirable and are of particular relevance for invest igator and GSKCH assessment of the SAE report: Date of onset of AE Date AE stopped, if relevant Study product start date Study product end date if relevant Act io n taken on study product Outcom e if known
The SAE form, completed as fully as possible, and SAE fax cover sheet must be faxed or e -mailed to the appropriate GSKCH Study Manager as soon as possible, but not later than 24 hours af ter study si te personnel l earn of the event. The GSKCH Study Manager shoul d be notified of the situat io n by telephone or email.
Fax Serious Adverse Events to: UK: PPD
The GSKCH Study Manag er will be responsible for forwarding the SAE form to the Case Management Group, Global Clinical Safet y and Phamacovigilance, the Medical Di rector responsible for the study and other GSKCH personnel as appropriate via em ail.
The init ial report will be fo ll owed up wi th m ore inform at io n as relevant, or as requested by the GSKCH study m anager.
7.5 . Fo llow -up of Adverse Event sand Serious Adverse Event s
Follow -up of AEs and SAEs: After the init ial report, the invest igator is requir ed to proactively fo llo w up wi th each subject and provide further informat io n on the subject’s condit io n. All AEs/SAEs will be fo llo wed unt il reso lut io n, until the condit io n stabilizes, unt il the event is otherwise explained, or until the subject is lost t o f ollow -up.
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The invest igator is obligated to perform or arrange for the conduct of supplemental m easurements and/or evaluat io ns as may be indicated or as
requested by GSK to el ucidate as fully as possible the nature and/or causalit y of the AE or SAE. In vest igators are not obliged to actively seek AEs or SAEs in former subjects. However, if the invest igator learns of any SAE, including the death, at any time after a subject has been discharged from the study , and considers the
event reasonably related to th e invest igat io nal product or study parti cipat io n, th e invest igator will pro mpt ly notify GSKCH. The invest igator will submit any updated SAE data to GSK within the designated reporting time frames.
Regulatory and ethics reporting requirements for SAE s:
The invest igator will pro mpt ly report all SAEs to GSKCH wit hin the designated reporting timeframes (within 24 hours of learning of the event). GSKCH has a legal responsibilit y to notify , as appropri ate, the l ocal regul atory authori ty and other regul at ory authori ti es about the safety of a product under clinical investigation. Prompt notification of SAEs by the investigator to GSKCH is essent ial so that l egal obligat io ns and ethical responsibilit ies towards the safet y of subjects are met. GSKCH will co mply wi th country specific regul atory requi rements relating to safet y reporting to the regulatory authori ty , IEC and invest igators. Invest igator safet y reports are prepared according to GSKCH policy and are fo rwarded to invest igators as necessary. An inves tigator safety report i s prepared for a SAE(s) that is both attributable to investigational product and unexpected. The purpose of the report is to fulfill specific regulatory and GCP requirements, regarding the product under investigation. An invest igato r who receives an invest igator safety report describing a SAE(s) or other specific safet y informat io n (e.g., summary of list ing of SAEs) fro m GSKCH will file it with the Invest igator Brochure (or safet y statem ent) and will notify the IRB or IEC, if appropr iat e according to local requirements.
7.6. Definition of and Procedure for Reporting Medical Device Incidents
Medical devices are being provided by GSKCH for use in this study; the medical device in this study i s th e study toothpaste. GSKCH medical device incidents,
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inc luding those resulting fro m malfunct io ns o f th e device, must be detected, docum ented, and reported by the investi gator on the CRF throughout the study .
7.6.1. Definition of an Incident
Definition of an Incident: Any malfunct io n or deteri orati on in the character is ti cs and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use
which, direct ly or indirect ly, might lead to or might have lead to the death of a pati ent or user or of other persons or to a serious deterioratio n in their state of healt h.
7.6.2. Reporting of Incidents and Malfunctions
Inci dent Reporting to GSKCH: All incidents must be reported to GSKCH within 24 hours (or sooner if possible) of the investigator or designee becoming aware of the situation. Any medical device incident occurring during the study will be documented in th e subj ect's m edical records, in accordance wit h the investigator's normal clinical practice, and on the appropriate Incident Report Form. In addit io n,
fo r incidents fulfilling the definit io n of an AE or an SAE, the appropriate AE CRF page or SAE form will be co mp leted and reported as per the AE and SAE reporting sections. The Incident Report Form will be co mp leted as thoroughly as possible and si gned by the investigator before transmittal to GSKCH. It is very important th at the investigator describes any correc tive or remedial act io ns taken to prevent recurrence of the incident. The completed Incident Report Form should be faxed or emailed to the appropriate GSKCH Study Manager as soon as possible, but not later than 24 hours af ter study si te personnel l earn of th e event. If there is an SAE, the com pleted SAE pages should be sent together with this report form. However, if a copy of the SAE report i s sent wi th this form , thi s does not repl ace the procedure to report an SAE. The original Incident Report Form wil l remain wi th the subject’s records. The GSKCH Study Manager shoul d be notified of the situation by telephone or em ail. Fax the Incident Report Forms to: UK: PPD
The GSKCH Study Manager will be responsible for forwarding the Incident Report Fo rm to the Case Management Group, Global Clinical Safet y and Pharmacovigilance, the Medical Director responsible for the study and other
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GSKCH personnel as appropriate.
The init ial report will be fo llo wed up wi th m ore inform at io n as relevant, or as requ ested by the GSKCH study m anager.
Reporting of Malfunctions to GSKCH: The invest igator will fo llo w the fo llo wing di rect io ns regarding device failure (m alfunct io n): Notify GSKCH immediately . Schedule the subject to return to the site prompt ly to return t he fa iled device. Record any i nci dents on the CRF and Incident Report Form fo llo wing instructi ons given in the sect io n above.
Return the failed device to the sponsor as soon as possible, including docum entati on of the details o f th e f ailure.
7.6.3. Follow- up of Incidents
Follow -up of Incidents: During the study : All incidents will be fo llo wed until reso lut io n of the event, until the condit io n stabilizes, unt il the condit io n is otherwise explained, or until the subject is lost to fo llo w- up. Thi s applies to all subjects, including those withdrawn prem aturely . The invest igator is responsible for ensuring that follow -up includes any supplemental invest igat io ns as m ay be indicated to el ucidate as com pletely as pract ical the nature of the incident. New or updated informat io n will be recorded on the originally co mp leted fo rm wi th all changes signed and dated by the investi gator.
After the study : Invest igators are not obligated to actively seek reports of incidents in former subjects. However, if the invest igator lear ns of any incident at any time after a subject has been discharged fro m th e study , and such incident i s reasonably rel ated to a GSKCH medical device provided for the study , the invest igator will pro mpt ly notify GSKCH.
Regulatory and Ethics Reporting Requirements for Incidents: The invest igator will pro mpt ly report all incidents occurring with any GSKCH medical device provided for use in the study wi thin 24 hours. GSKCH has a legal responsibilit y to notify appropri ate regulatory bodies and other entit ie s about certain safety i nformat io n rel at ing to medical devices being used in
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clinical studies. Prompt notificat io n of incidents by the investigator to GSKCH is essent ial in order to meet legal obligat ions and ethical
responsibilit y towards the safet y of subjects. The invest igator, or responsible person according to local requirements, will com ply wi th the applicable l ocal regulatory requi rem ents rel at ing to the reporting of incidents to th e IEC.
7.7. Collection of Pregnancy Information
7.7. 1. Tim e Period for Collecti ng of Pregnancy Information Collection of Pregnancy Information: Pregnancy informat ion will be co llected on all pregnancies reported fo llo wing administration of any i nvesti gati onal product. Inform at io n on pregnancy ident ified during the screening phase and prior to investigational product administration does not need to be collected.
7.7. 2. Action to be Taken if Pregnancy Occurs Action to be Taken: The invest igator will co llect pregnancy information on any subject who beco me s pregnant while participat ing in the study af ter administrati on of the investigat io nal product . The invest igator will record pregnancy informat io n on the appropriate form and submit it to GSKCH within 2 weeks of learning of the subject beco ming pregnant. The subjec t will be followed to determine th e outcom e of the pregnancy. Informat io n on the status of the mother and infant / neonate (including conco mit ant m edicat io ns taken by the m oth er during the pregnancy ) will b e f orwarded to GSKCH. Generally, follow -up will be no l onger than 6 to 8 weeks following the estimated delivery date. Any termination o f th e pregnancy will be reported. While pregnancy i ts elf is not considered to be an AE, any pregnancy com plicat io n or el ect ive terminat io n fo r m edical reasons will be reco rded as an AE or SAE. A spontaneous abortion is always considered to be an SAE and will be reported as such. An SAE occurring in associat io n wi th a pregnancy, brought to the invest igator’s attention after the subject completed the study and considered by t he investigator as possibly related to the investigational product, m ust be prom ptly forwarded to GSK. While the invest igator is not obliged to actively seek this information in fo rm er study parti cipants, he or she may l earn of an SAE through spontaneous
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reporting. For non -medicinal or licensed products with no pregnancy warning on the
label, use the following text: “There is no requirement for the subject to be wi th drawn from the study as a resul t of the pregnancy. However if they are wi th drawn, thi s shou ld be recorded in the appropriate section o f th e CRF.”
8. DATA MANAGEMENT
For thi s study subject data will be entered into an electronic case report form, using a GSKCH validated data sy stem .
8.1. Source Documents/ Data
The source documents (e.g. hospital records, clinical and office charts, laboratory
notes, m em oranda, subjects’ diaries or evaluat io n checklists, pharmacy dispensing records, recorded data from automated instruments, microfiches, phot ographic negat ives, microfilm or magnetic media, x -rays, subject files and records kept at the pharmacy, at the laboratory and at the m edico -technical departments invo lved in the clinical study ) which contain the source of data recorded in the CRF should b e specified in the Source Document Designat io n Form. In so me cases the CRF can be used as a source document.
Each subject will be assigned and ident ified by a unique Screening Number. Any reference made to an individual subject within the study must be do ne using the unique Screening Number. 8.2 . Electronic Case Report Form
A CRF is a printed, optical, or electronic document designed to record all of the protocol requi red inform at io n to be reported to the sponsor on each trial subject.
For each subject w ho has given informed consent/assent and has been screened, CRF must be completed and signed by the Principal Investigator (or auth ori zed desi gnee) to certify that the data are com plete and correct.
Management of clinical data will be performed in accord ance with applicable GSKCH standards and data cleaning procedures to ensure the integrity o f th e data e.g. rem oving errors and inconsistencies in the data.
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In order to protect the privacy of subjects, no Personally Identifiable Inform at io n (PII) (i ncludin g the subject's name or init ials or birth date) is to be recorded in the
CRF or as part of the query text.
Ad verse events and conco mit ant medicat io ns terms (if applicable) will be coded using MedDRA (Medical Dictionary f or Regul atory Activi ti es) and an int ernal validated m edicat io n di ct io nary, GSKDrug.
Subject data will be entered into GSKCH defined CRFs and transmitted electronically
to GSKCH in a validated (21 CFR Part 11 compliant) web -based electronic data capture system (InForm TM ).
All CRF pages shou ld be completed during a subject assessment when the CRF has been designated as the source. Data that is sourced elsewhere should be entered into th e CRF in an agreed upon timeframe between the Investigator and Sponsor.
The CRFs (including queries, quer y responses and audit trails) will be retained by GSKCH. Site data archived compact discs (CD(s)) prepared by a thi rd party will be sent to the investigator to maintain as the investigator copy f ol lo wing the decommissio ning of the study . 8.3 . Data Handling
Docum entati on of all data m anagement activit ies should allow step -by- step retrospective assessment of data qualit y and study perform ance. Any changes or correcti ons to data will be performed in the Electronic Data Capture (EDC) Sy stem , and it will include rationale f or changes. The EDC system has an audit trail, which will provide a complete record of the changes and corrections endorsed by the Invest igator.
8.3.1 . Data Queries Programmed edit checks will be generated automatically , as the data is being entered int o the system . Data Management will also run reports and list ings on the CRF data, in addi ti on to the queries already programmed and generated by the system , to rai se manual queries as needed for site clarificat io n or correcti on. The Clinical Dictionary Development and M anagement Group will raise queries as needed on safet y data to code the terms (Adverse Events and Drugs) are reported appropriately .
The study m oni tor at the study si te will review the CRFs in accordance with the mo nit oring plan, and any queries will b e g enerated in the EDC Sy stem to the Invest igator or designee, enabling the errors to be addressed in parallel wit h Data
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Management review. Monitor can also run reports and list ings on the CRFs, to raise manual queries as needed for site clarificat io n or corr ecti on
8.4. Processing Patient Reported Outcomes
Pati ent reported outcome (PRO) data are collected direct ly fro m th e subject PRO measures e.g. diary cards, questionnaires etc, and entered into the sponsor’s clinical data m anagement system (DMS) by the study si te representative. In instances where th e PRO data is entered into the DMS by GSKCH, the PROs will be anonymised, and fo rwarded to GSKCH for entry , as agreed and documented ah ead of the study starting. PROs that are source will be retained by the invest igator and certified copies will be sent to GSKCH.
In order to protect the privacy of subjects, no Personally Identifiable Inform at io n (PII) (i ncluding the subject's name or ini ti als or bi rth date) i s to be recorded on all PRO’s that will be forwarded to GSKCH.
In thi s study the DHEQ i s a PRO. The DHEQ will be completed by the subjects as described in sect io n 6.2.1. A member of the study si te staff will enter the data into th e CRF. 9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES 9.1 Sample S ize Determination
The sample size is based on DHEQ total Score, restrictions, adaptation, social impact, em oti onal impact and identit y, f rom a previ ous study [GSKCH Study RH01897] .
A sample size o f 60 subjects will have at least 90% power to detect significant changes to week 24 for each of the DHEQ variables, with a significance level (alpha) of 0.05 using a two -si ded one -sample t -test. No adjustments for mult iple testi ng have been used. Approximately 75 eligible subjects will be allocated t he study toothpaste in order to ensure th at approximately 60 subjects com plete the study . Si xt ysubjects will provide reasonable precisio n on estimates of DHEQ response and clinical DH assessments. 9. 2. General Considerations
9.2.1. Definition of Analy sis Populations The Safet y popul at io n will consist of all subjects who received th e study toothpaste .
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The int ent io n to treat (ITT) population will b e defined as all subjects who received th e study toothpaste and have at least one post -baseline DHEQ/clinic al assessment.
The per -protocol (PP) populat io n will be defined as all subjects who received th e study toothpaste and have at least one post -baseline DHEQ/clinical efficacy assessment and have no protocol vio lat io ns deemed to affect DHEQ/clinical efficacy assessments during the study . Further details will be provided in the statistical analysis plan (SAP).
Vi ol at io ns deemed to affect DHEQ/clinical efficacy assessments will be identified between the Biostatistician and Medical Director or designee pre analys is.
Analys is of the DHEQ and clinical efficacy m easures (Schiff, LMS) will be perform ed on th eITT populat io n. Analysis on the PP populat io n will also be perform ed if there i s m ore than 10% difference in the number of subjects betwe en th e ITT and PP popula ti ons.
9.2.2. Exclusion of Data from Analysis Any of the fo llo wing will be considered a protocol vio lat io n which ma ywarrant
exclusio n of data or the subject fro m efficacy analysis:
Vi ol at io n of inclusio n or exclusio n cri teri a that are deem ed to affect efficacy. Medical history which is deemed to affect efficacy . Use of prohibited treatment or medicat io n before or during the study , which is felt to affect the assessment of efficacy. Treatment non -com pliance Assessments outside the scheduled t ime windows Protocol deviat io ns captured in CRF. Any other reason ident ified likely to aff ect efficacy
Protocol vi ol at io ns which warrant exclusio n fro m efficacy an alysis will be ident ified between the statist ic ian and medical director or designee ahead of database lock .
9.2.3. Criteria for Evaluation DH EQ me asures capture d in the study will be used evaluate changes in oral healt h rel ated in qualit y of l ife over time. OST abnormalit ies, incidents and AEs reported in th e study will be used for safet y eval uati ons of the study treatm ents.
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9.2.4. Criteria for Assessing Efficacy
There are no formal success criteria in this study however i t i s expected that statist ically significant changes from baseline will be observed for the DHEQ measures, in particular the Total score.
9.2.5. Criteria for Assessing Tolerability Saf et y will be assessed with respect to A Es, Incidents and OST ab norm ali ti es (oral tol erabilit y) .
9.2.6 .Handling of Dropouts and Missing Data
No data will be imputed in the case of dropouts or missing data.
9.2.7 .Other Issues
An int erim analysis is not planned for this study .
9.3. Statistical Methods and Analytical Plan
More details of the proposed statist ical analysis will be documented in the statistical analysis plan (SAP) , whi ch w ill be written fo llo wing finalisation of the protocol and pri or to study unblinding.
Sel ected raw data will be listed as defined in the SAP .
9.3. 1. Demographic and Baseline Characteristics Descript ive statistics (number of subjects, mean, standard deviat io n, median, minimum and maximum for continuous variables, and frequency and percentage for categori cal variables) will be provided for demographic and baseline data.
9.3. 2. Prim ary Analysis
The fo llo wing DHEQ endpo int s will be analysed :
Secti on 1, questi ons 7, 8 and 9 as separate questions Total Score ( 34 item total from Sect io n 2 questions 1 to 34) Dom ains : 1. Restrictions (4 item total from Sect io n 2 questions 1 to 4) 2. Adaptation (12 item total fro m Secti on 2 questi ons 5 to 16) 3. Social Impact (5 item total fro m Secti on 2 que sti ons 17 to 21) 4. Em oti onal Im pact (8 i tem total f rom Secti on 2 questi ons 22 to 29) 5. Identity (5 item total fro m Secti on 2 questi ons 30 to 34) Gl obal Oral Heal th Rat ing (response to Section 2 question 35)
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Effect on Life Overall (4 i tem total f rom Sect io n 2 questions 36 to 39)
ABOVE DHEQ ENDPOINTS WILL BE ANALYSED USING MIXED EFFECT AN OVA WITH VISIT AND SITE AS FIXED EFFECT, SUB JECT AS
RANDOM EFFECT. ADJUS TED MEANS WILL BE CO MPUTED FOR EACH VISIT. USING THIS MODEL THE POST BAS ELI NE VISITS WILL BE COMPARED TO THE BASELINE VISIT AND D IFFERENCE OF THEIR EFFECT WILL BE COMPU TED ALONG WITH P -VALU ES AND 95% CONFIDENCE INTERVALS .
THE VISIT BY SITE IN TERACTION WILL BE IN VESTIGATED BY INCLUDE ING THE VISIT BY SITE IN TERACTION TERM.
IF THE V ISIT BY SITE INTERAC TION TERM IS NOT SIG NIFICANT AT THE 10% LEVEL OF SIGNIFICANC E THEN THIS TERM WILL BE REMOVED FROM THE MOD EL.
IF THE VISIT BY SITE INTERACTION TERM IS SIG NIFICANT AT 10% LEV EL OF SIGNIFICANCE T HEN THE INTER ACTION WILL BE INCLUDED IN THE MODEL AND ALL MODEL ESTIMA TES (ADJUSTED MEANS, 95% CI’S ANF P- VALUES) FOR WITHIN A ND BETWEEN VISITS WILL BE REP ORTED SEPARATELY FOR EACH SITE BASED ON THE RESULTS FROM VISIT BY SITE I NTERACTION.
Each of the DHEQ endpo int s will be summarised by t ime po int (B aseline , Week 4, 8, 12, 16, 20 and 24) together wi th changes fro m baseline .
Standard summary m easures together wi th the changes from baseline ,95% CIs and p - values of changes from baseline will be presented .A plot of m eans of raw scores over time (mea n standard errors) will also be presented for all measures. PRESENTATIONS OF ENDPOINT SUMMARIES WILL ALSO BE PERFORMED BY SITE .NO INFERENCES WITHIN SITE WILL BE PROVIDED.
P-values will be provided to test for non -zero changes from baseline in all measur es. Due to the exploratory n ature of the study n o correcti on of FOR mult ip le testing will be perform ed.
THE ASSUMPTION OF NO RMALITY AND HOMOGENE ITY OF VARIANCE IN THE ANCO VA MODEL WILL BE INV ESTIGATED. VIOLATION OF THESE A SSUMPTIONS MAY BE OV ERCOME USING SUITABLE TRANSFORMAT ION OR PERFORMING A NON- PARAMETRIC TEST (E.G ., THE WILCOXON SIGN ED -RANK TEST).
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9.3. 3. Exploratory An alys es
The fo llo wing exploratory analyses will be conducted.
At each time po int the m ean Schiff Sensit ivit y Score (for the two test teeth and all qualifying teeth) and mean LMS scores [each of 4 scales (descript io n, tol erabilit y,
descript io n, intensit y] as well as the change fro m baseline will be calculated.
THE MEAN SCHIFF SENSI TIVITY (TWO TEST TEETH), ME AN SCHIFF SENSITIVITY ( ALL QUALIFYING TEETH )AND MEAN LMS SCORE WILL BE ANALYSED USI NG THE SAME MODEL MENTI ONED AT PRIMARY ANALYSIS AND SIMILAR STATISTICS WILL BE P ROVIDED.
THE VISIT BY SITE INTERA CTION WILL ALSO BE INVESTIGATED AS PER THE PROCEDURE MENTIONED AT PRIMARY ANALYSIS.
Standard summary m easures together with the changes from baseline , 95% CIs and p - values of changes fro m baseline will b e presented . A plot of m eans of raw scores over time (m ean standard errors) will also be presented for all measures VARIABLES .
Due to the exploratory n ature of the study n o correcti on of FOR mult iple testing will be perform ed.
The percentage of teeth that are sensit ive (Schiff sensit ivit y score >0 of all qualifying teeth fro m screening (term ed 'the qualifying teeth' ) will be summarised for each timepo int and also plotted over time.
PRESENTATIONS OF ENDPOINT SUMMARIES WILL ALSO BE PERFORMED BY SITE. NO INFERENCES WITHIN SITE WILL BE PROVIDED.
THE ASSUMPTION OF NO RMALITY AND HOMOGENE ITY O F VARIANCE IN THE ANCO VA MODEL WILL BE INV ESTIGATED. VIOLATION OF THESE A SSUMPTIONS MAY BE OV ERCOME USING SUITABLE TRANSFORMAT ION OR PERFORMING A NON- PARAMETRIC TEST (E.G ., THE WILCOXON SIGN ED -RANK TEST).
9.3. 4. Safety Analys es AEs, incidents and OST abnormalit ies will be listed by treatm ent and reviewed.
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9.3. 5. Other Analys es
No f urther analys es are planned.
10 . STUDY GOVERNANCE CONSIDERATIONS 10 .1 .Po sting of Information on Publicly Available Clinical Trials Regist ers
Study i nform at io n fro m this protocol will be posted on publicly av ailable clinical trial regi sters before enro lment of subjec ts begins.
10.2. Regulatory and Ethical Considerations, Including the Informed Consent
The study will be conducted in accordance with all applicable regulatory requi rements, and wi th GSK policy.
The study will al so be conducted in accordance with ICH Good Clinical Pract ice
(GCP), all applicable subject privacy requirements, and the guiding principles of the current version of the Declarat io n of Helsinki. This includes, but is not limited to, the fo llo wing:
Before init iat ing a trial, the invest igator/institution should have written and dated approval/ fa vourable opini on f rom the IEC for the trial protocol (i ncluding amendments), written informed consent form, consent form updates, subject recruit me nt procedures (e.g., adverti sements), investigator brochure/ safety statement (including any updates) and any other written inform at io n to be provided to subjects. A letter or certificate of approval will be sent by the invest igator to the sponsor prior to init iat io n of the study , and also when subsequent amendments to the protocol are made. Si gned informed consent to be obtained for each subject before participation in the study (and f or am endments as applicable) Invest igator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviat io ns to IEC) GSK will provide full details o f th e above procedures, either verbally, in wri ting, or both.
10.3. Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK or desi gnee (i .e. thi rd party v endor) m oni tors will contact the si te pri or to the start of
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th e study to review wi th the si te staff the protocol , study requi rements, and thei r responsibilit ies to satisfy regulatory , ethi cal, and GSK requirements.
When reviewing data collect io n procedures, the discussion will include ide nt ification,
agreem ent and documentati on of data i tem s f or which the CRF will serve as the source document.
GSK or designee will mo nit or the study and si te activi ty to verify that the:
Data are authentic, accurate, and complete. Saf et y and ri ghts of subjec ts are being protected.
Study i s conducted in accordance with the current ly approved protocol and any other study agreements, GCP, and all applicable regulatory requi rements.
The extent and nature of monitoring will be described in a written monitoring pl an on file at GSKCH. The invest igator (or designee) agrees to allow the monitor direct access to all relevant documents and agrees to co- operate wi th the m oni tor to ensure th at any problems detected in the course of these mo nit oring visits are resolved.
10 .4. Quality Assurance
To ensure compliance wit h GCP and all applicable regulatory requi rements, GSK may conduct a qualit y assurance assessment and/or audit of the site records, and the regul atory agencies may conduct a regul atory i nspecti on at any ti me during or a ft er com plet io n of the study .
In the event of an assessment, audit or inspect io n, the invest igator (and inst it ut io n) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all rel evant docum ents and to allocate their time and the time o f th ei r staff to di scuss the conduct of the study , any findings/relevant i ssues and to implement any correcti ve and/or preventative act io ns to address any findings/issues ident ified.
The sponsor will be available to help investigators prepare for an inspection. 10.5. Conditions for Terminating the Study
Upon com plet io n or premature discont inuat io n of the study , the GSKCH m oni tor will conduct site closure activit ies with the invest igator or site staff, as appropriate, in accordance with app licable regulat io ns including GCP, and GSKCH Standard Operating Procedures.
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Both GSKCH and the Invest igator reserve the right to temporarily suspend or prem aturely discontinue this study at any ti me fo r reasons including, but not limited to, safet y or ethi cal issues or severe non -co mp liance. For mult icenter studies (if applicable), this can occur at one or more or at all sites.
If the tri al i s prematurely terminated or suspended for any reason, the invest igator site shoul d prom pt ly inform the trial subjec ts and should assure appropriate therapy / fo llo w- up for the subjects. Where required by the applicable regulatory requi rements, GSKCH should inform the regulatory authori ty (i es).
In addit io n:
If the invest igator terminates or suspends a trial without pr io r agreement of GSKCH, the investigator site should prompt ly info rm the sponsor and the IEC, and should provide the sponsor and the IEC a detailed written explanat io n of the terminat io n or suspensio n. If the GSKCH terminates or suspends a trial, the inves ti gator shoul d prom pt ly inform the IEC and provide the IEC a detailed written explanat io n of the termination or suspensio n.
If the IEC terminates or suspends its approval/favorable opinio n of a tri al , the investigator should prompt ly notify the GSKCH and provi de GSKCH wi th a detailed written explanat io n of the terminat io n or suspensio n.
10.6. Records Retention
Fo llo wing cl osure of the study , the invest igator must maintain all site study records (except for those required by local regulations to be maintained else where), in a safe and secure location.
The records (study / si te m aster file) must be maint ained to allow easy and timely retri eval , when needed (e.g., for a GSK audit or regulatory i nspect io n) and must be available for review in conjunct io n wi th assessme nt of the facilit y, supporting system s, and rel evant si te staff.
Where permitted by l ocal l aws/regul at io ns or institutional po licy, so me or all o f th ese records can be maintained in a format other than hard copy (e.g., microfiche, scanned, el ectroni c); how ever, caution needs to be exercised before such act io n is taken.
The invest igator must ensure that all reproductions are legible and are a true and accurate copy of the ori ginal an d m eet accessibilit y and retri eval standards, including re -generating a har d copy , if required. Furtherm ore, the invest igator must ensure
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th ere is an acceptable back -up of these reproductions and that an acceptable qualit y control process exists for making these reproductions.
The invest igator must assure that the subject’s anon ymit y will be m aintained. On
CRFs or other documents submitted to GSKCH, subjects should not be ident ified by th ei r names or init ials, but by an i dent ificat io n code. The invest igator should keep a separate log of subjects’ codes, names and addresses. Doc uments not for submissio n to GSKCH, e.g. subjects’ written consent forms, should be maintained by the investigator in strict confidence.
GSK will inform the invest igator of the time period for retaining these records to com ply wi th all applicable regul ator y requi rements (GSKCH recommends that docum ents be kept for 10 y ears). The invest igator is also required to keep subject ident ificat io n codes on file for at least 15 y ears aft er com pl et io n or di scont inuat io n of
th e study . The minimum retent io n time will me et the stri ctest standard applicable to th at si te f or the study , as di ctated by any i nst it uti onal requi rements or l ocal l aws or regul at io ns, GSK standards/procedures, and/or institut io nal requirements.
No study document should be destroy ed wi th out a pri or written agreement between
GSKCH and the invest igator. The invest igator must notify GSK of any changes in the archival arrangements, including, but not limited to, archival at an off -si te f acili ty or transfer of ownership of the records in the event the i nvest igator is no longer associ ated wi th the si te. 10.7. Provision of Study Results to Investigators, posting of Information on Publicly Available Clinical Trials Registers and Publication
Where required by applicable regul atory requi rements, an invest igator signatory will be ident ified fo r the approval of the clinical study report. The invest igator will be provi ded reasonable access to statist ical tables, figures, and relevant reports and will have the opportunit y to review the complete study resul ts at a GSK si te or other mutually -agreeable location.
GSK will also provide the invest igator with the full summary o f th e study resul ts. The invest igator is encouraged t o share the summary resul ts wi th the study subjects, as appropri ate.
The procedures and timing for public disclosure of the results summary and for development of a manuscript for publicat io n will be in accordance with GSK Policy.
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A manuscript will be prog ressed for publicat io n in th e sci ent ific literature if the resul ts provi de important sci ent ific or medical knowledge.
11 . REFERENCES
Addy M., Dent ine Hypersensit ivit y: definit io n, prevalence, dist ribut io n and aetio lo gy . In Tooth Wear and Sensitivity ; 2000; pp 239 –248.
Addy M., Mostafa P., Absi E., Adams D., Cervical dentin hypersensit ivit y. Eti ol ogy and management with particular reference to dentifrice. In Row e NH, ed. Proceedings of Symposium on Hypersensitive Dentin. Origin and Management. University of Michigan, Ann Arbor, MI, ; 1985; pp 146 –167. Baker S. R., Gibson B. J., Sufi F., Barlow A., Robinson P. G., The Dent ine Hy persensi ti vi ty Experi ence Quest io nnaire: A lo ngi tudinal v alidat io n study . J. Clin. Periodontol. 2014 , 41 , 52 –59. Bekes K., John M. T., Schaller H. G., Hirsch C., Oral health -related quali ty of life in pati ents seeking care for dentin hypersensit ivit y. J. Oral Rehabil. 2009 , 36 , 45 –51.
Boi ko O. V., Baker S. R., Gibson B. J., Locke r D., Sufi F., Barlow A. P. S., Robinson P. G., Construction and validat io n of the qualit y of life measure for dentine hypersensit ivit y (DHEQ). J. Clin. Periodontol. 2010 , 37 , 973 –980. Brannstrom M., Astrom A., A Study on the Mechanism of Pain Elicited Fro m th e Dent in. J. Dent. Res. 1964 , 43 , 619 –625. Canadian Advisory Board, Consensus -Based Recommendat io ns fo r the Di agnosis and Management. Joournal Can. Dent. Assoc. 2003 , 69 , 221 –226. Chaknis P., Panagakos F. ., DeVizio W., Sowinski J., Petrone D., Proskin H. , Silica as com pared to a denti f ri ce conta ining 0 . 454 % stannous fluoride , sodium hexametaphosphate and zinc lactate and to a dentifrice containing 0 . 243 % NaF on dent in hypersensit ivit y reduct io n : An 8 -week study . Am. J. Dent. 2011 , 24 , 14A – 20A. Docimo R., Montesani L., Maturo P., Costacurta M., Bartolino M., Zhang Y. P., DeVi zi o W ., Del gado E., Cummins D., Dibart S., et al., Comparing the efficacy in reducing dentin hypersensit ivit y of a new toothpaste containing 8.0% arginine, cal cium carbonat e, and 1450 ppm fluoride to a benchmark commercial desensit izing toothpaste containing 2% potassium io n: An eight -week clinical study . J. Clin. Dent. 2009 , 20 , 137 –143. Du M., Ji ang H., Tai B., He T., Chang J., Sun L., De -sensit izing effect of a stannous containing sodium fluoride novel dent ifr ice. J Dent Res 2011 , 90 , Poster Session. Gillam D., Orchardson R., Advances in the treatment of root dentine sensit ivit y: mechanisms and treatment principles. Endo Top. 2006 , 13 , 13 –33.
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Gracely R. H., McGrath P., Du bner R., Ratio scales of sensory and affect ive verbal pain descriptors. Pain 1978 , 5, 5 –18.
GSKCH Study RH01685, GSKCH Clinical Study Report, RH01685 .
GSKCH Study RH01897, GSKCH Clinical Study Report, RH01897.
GSKCH Study RH02026, GSKCH Clinical Study Repo rt, RH02026 . Hall R. ., Embery G., Shellis R. ., Biological and structural features of enamel and dent in: current concepts relevant to erosion and dent in hypersensit ivit y. In Tooth
Wear and Sensitivity ; Addy, M., Embery , G., Edgar, W. ., Orchardson, R., Ed s.; Martin Dunitz Ltd, London, 2000; pp 3 –19.
He T., Barker M. L., Qaqish J., Sharma N., Fast onset sensit ivit y relief of a 0.454% stannous fluoride dent ifr ice. J. Clin. Dent. 2011 , 22 , 46 –50.
Heaton L., Barlow A., Coldwell S., Development of labeled magni tude scales for the assessment of pain of dentin hypersensit ivit y. J. Orofac. Pain 2013 , 27 , 72 –87. Jokovic a, Locker D., Stephens M., Kenny D., Tompson B., Guy att G., Validit y and reliabilit y of a quest io nnaire for measuring child oral -healt h- rel ated qual it y of l ife. J. Dent. Res. 2002 , 81 , 459 –463. Laster L., Laudenbach K. W., Stoller N. H., An evaluat io n of clinical tooth mobilit y measurements. J. Periodontol. 1975 , 46 , 603 —607. Lobene R. R., Weatherford T., Ross N. M., Lamm R. A., Menaker L., A modified gingival index for use in clinical trials. Clin. Prev. Dent. 1986 , 8, 3 –6. Ni L., He T., Chang J., Cheng R., Sun L., De -sensitizing effect of a Stannous containing sodium fluoride toothpaste. J Dent Res 2011 , 90 . Orchardson R., Changes in extracellular fl uid composi ti on which exci te axons. J. Physiol. 1975 , 245 , 14P —16P. Orchardson R., Collins W. J. ., Clinical features of hypersensit ive teeth. Br. Dent. J. 1987 , 162 , 253 –256. Parkinson C., Hughes N., Jeffery P., Jain R., Kennedy L., Qaqi sh J., Gallo b J. T ., S M., The efficacy of an experimental dent ifr ice containing 0.454% w/w stannous fluori de in providing relief fropm the pain of dent in hypersensit ivit y: An 8 -week clinical study . Am. J. Dent. 2013 , 26 , 25A –31A. Pradeep a R., Sharma A., Comparison of cl inical efficacy of a dent ifr ice containing cal cium sodi um phosphosilicate to a dentifrice containing potassium nitrate and to a pl acebo on dentinal hypersensit ivit y: a rando mized clinical trial. J. Periodontol. 2010 , 81 , 1167 –1173.
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Schiff T., Dotson M., Co hen S., Efficacy of a dentifrice containing potassium nitrate, sol uble pyrophosphate, PVM/MA copolymer, and sodium fluoride on dent inal hypersensit ivit y: a twelve -week study . J. Clin. Dent. 1994 , 5, 87 –92.
Schiff T., Zhang Y., DeVizio W., Stewart B., Chakn is P., Petrone M., Volpe A., Proskin H., A randomized clinical trial of the desensit izing efficacy of three dent ifr ices. Compend. Contin. Educ. Dent. 2000a , 27 , 4 –10.
Schiff T., Bonta Y., Proskin H., DeVizio W., Petrone M., Volpe A., Desensit izing efficacy of a new dent ifr ice containing 5.0% potassium nitrate and 0.454% stannous fluori de. Am. J. Dent. 2000b , 13 , 111– 115.
Schiff T., He T., Sagel L., Baker R., Efficacy and safet y of a novel stabilized stannous flouride and sodium hexametaphosphate dent ifr ice fo r dental hypersensit ivit y. J. Contemp. Dent. Pract. 2006a , 7, 1 –10.
Schiff T., He T., Sagel L., Baker R., Efficacy and Safet y of a Novel Stabilized Stannous Fluoride and Sodium Hexametaphosphate. J. Contemp Dent. Pract. Pract. 2006b , 7, 1 –10. Sharma N., Ro y S., Kakar A., Greenspan D. C., Scott R., A clinical study com paring oral f orm ulat io ns containing 7.5% calcium sodium phosphosilicate (novamin??), 5% potassi um ni trate, and 0.4% stannous fluoride for the management of dent in hypersensit ivit y. J. Clin. D ent. 2010 , 21 , 88 –92. Sharma N., Roy S., Kakar A., Greenspan D., Scott R., Instant Sensit ivit y Relief o f a Stannous containing Sodium Fluoride Dentifrice. J. Dent. Res. 2011 , 90 , Oral Presentation. Sharma S., Shetty N. J., Uppoor A., Evaluat io n of the clin ical efficacy of potassi um nit rate desensit izing mouthwash and a toothpaste in the treatment of dentinal hypersensit ivit y. J. Clin. Exp. Dent. 2012 , 4, 28 –33. Sl ade G., Spencer A., Development and evaluat io n of the Oral Healt h Im pact Profile. Community Den t Heal. 1994 , 11(1) , 3–11. Sl ade G. D., Derivat io n and validat io n of a short -form oral heal th impact profile. Community Dent. Oral Epidemiol. 1997 , 25 , 284 –290. Dentine Hypersensitivity: Developing a Person -Centred Approach to Oral Health ; Robinson, P. G., Ed.; Elsevier Inc.: London, 2015.
12 . APPENDICES 12 .1. Appendix 1 -Abbreviations
Abbreviations
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AE Ad verse Event CD Com pact Di sc CRF Case Report Form DH Dent ine Hypersensit ivit y DHEQ Dent ine Hypersensit ivit y Experience Quest io nnaire
EAR Erosi on, Abrasio n, Recession EDC Electronic Da ta Capture GCP Good Clinical Pract ice GSKCH Gl axoSmi th Kline Consumer Healthcare ICH International Conference on Harmonizat io n of Technical Requirements fo r Registrati on of Pharmaceut icals fo r Hum an Use IEC Independent Ethics Committee ITT Intention to Treat OHT Oral Hard Tissue OST Oral Sof t Ti ssue PII Personally Ident ifiable Informat io n LMS Labelled Magnitude Scales PP Per Protocol ppm Parts per millio n PRO Pati ent Reported Outcome SAE Seri ous Adverse Event
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12.2 . Appendix 2– DHEQ
Example
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12.3. Appendix 3 –Instructions for LMS Training Exercise
Subjects will be given instructions for using the LMS and asked to complete the LMS training exercise form. The investigator or designee should read the instructions al oud while the subject reads along. Subjects will be permitted to ask questions. However, most questions should be answered by rereading the ap propri ate secti on of th e instructi ons. The invest igator, or designee, will then determine whether the subject understands how to use the LMS based on the line scale training exercise answers and the criteria below. Interpretation of the Line Scale Trainin g Exercise
The obj ect ive o f thi s exercise i s NOT to determine whether the subject can get the exact answers, but to determine whether they understand the concept. Therefore, the fo llo wing general criteria are suggested: Are markings only on the verbal des cri ptors? If so, provi de f eedback that they
are to use the ent ir e scale, including areas between the descriptors. Are subjects marking on the same place on all the scales for one stimulus (parti cularly if the LMS measures are all presented on one page?) If so, make sure subjects understand what each scale is meant to measure (intensit y, durati on, abilit y to tol erate, and descript io n) and that stimuli will likely
produce different marks on each scale. The stimuli are presented generally in increasing int ensi ty . Are subjects indicat ing an increasing intensit y across stimuli? Are subjects marking their ratings wit h an “X” on the scale? If not (subjects are ci rcling descri ptors, m aking unclear m arks, etc.), provide feedback on the use of the correct mark. If subjects appear unable to complete each o f th e LMS scales (intensit y, durati on, tol erabilit y and descript io n) wi th the appropri ate response (s), the invest igator/ designee should talk them through the grading o f the first two LMS scenarios, if requi red. If the marks are generally correctly ordered, but far from their true posi ti ons, the investigator/ designee should try to get the subject to verbalize why th ey placed the m arks as they did. However, the investigator/ designee should be careful not to pr essure the subject to change their responses. One approach would be fo r the investigator/ designee to start with an item that the subject did well, ask about th at and then cont inue by asking about an item where they did less well. If subjects are not able to provi de proper responses to the stimuli quest io ns across all fo ur figure scales, it is unlikely they will provide appropri ate responses on the clinical response LMS scales. These subjects should be disqualified.
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Subject Instructions for LMS Training Exercise (Example)
“T he purpose of t his exercise is to int roduce yo u to th e scales yo u will be using. There are no right or wrong answers.
Pl ease read each item carefully. Then try to rem ember or imagine what each sensat io n feels like. I f yo u haven’t had exactly th e experi ence described, try t o think of something similar.
The scales yo u will be using each have words th at can be used to describe different feelings or sensat io ns peopl e have in th ei r mouths. A s yo u think about each sensat io n, yo u shoul d t hink about th e word th at best describes what th at sensat io n feels like. T hen, if appropri ate, yo u can “fine tune” yo ur rating by marking th e line between th at word and the next word up or down the scale.
FOR EACH ITEM PLEASE INDICATE HOW YOU WOULD RATE THE FEELING DESCRIBED BY PLACING AN ”X” ON THE LINE. Y OU MAY MARK ANYWHERE ALONG THE LINE.
Please turn to the next page for the first example in this exercise.
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Let’s start with this example.
The touch of a pill on your tongue.
Have you ever experienced this feeling or sensat io n before?
(Please circle one): Yes / No
Fi rst pl ease rate the INTENSITY of thi s feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark any where on the line, including between the descript ive words.
NO PAINDIM DULL SHARPSTABBING
NOT TO SCALE
Please turn to the next page.
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Still thinking about the touch of a pill on your tongue, please rate the DURATION of thi s feeling or sensation.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NO PAIN TEMPORARYQUICK LINGERING CHRONIC
NOT TO SCALE
Please turn to the next page.
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Still thinking about the touch of a pill on y our tongue, please rate how much yo u are able to TOLERATE wi th this feeling or sensation.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descri pt ive words.
NO PAIN TOLERABLEUNCOMFORTABLEUNNERVING UNBEARABLE
NOT TO SCALE
Please turn to the next page.
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Finally , thinking about th ethe touch of a pill on your tongue , pl ease give a rating th at DESCRIBES th e kind of feeling or sensat io n thi s is.
Mark the scale below with an “X” t o indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
ACHE NO PAIN TWINGE THROBBINGSHOOTING
NOT TO SCALE
Please turn to the next page.
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Let’s try thi s example.
The pain from biting your to ngue.
Have you ever experienced this feeling or sensat io n before?
(Please circle one): Yes / No
Fi rst pl ease rate the INTENSITY of thi s feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sens at io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NO PAINDIM DULL SHARPSTABBING
NOT TO SCALE
Please turn to the next page.
Still thinking about the pain from biting your tongue , please rate the DURATION of thi s feeling or sen sati on.
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Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the
descript ive words.
NO PAIN TEMPORARYQUICK LINGERING CHRONIC
NOT TO SCALE
Please turn to the next page.
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Stil l thinking about the pain from biting your tongue , please rate how much yo u are able to TOLERATE wi th this feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhe re on the line, including between the descript ive words.
NO PAIN TOLERABLEUNCOMFORTABLEUNNERVING UNBEARABLE
NOT TO SCALE
Please turn to the next page.
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Finally , thinking about th ethe pain from biting your tongue , pl ease give a rating th at DESCRIBES th e kind of feeling or sensat io n thi s is.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
ACHE NO PAIN TWINGE THROBBINGSHOOTING
NOT TO SCALE
Please turn to the next page.
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Le t’s try one l ast example.
The pain of a persistent toothache.
Have you ever experienced this feeling or sensat io nbef ore?
(Please circle one): Yes / No
Fi rst pl ease rate the INTENSITY of thi s feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NO PAINDIM DULL SHARPSTABBING
NOT TO SCALE
Please turn to the next page.
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Still thinking about the pain of a persistent toothache, please rate the DURATION of thi s feeling or sensation.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NO PAIN TEMPORARYQUICK LINGERING CHRONIC
NOT TO SCALE
Please turn to the next page.
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Still thinking about the pain of a persistent toothache, please rate how much yo u are able to TOLERATE wi th this feeling or sensation.
Mark the scale below with an “X” to indicate the best descr ipt io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NO PAIN TOLERABLEUNCOMFORTABLEUNNERVING UNBEARABLE
NOT TO SCALE
Please turn to the next page.
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Finally , thinking about the pain of a persistent toothache , please give a rating that DESCRIBES th e kind of feeling or sensation this is.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive w ords.
ACHE NO PAIN TWINGE THROBBINGSHOOTING
NOT TO SCALE
You have finished the practice exercise, and you are now ready to take part in the main part of the study.
If you have any questions about this exercise, please let a member of the study staff know.
If you feel that you understand how to use these scales, please see a member of the study staff, who will start you on the main part of the study.
Thank you for your time!
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12.3. APPENDIX 3 -SUBJECT INSTRUCTIONS FOR LMS TRAINING EXERCISE
Subjects will be given instr uctions for using the LMS and asked to complete the LMS training exercise form. The investigator or designee should read the instructions al oud while the subject reads along. Subjects will be permitted to ask questions. However, most questions should be answered by rereading the appropriate section of th e instructi ons. The invest igator, or designee, will then determine whether the subject understands how to use the LMS based on the line scale training exercise answers and the criteria below.
Interpretat ion of the Line Scale Training Exercise
The obj ect ive o f thi s exercise i s NOT to determine whether the subject can get the exact answers, but to determine whether they understand the concept. Therefore, the fo llo wing general criteria are suggested: Are ma rkings only on the verbal descri ptors? If so, provi de f eedback that they are to use the ent ir e scale, including areas between the descriptors.
Are subjects marking on the same place on all the scales for one stimulus (parti cularly if the LMS measures are all presented on one page?) If so, make sure subjects understand what each scale is meant to measure (intensit y, durati on, abilit y to tol erate, and descript io n) and that stimuli will likely produce different marks on each scale. The stimuli are presente d generally in increasing intensit y. Are subjects indicat ing an increasing intensit y across stimuli? Are subjects marking their ratings wit h an “X” on the scale? If not (subjects are ci rcling descri ptors, m aking unclear m arks, etc.), provide feedback on th e use of the correct mark. If subjects appear unable to complete each o f th e LMS scales (intensit y, durati on, tol erabilit y and descript io n) wi th the appropri ate response (s), the invest igator/ designee should talk them through the grading o f the first tw o LMS scenarios, if requi red. If the marks are generally correctly ordered, but far from their true posi ti ons, the investigator/ designee should try to get the subject to verbalize why th ey placed the m arks as they did. However, the investigator/ designe e shoul d be careful not to pressure the subject to change their responses. One approach would be fo r the investigator/ designee to start with an item that the subject did well, ask about th at and then cont inue by asking about an item where they did less w ell. If subjects are not able to provide proper responses to the stimuli quest io ns across all fo ur figure scales, it is unlikely they will provide appropri ate responses on the clinical response LMS scales. These subjects should be disqualified.
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Subject Instructions for LMS Training Exercise (Example) The purpose of this exercise is to introduce y ou to the scales y ou will be using. There
are no ri ght or wrong answers.
Pl ease read each item carefully. Then try to rem ember or imagine what each sensat io n fe els like. I f yo u haven’t had exactly th e experi ence described, try t o think of something similar.
The scales yo u will be using each have words th at can be used to describe different feelings or sensat io ns peopl e have in th ei r mouths. A s yo u think about each sensat io n, yo u shoul d think about th e word th at best describes what th at sensat io n feels like. T hen, if appropri ate, yo u can “fine tune” yo ur rating by marking th e line between th at word and the next word up or down the scale.
FOR EACH ITEM PLEASE IND ICATE HOW YOU WOULD RATE THE FEELING DESCRIBED BY PLACING AN ”X” ON THE LINE. Y OU MAY MARK ANYWHERE ALONG THE LINE.
Please turn to the next page for the first example in this exercise.
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Let’s start with this example.
The touch of a pill on your tongue.
Have you ever experienced this feeling or sensat io n before? (Please circle one): Yes / No
Fi rst pl ease rate the INTENSITY of thi s feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
Please turn to the next page.
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Still thinking about the touch of a pill on your tongue, please rate the DURATION of thi s feeling or sensatio n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
Please turn to the next page.
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Still thinking ab out the touch of a pill on your tongue, please rate how much yo u are able to TOLERATE thi s feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, i ncl uding between the descript ive words.
NOT TO SCALE
Please turn to the next page.
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Finally , thinking about the touch of a pill on your tongue , pl ease give a rating that DESCRIBES th e kind of feeling or sensation this is.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
Please turn to the next page
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Let’s try thi s example.
The pain from biting your tongue.
Have you ever experienced this feeling or sensat io n before? (Please circle one): Yes / No
Fi rst pl ease rate the INTENSITY of thi s feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
Please turn to the next page.
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Still thinking about the pain from biting your tongue , please rate the DURATION of thi s feeling or sensation.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
Please turn to the next page.
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Still thinking abo ut the pain from biting your tongue , please rate how much yo u are able to TOLERATE this feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or
sensat io n. Rem ember, y ou can m ark anywhere on the line, incl uding between the descript ive words.
NOT TO SCALE
Please turn to the next page.
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Finally , thinking about the pain from biting your tongue , please give a rating that DESCRIBES th e kind of feeling or sensation this is.
Mark the scale below with an “ X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
Please turn to the next page.
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Let’s try one l ast example.
The pain from persiste nt toothache .
Have you ever experienced this feeling or sensat io n before? (Please circle one): Yes / No
Fi rst pl ease rate the INTENSITY of thi s feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
Please turn to the next page.
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Still thinking about the pain of a persistent toothache, please rate the DURATION of thi s feeling or sensati on.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
Please turn to the next page.
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Still thinking about the pain of a persistent toothache, please rate how much yo u are able to TOLERATE thi s feeling or sensat io n.
Mark the scale below with an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
Please turn to the next page
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Finally , thinking about the pain of a persistent toothache , pl ease give a rating that DESCRIBES th e kind of feeling or sensation this is.
Mark the scale below wit h an “X” to indicate the best descript io n of that feeling or sensat io n. Rem ember, y ou can m ark anywhere on the line, including between the descript ive words.
NOT TO SCALE
You have finished the practice exercise, and you are now ready to take part in the main part of the study.
If you have any questions about this exercise, please let a member of the study staff know.
If you feel that you understand how to use these scales, please see a member of the study staff, who will start you on the main par t of the study.
Thank you for your time!
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12.4. APPENDIX 4 -LMS SUBJECT ASSESSMENT FORM (EXAMPLE)
Screening No. S______Protocol: 204930
Tooth No: Labelled Magnitude Scales Visit No: ____ Date : __ __/ __ __/ __ __
Pl ease rate the INTENSITY/DURATION/TOLERABILITY/DESCRIPTION of this feeling or sensation. Mark the scales below with an “X” to indicate the best description of that feeling or sensation. Remember , you can mark anywhere on the line, including between the descriptive words.
INTENSITY DURA TION TOLERABILITY DESCRIPTION
CHRONIC UNBEARABLE SHOOTING
STABBING THROBBING
SHARP LINGERING UNNERVING QUICK ACHE
DULL UNCOMFORTABLE TEMPORARY TWINGE TOLERABLE DIM
NO PAIN NO PAIN NO PAIN NO PAIN
Score: mm mm mm mm
Final v1.0 16 Oct 15 Scorer initials (site staff):
NOT TO SCALE
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SIGNATURE PAGE
Clinical Protocol 204930
Date Signed By
08-Sep-2016 17:03:11 PPD Justification Approved
Date Signed By 09-Sep-2016 05:32:57 PPD Justification Biostatistics Approval
Date Signed By 09-Sep-2016 15:29:05 PPD Justification Approved
Date Signed By 12-Sep-2016 05:12:42 PPD Justification Clinical Operations Approval
Date Signed By
Justification
Date Signed By
Justification
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