Nonpharmacologic Reduction of Periprocedural Pain, Anxiety,and Prescription Drug UseStudy Chairman or Principal Investigator:Elvira V. Lang, MD, FSIR, FSCEH. CEO of the applicant organization Hypnalgesics,LLC d/b/a Comfort Talk Supported by:The National Center for Complementary and Integrative Health1 R43 AT009517-01Study Intervention Provided by:n/aSponsor of IND (IDE):n/aStudy Product Guidelines and Considerations1 of 44Version 1.029 MAR 2012

Tool Revision HistoryVersion Number 3:version Date: 10/26/2017Summary of Revision Made:Added a /-2min window for collection of the q10 min data on the dental chair to avoidprotocol violation in case the dental procedure results in expected or realized delay ofsamplingVersion Number: 2Version Date: 9/8/2017Summary of Revisions Made:More detail and validation provided for scales usedApproach to intermittent missing data insertedVersion Number: 1Version Date: 8/31/2017Summary of Revisions Made:TABLE OF CONTENTSPageNonpharmacologic reduction of periprocedural pain, anxiety, and prescription drug use. 1Tool Revision History . 2TABLE OF CONTENTS . 2STUDY TEAM ROSTER. 5PARTICIPATING STUDY SITES . 5PRÉCIS . 51. STUDY OBJECTIVES. 81.1Primary Objective . 81.2Secondary Objectives. 82. BACKGROUND AND RATIONALE . 92.1Background on Condition, Disease, or Other Primary Study Focus . 92.2Study Rationale . 103. STUDY DESIGN. 15Protocol Template, Version 1.02 of 44

4. SELECTION AND ENROLLMENT OF PARTICIPANTS . 164.1Inclusion Criteria . 164.2Exclusion Criteria . 174.3Study Enrollment Procedures . 175. STUDY INTERVENTIONS . 195.1Interventions, Administration, and Duration . 195.2Handling of Study Interventions . 195.3 Concomitant Interventions . 195.3.1 Allowed Interventions . 195.3.2 Required Interventions . 195.3.3 Prohibited Interventions . 205.4Adherence Assessment . 206. STUDY PROCEDURES . 206.1Schedule of Evaluations . 216.2 Description of Evaluations . 226.2.1 Screening Evaluation . 226.2.2 Enrollment, Baseline, and/or Randomization . 236.2.3 Blinding. 246.2.4 Followup Visits . 256.2.5 Completion/Final Evaluation . 257. SAFETY ASSESSMENTS . 267.1Specification of Safety Parameters . 267.2Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters . 267.3 Adverse Events and Serious Adverse Events . 27Adverse Event (AE) . 27Unanticipated Problems (UP) . 27Serious Adverse Event (SAE). 287.4Reporting Procedures . 287.5Followup for Adverse Events . 287.6Safety Monitoring . 288. INTERVENTION DISCONTINUATION . 289. STATISTICAL CONSIDERATIONS . 299.1General Design Issues . 299.2 Sample Size and Randomization . 30Treatment Assignment Procedures . 31Protocol Template, Version 1.03 of 44

9.3Definition of Populations . 329.4Interim Analyses and Stopping Rules . 329.5 Outcomes . 329.5.1 Primary Outcome . 339.5.2 Secondary Outcomes . 339.6Data Analyses . 3410. DATA COLLECTION AND QUALITY ASSURANCE . 3610.1Data Collection Forms . 3610.2Data Management . 3610.3 Quality Assurance . 3610.3.1 Training . 3610.3.2 Quality Control Committee. 3710.3.3 Metrics . 3710.3.4 Protocol Deviations . 3710.3.5 Monitoring . 3811. PARTICIPANT RIGHTS AND CONFIDENTIALITY . 3911.1Institutional Review Board (IRB) Review . 3911.2Informed Consent Forms . 3911.3Participant Confidentiality . 3911.4Study Discontinuation . 4012. COMMITTEES. 4013. PUBLICATION OF RESEARCH FINDINGS . 4014. REFERENCES . 4015. SUPPLEMENTS/APPENDICES . 44I. Procedures ScheduleII. Informed Consent Form TemplateIII. Other (add as many appendices as necessary)Protocol Template, Version 1.04 of 44

STUDY TEAM ROSTERThis is a clinical trial under the auspices of an SBIR grant to the applicantorganization Hypnalgesics, LLC with the Principal investigator, Elvira V. Lang, MDand is conducted at the Tufts School of Dental Medicine in Boston with the sitePrincipal Investigator Roald J. Kulich, PhD ([email protected]).Dr. Lang can be reached at 157 Ivy Street, Brookline, MA 02446, Tel: (978) 4049724 and FAX 617 734 9087, [email protected] Kulich can be reached at Tufts University School of Dental Medicine, OneKneeland Street, Boston, MA 02111. Tel: (617) 636-2147, Fax: (617) 636-3511.PARTICIPATING STUDY SITESThis is a single center study. The study site is Tufts University School of DentalMedicine, One Kneeland Street, Boston, MA 02111. Tel: (617) 636-2147, Fax: (617)636-3511. The principal investigator at the site and site address is Ronald Kulich,PhD ([email protected]).PRÉCISStudy TitleNonpharmacologic reduction of periprocedural pain, anxiety, and prescription druguseObjectivesObjectives of this Phase I pilot trial are to provide data towards assessing andfacilitating feasibility of a larger scale Phase II trial in which the effects of acalmative Comfort Talk app can be unequivocally evaluated.Towards this goal we will pursue following outcome parameters forPhase I: Feasibility/acceptability assessment:Primary outcome parameter:ability to obtain complete on-site data sets from at least 90% of patientsenrolled (with at least 40% from patients in the app group and at least 40%from patients in the control group).Secondary outcome parameters: ability to enroll 60 patients by day 150 after initiation of recruitment in theclinic ( day 1) Obtain 38 packages of filled out diary cards (at least 16 from patients in theapp group and at least 16 from patients in the control group)Protocol Template, Version 1.05 of 44

90% of patients in app group listen to app 5 minPhase II preparationprimary outcome parameter anxiety at the end of the waiting room timeSecondary outcome parameters pain the end of the waiting room time anxiety during treatment pain during treatment anxiety during 1 week after treatment pain during 1 week after treatment use of units of sedatives and analgesics during 1 week after treatment patient satisfactionDesign and OutcomesThe design is a single-blind, placebo controlled clinical trial to test the feasibility ofthe trial design assessing the ability of a Comfort Talk app to nonpharmacologicallyreduce anxiety, pain, and periprocedural drug use in individuals 18 years of age andolder undergoing outpatient treatment in the Craniofacial Pain Center of the TuftsSchool of Dental Medicine.The trial is a single-site pilot trial to assist in sample size estimation in a pivotal trialto test the hypothesis that listening to a Comfort Talk app with calmative contentreduces pain, anxiety, and post-procedural medication use.Eligible patients at the Craniofacial Pain Center at the Tufts School of DentalMedicine (TUSDM) will be randomized to listen to a tablet containing a calmativeComfort Talk app or app with white noise on an intent-to-treat basis. Their anxietyand pain measures will be recorded on validated 0-10 scales and before listening, atthe end of the waiting room period, and every 10 minutes ( /- 2 minutes) while on thedental chair.All patients will be given a packet with diary cards to record their levels of anxiety,pain, and drug use daily for 7 days after their visit and asked to send those back.Subjects will be mailed a 25 check upon returning their diaries.Patients randomized to the Comfort Talk app will receive a download coupon forthe app before leaving TUSDM, those randomized to the control condition (whitenoise) will receive a download coupon after they send in their diary cards.Interventions and DurationApproximately 1 hour and 15 minutes (Up to 30 minutes more than the scheduledstandard of care visit, which will typically last up to 45 minutes):Protocol Template, Version 1.06 of 44

Patient will be asked to come in ½ hour early before an already scheduledappointment. They will be taken to a private area, report their demographics, and ifeligible consented and fill out a NIDA Quick Screen.The participant will then be verbally asked to indicate his/her pain and anxiety levelson validated 0-10 scales. The research assistant will then hand the participant a tabletcontaining, depending on the group attribution, either the app (App Group) or whitenoise (Control Group) and will be shown how to operate the tablet.Participant will then return to the clinic waiting area with the tablet and wait for theirregularly scheduled appointment. The patient will be at liberty to when and for howlong to listen. At the end of the waiting room period the participant will be queriedagain for their levels of pain and anxiety.After the participant enters the treatment room, he or she will be able to continue tolisten to the app or white noise on the tablet. The research assistant will ask theparticipant every 10 min ( /- 2 minutes) to indicate their pain and anxiety levels. Theresearch assistant will note the duration of chair time, the amount of lidocaine given,if any or which other medications were given during the appointment, and whetherthe dental practitioner prescribed opioid, prescription or non-prescription drugs at theend of the visit.Before leaving home, the participant will be asked to fill out a satisfaction surveybased on a modified Press Ganey Template. The participant will then receive a diarycard on which to note pain, average and maximal pain as well its location, use of nonprescription, prescription, and opiate drugs, use of the app, and be provided prestamped envelopes. Patients will be asked to complete the diary daily before bedtimefor 7 days.Sample Size and PopulationThe pilot will be conducted in the Craniofacial Pain Center of TUSDM. Patientsincluded in the trial will be those who come for the procedures offered in theCraniofacial Pain Center such as fitting and adjusting dental bite appliances, fittingand adjusting oral appliances for management of sleep apnea, trigger point therapy,botulinum toxin therapy, and various craniofacial and cervical nerve blocks for painmanagement. Procedures last on the average 45 min.Subjects will be randomized to one of four tablets using a randomization plangenerated by SAS version 9.4 PROC PLAN. Given that four tablets will be availableat one time, four subjects will be randomized per block. Given a total sample size of72, subjects will be randomized to 18 blocks.Protocol Template, Version 1.07 of 44

1. STUDY OBJECTIVES1.1Primary ObjectiveThe primary objective concerns feasibility/acceptability of the trial design. This will beassessed by the ability to obtain complete on-site data sets from at least 90% ofpatients enrolled (with at least 40% from patients in the app group and at least 40%from patients in the control group).1.2Secondary ObjectivesSecondary objectives further assess overall feasibility of the trial design and aim toobtain sufficient data to assess the ability to calculate reliable sample sizerequirements for Phase II.Feasibility parameters: ability to enroll 60 patients by day 150 after initiation of recruitment in the clinic( day 1) Obtain 38 packages of filled out diary cards. (at least 16 from patients in the appgroup and at least 16 from patients in the control group)90% of patients in app group listen to app 5 minSince a significant reduction in anxiety in the waiting room is the main ingredient thatunderlies all other hypothesized effects for Phase II outcomes, even in the face ofproven technical feasibility of trial execution, it was also taken into consideration forsample size calculations.We hypothesize that use of the active Comfort Talk app results in a reduction inanxiety by 35% at the end of the waiting room time. This degree of reduction inanxiety is clinically significant based on prior work in a clinical trial thatdemonstrated that a 35% difference in anxiety at the onset of an invasive medicalprocedure is associated with significant differences in the subsequent experience ofpain and anxiety during the procedure, need for opioid analgesics and sedatives, andthe overall length of the procedure (1). These factors directly affect procedure safetyand throughput (e.g. economical efficiency).Secondary clinical outcome parameters will be: anxiety at the end of the waiting room time pain the end of the waiting room time anxiety during treatment pain during treatment anxiety during 1 week after treatment pain during 1 week after treatment use of units of sedatives and analgesics during 1 week after treatment patient satisfactionProtocol Template, Version 1.08 of 44

2. BACKGROUND AND RATIONALE2.1Background on Condition, Disease, or Other Primary Study FocusIn the US, 100 Million surgical and 300 Million dental procedures are performed annually(2-4). An estimated 20 to 30% of patients fear these procedures, and 8.75% severely so (5,6). Thus a considerable faction of the population is affected. Some patients don’t keep theirappointments, delaying treatment (5, 7-11). Others who present for their procedures aredistressed in the waiting room (see also 2.2).Healthcare professionals mainly rely on opioids and sedatives for management (12, 13).However, even under medical supervision during procedures and with dosages usually welltolerated, these drugs can cause cardiovascular and respiratory compromise and death (14).Of concern is the increasing practice of IV sedation in dental offices, which typically lackresuscitative experience (11). Drugs prescribed to manage pain after discharge feed into theopioid epidemic. Every day 80 people die from overdoses, half of them caused byprescription drugs (15).The majority of surgeries are now performed in outpatient settings (16). At discharge,typically neither doctors –nor their patients– know what the patients’ analgesia needs will beduring recovery. Ample amounts of opioids are then prescribed as a time-saving solution.Particularly patients who didn’t learn how to deal with potentially painful sensations duringgeneral anesthesia then can suddenly find themselves at home unprepared to cope. In onestudy, such patients used 8x the amount of morphine equivalents (23.9 vs 3 mg) theircounterparts took who were awake and had to cope during their surgery (17). Comfort duringand after conscious surgery, however, requires well-developed coping skills (17-20), orexternal guidance therein. Our prior large-scale clinical trials showed that guiding patients inself-hypnotic relaxation at the onset of invasive medical procedures can provide such copingskills. The results were sustained reductions in pain and anxiety; drug use, complications,procedure time, and cost decreased while satisfaction increased (21-24). The benefits of suchlive-guided interventions have also been shown by other researchers (25-42). Trainedpersonnel to provide such services, however, are not widely available. Empowering patientsdirectly with a validated app that they can adjust to their needs in the moment is a desirablealternative.The long-term goal is to provide a validated practical means of non-pharmacologic reductionof pain, anxiety, and need for post-procedure prescription drugs achieved through a ComfortTalk app for the patients undergoing these procedures. Our large-scale clinical trialsshowed that short Comfort Talk scripts spoken live by trained personnel at the beginning ofinvasive procedures change the mode of distress processing with a sustained reduction inpain and anxiety (21, 22, 24). Also drug use, complications, and procedure time significantlydecreased while patient satisfaction and operational efficiency increased. Comfort Talkverbiage used live by MRI personnel resulted in significantly more patients keeping theirappointments and completing their examinations (7). An app that could provide similarbenefits is highly desirable. While the Comfort Talk app approach will be applicable toprocedures in general, dentistry is chosen as the test environment. Dentistry is not only aProtocol Template, Version 1.09 of 44

common source of anxiety and pain but also ranks as the second largest prescriber group ofaddictive drugs.2.2Study RationaleScientific PremiseThe app is designed for use by individuals awaiting medical/dental procedures. Afterchoosing the options on the Comfort Talk app, the patient listens to the recording viaearphones. Specifically the study will be performed in the dentistry waiting room.The text content of the Comfort Talk app is based on clinically-tested scripts which werevalidated in three large-scale, federally-funded, clinical trials with 678 patients inrandomized sequence and published in peer-reviewed journals (21, 22, 24). Use of thesescripts with patients at the time they presented for medical procedures was associated withsignificant reductions in pain, anxiety, need for narcotics and sedatives, and adverse effects.Live use of the script language and word snippets developed in clinical practice by medicalpersonnel was further tested with patients presenting for MRI scans in a multicenter trialencompassing a total of 97,000 patients. Having personnel trained in using live ComfortTalk scripts and word snippets was associated with a significant reduction in non-completionof scans due to claustrophobia and disruptive patient motion compared to baseline caseswithout training and use (7). In a further randomized trial assessing the effect of trainingpersonnel in delivery of script elements, trained sites had more efficient patient throughput, alower no-show rate, greater patient satisfaction, and overall higher patient volume (43).Our research showed that being in a waiting room is fraught with considerable distress for apatient based on a study with 214 women who were awaiting either a diagnostic procedure(breast biopsy), invasive embolization of benign uterine fibroids, or a higher risk andinvasive chemoembolization of malignant liver cancers (44). All three patient groupsexperienced abnormally high mean scores on Perceived Stress, Impact of Event, and Centerfor Epidemiologic Studies Depression Scales. The diagnostic breast biopsy group had thehighest anxiety levels which were elevated to an abnormal level. One may conclude that theuncertainty of diagnosis in that case was associated with greater stress than was awaitingmore invasive and potentially higher risk treatment. The adverse impact of uncertainty wasalso borne out in another study that showed that waiting after a biopsy for days withoutknowing the diagnosis resulted in abnormal stress responses similar to having been informedof a cancer diagnosis, as measured by salivary cortisol profiles (45).In case of uncertainty and ambiguity, the natural mental processing is geared to choose themore negative interpretation, such as pain or danger (46, 47). Once a painful stimulus hasoccurred one also tends to be more attentive to external cues that could indicate pain, evenwhen there is none (48). Expectancy then further shapes pain-intensity processing in thebrain (49).The mechanism by which the app-delivered verbiage is postulated to reduce pain and anxietywas elaborated in prior large-scale clinical trials evaluating procedures of varying degrees ofinvasiveness and procedural risk: outpatient large core breast biopsy performed with localProtocol Template, Version 1.010 of 44

anesthetic only (21), vascular and percutaneous renal interventions performed with access toIV conscious sedation (24), and tumor embolizations performed with conscious sedationwhich are higher risk procedures that induce tissue ischemia (22).Three essential premises underlie the mechanism of action:1. Under standard care conditions, acute anxiety and pain increased linearly over time as isevident in Fig. 2-3. The steepness of the pain curve was relatively independent of stimulusseverity and medications administered, and was indistinguishable among three types ofprocedures of vastly different invasiveness and risk (50). Time zero on Figs. 2 and 3 waspatient entry into a procedure suite and initial preparation and positioning. Based on ourwork in the MRI setting, we speculate that the increase in pain and anxiety also happenswhen a patient is not instrumented, and thus the length of time becomes the limiting factor inthe patient’s intolerance for remaining on the examination table (7).Fig. 1: Course of pain perception during procedures of widelyvarying invasiveness and potential for pain stimuli (from (50)).2.) When patients were read a short 1-3 minute self-hypnotic relaxation script by trainedpersonnel at the onset of these procedures, pain no longer increased over time in all threetrials, even in procedures that lasted hours (Example, Fig. 2) This implies that afundamental and sustained change in the mode of processing pain and anxiety can beachieved through a short set of suggestions at a time when the patient is exposed to anambiguous situation and potentially painful stimuli. In cases performed under IVconscious sedation, patients in the script group also requested and received significantlylower doses of sedatives and narcotics and had more stable vital signs, fewer complications,and shorter procedures times.Protocol Template, Version 1.011 of 44

Fig. 2: 1-3 minutes of comforting words (red line) at the onset of renal/vascular proceduresprevented the naturally occurring increase in anxiety and pain over time under standard careconditions (blue line) and allowed procedures to be completed faster (from (24)).Use of a self-hypnotic relaxation Comfort Talk script or Comfort Talk snippets of helpfulsuggestions and hypnoidal language also had significant benefits when delivered live bytrained MRI personnel. In a clinical trial with 97,712 patients, incompletion scans due toclaustrophobia and disruptive patient motion decreased significantly from 2.3 pre ComfortTalk training to 1.4% post training, indicating improved patient tolerance (7). Two sites inthis trial (Tufts Medical Center and The Ohio State University Hospital MRI) used this benefitadditionally to perform more lengthy and combined procedures.In a subsequent trial six MRI sites were randomized to receive training in delivery of thelanguage elements provided in the app. in the setting of a saturated market, three sites weretrained, three were not. Analysis of 27,425 patient visits showed better patient retention,attendance at examinations, improved throughput and satisfaction with treatment in thetrained sites compared to non-trained sites (43).Better patient tolerance is also reflected in a current clinical trial, funded by NCCIH-SBIRR44 AT006296 with 29,772 patients at Duke University MRI. Enabling personnel to deliverthe verbiage snippets by script or conversationally also resulted in significant reductions in 1.)patients’ use of oral sedatives in the waiting room, 2.) extra time due to patient disruptivemotion or claustrophobia, and 3.) MRI study incompletions (Fig. 3).Protocol Template, Version 1.012 of 44

Fig. 3 Data obtained at Duke Medical Center MRI before and after Comfort Talktraining enabling personnel to deliver verbiage integrated in the Comfort Talk app3.) Elevated anxiety levels immediately prior to invasive procedures are a predictor of higheranxiety and pain during procedures, need for drugs, and procedure time (1). These findingsconcur with reports that identify anticipatory anxiety right before surgery and/orinterventions as a predictor of poor patient compliance, greater pain, poorer outcomes,delayed recovery, and maladaptive postoperative behavior (1, 18, 51-61). A validated patientComfort Talk app, that patients can use to assist with coping in the waiting room, thuspromises to not only b

Craniofacial Pain Center such as fitting and adjusting dental bite appliances, fitting and adjusting oral appliances for management of sleep apnea, trigger point therapy, botulinum toxin therapy, and various craniofacial and cervical nerve blocks for pain