De-Implementing Opioid Use and Implementing Optimal Pain Management Following Dental Extractions
Phase: NA
Conditions: Tooth Extraction
Sponsor: HealthPartners Institute

De-Implementing Opioid Use and Implementing 
Optimal Pain Management Following Dental Extractions 
Protocol Number: 17-085-E 
National Clinical Trial (NCT) Identified Number:  03584789 
Principal Investigators:  D. Brad Rindal, DDS and Shannon Gwin Mitchell, PhD 
Funded by: National Institute of Dental and Craniofacial Research 
Version Number:  v.6.0 
 
28 December 2020 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.1 Synopsis; 1.3 
Schedule of 
Activities 
Extended the enrollment period. 
Due to the impact of COVID-19 on care 
delivery, the enrollment period will be 
extended to meet patient accrual goals. 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 4 
1 
PROTOCOL SUMMARY ............................................................................................................................... 5 
1.1 
Synopsis ................................................................................................................................................ 5 
1.2 
Schema ................................................................................................................................................. 7 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 8 
2 
INTRODUCTION ............................................................................................................................................ 9 
2.1 
Study Rationale .................................................................................................................................... 9 
2.2 
Background ........................................................................................................................................... 9 
2.3 
Risk/Benefit Assessment .................................................................................................................. 10 
2.3.1 
Known Potential Risks ................................................................................................... 10 
2.3.2 
Known Potential Benefits .............................................................................................. 12 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 12 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 13 
4 
STUDY DESIGN ........................................................................................................................................... 14 
4.1 
Overall Design .................................................................................................................................... 14 
4.2 
Scientific Rationale for Study Design .............................................................................................. 14 
4.3 
Justification for Dose ......................................................................................................................... 14 
4.4 
End of Study Definition ..................................................................................................................... 14 
5 
STUDY POPULATION ................................................................................................................................ 16 
5.1 
Inclusion Criteria ................................................................................................................................ 16 
5.2 
Exclusion Criteria ............................................................................................................................... 16 
5.3 
Lifestyle Considerations .................................................................................................................... 16 
5.4 
Screen Failures .................................................................................................................................. 16 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 16 
6 
STUDY INTERVENTION ............................................................................................................................ 17 
6.1 
Study Intervention(s) Administration ............................................................................................... 17 
6.1.1 
Study Intervention Description ..................................................................................... 17 
6.1.2 
Dosing and Administration ............................................................................................ 17 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 17 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 18 
6.4 
Study Intervention Compliance ........................................................................................................ 18 
6.5 
Concomitant Therapy ........................................................................................................................ 18 
6.5.1 
Rescue Medicine ............................................................................................................ 18 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 18 
7.1 
Discontinuation of Study Intervention ............................................................................................. 19 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 19 
7.3 
Lost to Follow-Up ............................................................................................................................... 19 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 20 
8.1 
Efficacy Assessments ....................................................................................................................... 20 
8.2 
Safety and Other Assessments ....................................................................................................... 20 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 21 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 21 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 21 
8.3.3 
Classification of an Adverse Event .............................................................................. 21 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 22 

  
 
 
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8.3.5 
Adverse Event Reporting .............................................................................................. 22 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 22 
8.3.7 
Reporting Events to Participants ................................................................................. 23 
8.3.8 
Events of Special Interest ............................................................................................. 23 
8.3.9 
Reporting of Pregnancy ................................................................................................ 23 
8.4 
Unanticipated Problems .................................................................................................................... 23 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 23 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 23 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 24 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 25 
9.1 
Statistical Hypotheses ....................................................................................................................... 25 
9.2 
Sample Size Determination .............................................................................................................. 25 
9.3 
Populations for Analyses .................................................................................................................. 26 
9.4 
Statistical Analyses ............................................................................................................................ 27 
9.4.1 
General Approach .......................................................................................................... 27 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 27 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 27 
9.4.4 
Safety Analyses .............................................................................................................. 28 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 29 
9.4.6 
Planned Interim Analyses ............................................................................................. 29 
9.4.7 
Sub-Group Analyses ..................................................................................................... 29 
9.4.8 
Tabulation of Individual participant Data .................................................................... 29 
9.4.9 
Exploratory Analyses ..................................................................................................... 29 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 30 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 30 
10.1.1 
Informed Consent Process ........................................................................................... 30 
10.1.2 
Study Discontinuation and Closure ............................................................................. 30 
10.1.3 
Confidentiality and Privacy ........................................................................................... 31 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 31 
10.1.5 
Key Roles and Study Governance .............................................................................. 31 
10.1.6 
Safety Oversight ............................................................................................................. 32 
10.1.7 
Clinical Monitoring .......................................................................................................... 33 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 33 
10.1.9 
Data Handling and Record Keeping ............................................................................ 33 
10.1.10 
Protocol Deviations ........................................................................................................ 34 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 34 
10.1.12 
Conflict of Interest Policy .............................................................................................. 34 
10.2 
Additional Considerations ................................................................................................................. 35 
10.3 
Abbreviations ...................................................................................................................................... 35 
10.4 
Protocol Amendment History ........................................................................................................... 36 
11 
REFERENCES ............................................................................................................................................. 38 
 
 
 
 

 
 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
Principal Investigators: 
Signed: 
 
Date: 12-28-2020 
 
Name: D. Brad Rindal, DDS 
 
Title: Co-Principal Investigator 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP), the United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812), and the 
National Institute of Dental and Craniofacial Research Terms and Conditions of Award 
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the HealthPartners Institutional Review Board (IRB) for review and approval.  Approval of 
both the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from participants 
who provided consent, using a previously approved consent form.

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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
De-Implementing Opioid Use and Implementing Optimal Pain 
Management Following Dental Extractions 
Study Description: 
The overarching goal of this project is to de-implement the reliance on 
opioid analgesics and to implement reliance on non-opioid analgesics to 
manage pain following dental extractions. Using a prospective, 3-arm 
cluster randomized trial design with dentists as the unit randomized and 
patient-level prescribing data as the primary outcome, the study team will 
compare different strategies to reduce the reliance on opioids and 
increase the use of alternative pain management approaches utilizing 
information support tools aimed at both providers and their patients. 
Objectives: 
 
Primary Objective: 
(1) To test the efficacy of two interventions (Clinical Decision Support with 
and without Patient Education), compared to treatment-as-usual to 
decrease opioid prescribing for dental extractions. 
 
Secondary Objectives: 
(1) To test the efficacy of two interventions (Clinical Decision Support with 
and without Patient Education), compared to treatment-as-usual to 
increase exclusive non-opioid pain management for dental extractions. 
(2) To compare the degree to which each of the 3 study arms (Clinical 
Decision Support with and without Patient Education, and treatment-as-
usual), facilitates shared provider and patient decision-making concerning 
pain management options for dental extractions. 
(3) To explore whether the study interventions lead to differences in 
patient experiences of post-extraction pain. 
 
 
Endpoints: 
Primary Endpoint: 
(1) Differential pre- to post-intervention change by study arm in the 
percentage of extraction encounters with an opioid prescribed. 
Secondary Endpoints:  
(1) Differential pre- to post-intervention change by study arm in the 
percentage of extraction encounters at which a provider recommended 
NSAIDs and/or APAP and did not prescribe opioids at the extraction 
encounter. 
(2) Study arm comparison of the mean of the patient-reported shared 
decision making composite score (composite of 3 components concerning 
management of post-extraction pain options: effort to explain, to listen, 
and to personalize) 
(3) Study arm comparison of the average patient-reported pain in 3-6 days 
following the extraction. 
 
Study Population: 
Providers: Up to 60 (target=51) practicing dental providers at 
HealthPartners with current Drug Enforcement Agency (DEA) license who 
performed at least 6 permanent tooth extractions in the baseline period 

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Patients: Up to 16,800 [8,400 baseline (target=6,900) and 8,400 
intervention (target=6,900)] dental patients age 16 and older, who have a 
permanent tooth extraction performed by a HealthPartners dental 
provider who is eligible for the study 
Phase: 
III 
Description of 
Sites/Facilities Enrolling 
Participants: 
21 HealthPartners dental clinics in Minneapolis- St. Paul metropolitan area 
Description of Study 
Intervention: 
Standard Practice: Usual care 
Clinical Decision Support (CDS):  Providers receive point-of-care 
information within the EHR. 
Clinical Decision Support plus Education (CDS-E):  Providers receive point-
of-care information within the EHR and their patients receive before and 
after extraction pain management education 
Study Duration: 
48 months 
Participant Duration: 
Providers: 27 months or 33 months for Providers participating in 
qualitative follow-up 
Patients: 1 month 

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1.2 
SCHEMA 
 
Qualitative 
Evaluation  
Post-Extraction 
Data Collection 
Intervention 
Abstraction 
Baseline 
Abstraction 
Intervention at 
Extraction 
Encounter 
For dental providers with a DEA number who performed at least 6 permanent tooth 
extractions in the baseline period: Abstract data from the EHR about pain management 
prescribing and recommendations for dental extractions to establish prescribing patterns 
and trends for each provider. 
Provider-level 
Randomization 
Randomize providers in equal allocation 
SP arm 
~17 Providers  
(~ 2300 pts) 
CDS arm 
~17 Providers  
(~ 2300 pts) 
CDS-E arm 
~17 Providers  
(~ 2300 pts) 
CDS arm intervention + 
Patients receive before 
and after extraction pain 
management education. 
Providers receive point-
of-care information 
within the EHR. 
 
Usual Care 
  
For patients who have an extraction performed, abstract data from EHR about 
demographics, comorbid conditions, opioid prescriptions, non-opioid analgesic 
recommendations and extractions. 
Conduct a phone-based follow-up with a subset of patients (n=1,200) who had extraction 
visits, obtain verbal consent to participate in the telephone survey. Assess patient 
knowledge about pain management strategies, the extent of shared decision-making 
about pain management, and patient-reported pain ratings. 
Interview a purposive sample of providers to assess the acceptability of the strategies and 
evaluate experiences with the intervention. 
  
  

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures: 
Providers 
Baseline Abstraction 
Week 1 – 52 
Cluster Randomization 
with Providers as the Unit 
Randomized 
Intervention  
Intervention Abstraction 
Week 53– 116 
Post-Extraction 
Data Collection 
Week 53-117 
Qualitative Evaluation 
Number of extractions performed 
X 
 
X 
X 
 
 
Demographics 
X 
 
 
X 
 
 
Provider type 
X 
 
 
X 
 
 
Clinic location 
X 
 
X 
X 
 
 
DEA license 
X 
 
X 
X 
 
 
APAP/NSAID recommendations 
X 
 
X 
X 
 
 
Opioid prescribing 
X 
 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
Administer intervention 
 
 
X 
 
 
 
Informed consent 
 
 
 
 
 
X 
Semi-structured interview 
 
 
 
 
 
X 
Procedures: 
Patients 
Extraction 
encounter 
Day 0, Week 1-64 
 
Survey call 
Day  4 (-1 day/+2 
days) 
 
Extraction date 
 
 
X 
 
 
 
Demographics 
 
 
X 
 
X 
 
Comorbid conditions 
 
 
X 
 
 
 
Patient visit count 
 
 
X 
 
 
 
Extraction complexity 
 
 
X 
 
 
 
Informed consent 
 
 
 
 
X 
 
Patient-reported outcomes 
 
 
 
 
X 
 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
The United States is in the midst of an epidemic of prescription drug overdose deaths, with deaths 
associated with prescription pain relievers of particular concern.1 Drug overdose has become the second 
leading cause of accidental death in the United States.2 Opioids are currently the most commonly 
prescribed class of medications in the United States.3  Opioid analgesics are among the most frequently 
prescribed drugs by dentists.6  The proposed trial will test the ability CDS elements to support optimal, 
non-opioid pain management following dental extraction and utilize opioid pain management only when 
clinically indicated by clinical contraindications for non-opioid analgesics. 
 
2.2 
BACKGROUND  
 
The opioid overdose epidemic. The United States is in the midst of an epidemic of prescription drug 
overdose deaths, with deaths associated with prescription pain relievers of particular concern.1 Drug 
overdose has become the second leading cause of accidental death in the United States.2 Opioids are 
currently the most commonly prescribed class of medications in the United States.3  Since 2000, the rate 
of deaths from drug overdoses has increased 137%, including a 200% increase in the rate of overdose 
deaths involving opioids (opioid pain relievers and heroin).4 Inappropriate prescribing of opioids has 
driven this unprecedented opioid epidemic, and the Centers for Disease Control and Prevention has 
strongly recommended fundamental changes in prescribing practices in order to address this public 
health emergency.5 
Dentists frequently prescribe opioids for pain management following tooth extractions. Opioid 
analgesics are among the most frequently prescribed drugs by dentists.6 For example, an estimated 5 
million people undergo third-molar extractions in the United States each year, resulting in postoperative 
pain, swelling, and discomfort, even when surgical complications are not present.7 The resulting 
postoperative pain lasts, on average, 3 to 5 days, and a multipronged approach to pain management 
often includes icing the jaw to reduce swelling, as well as some analgesics for pain relief. Many patients 
younger than 25 years are introduced to prescription opioids via postoperative dental pain management 
following third-molar surgery or wisdom tooth extraction.8 Recent evidence shows that exposure to 
opioid analgesic prescriptions following dental procedures are increasing over time.9 
NSAIDs+APAP are an effective alternative to opioids for post-extraction dental pain. Comprehensive 
reviews concluded that NSAIDs are remarkably effective analgesics for relieving postoperative dental 
pain and that opioid analgesics have a high incidence of adverse effects.10-12 Recent evidence concludes 
that the combination of ibuprofen-acetaminophen provides analgesia that is at least equivalent to that 
of commonly prescribed opioid combination formulations.13 Thus, NSAIDs+APAP provides a viable and 
evidence-based pain management alternative to prescription opioids.13 Nevertheless, most dental 
practitioners report that they prescribe opioid medications such as hydrocodone or oxycodone following 
third-molar extractions.14,15 Many practitioners appear to underestimate the immediate risks and the 
long-term harms associated with prescription opioids, even as they overestimate opioids’ therapeutic 
benefits.16 Strategies to support practitioners in de-implementing their overreliance on prescription 
opioids following dental extractions in favor of safer alternatives are urgently needed. 

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The role of the patient in pain management. Self-management skills such as patient education, decision 
making, and forming a patient-provider partnership have long been associated with chronic disease 
management22 but can be effective components of acute pain management as well. While patient-
provider shared decision making is considered the preferential choice when no clear treatment option is 
optimal,17 involving the patient in the decision process has distinct advantages with respect to 
medication adherence, as well.18 Collaborative decision making involving the patient and the dentist 
holds the potential to increase reliance on non-opioid medications.19 The study team will utilize this 
strategy to engage patients in the decision-making process related to the choice of analgesics to manage 
their pain following dental extractions. 
Clinical Decision Support (CDS) integrated in Electronic Health Records (EHRs). A well-designed CDS 
system can support dentists in providing optimal pain management for patients without resorting to 
opioids when a safer alternative would suffice. CDS provides pertinent clinical information to the 
dentist. It can provide evidence-based information and guidance in the form of prompts and reminders 
to inform clinical decisions about prescriptions. Finally, CDS can offer a mechanism for communicating 
with patients in the days following the procedure through features such as patient portals and 
automatic text reminders. In doing so, CDS can enhance education of patients about effective pain 
management strategies and potentially improve compliance with post-extraction care, resulting in a 
better experience during the week following the extraction. CDS also provides the advantage of ensuring 
fidelity of the implementation strategy. 
Public Health Impact. This cluster randomized trial with providers as the unit randomized will test the 
ability of CDS to support the de-implementation of prescription opioids to manage pain following dental 
extraction and promote the use of NSAIDs+APAP as an effective alternative in patients where this is 
appropriate. This study is highly significant because it could lead to a CDS tool that could help dental 
practitioners across the United States decrease their unnecessary prescribing of opioids following tooth 
extractions, a common dental procedure that affects millions of Americans each year. Public health will 
be promoted by decreasing the amount of opioids available in the community, which are a source of 
medication diversion, misuse, and overdose death. 
The CDS incorporates novel design features that will save significant time, ensure good fit into the 
dental care work flow, and facilitate the delivery of personalized care by providing the relevant medical 
history, informing best treatment decisions, and promoting more evidence-driven pain management 
following tooth extractions. This proposed implementation project has the potential to drive a major 
improvement in prescribing practices and the management of pain following tooth extractions in the 
field of dentistry. As new strategies for pain management are ready to be introduced into clinical 
practice, they can be readily integrated into this platform in a timely manner. 
2.3 
RISK/BENEFIT ASSESSMENT 
 
2.3.1 KNOWN POTENTIAL RISKS  
Potential risks to provider participants are considered minimal. Provider prescribing and documentation 
is a regular part of clinical practice and healthcare delivery. HealthPartners regularly reviews and utilizes 
this information (e.g., billing and claims). Across all study arms, a potential breach of confidentiality of 
study data may expose individual provider differences in prescribing and recommendations.  To 
minimize the potential of such a breach of confidentiality, no individually identifying information on 
provider behaviors collected as part of this research project will be made available in publications or 

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dissemination efforts. Results that are shared will be in aggregate form. If confidentiality were breached 
and quality of care were seriously out of range for one or more providers, academic or management 
leadership could conceivably use this information to the disadvantage of provider. Therefore, no 
identifying information on individual provider performance with respect to the clinical domains 
addressed in this study or any other aspect of care gathered as part of this research project will be made 
available to leaders or managers who make academic, employment, compensation, or disciplinary 
decisions. 
For providers assigned to the CDS or CDS-E arms, the study team expect exposure may shift individual 
prescribing and/or pain management recommendations following dental extractions.  In current dental 
practice, there is variation with regards to prescribing and pain management recommendations 
following dental extractions; the study team expects any shift in these behaviors to be within usual care.    
It is possible, although not intended, that repeat CDS exposure may impact these behaviors for other 
dental procedures, in that provider communication skills and efficacy may change. To minimize the 
potential risks associated with changing provider prescribing and/or pain management 
recommendations, the study team has designed the CDS to promote behaviors consistent with the 
American Dental Association guidelines and provider training will reiterate. 
Potential risks to patient participants are considered minimal. For patients in all study arms, there is a 
potential breach of privacy of individually identifying study data.  To minimize this risk, no individually 
identifying patient information will be made available in publication or dissemination efforts.  Results 
that are shared will be in aggregate form. 
For patients whose providers are exposed to the CDS, there are several additional potential risks.  First, 
the CDS may not display all relevant clinical information about the patient, as the CDS is limited to what 
is contained in the EHR.  Second, it is possible that the CDS could erroneously attribute a condition or 
drug to a patient based on the EHR. In the design phase, the study team will seek and feedback from 
multiple sources to ensure that the content and CDS firing is as accurate and appropriate as possible.  
Before implementation, several investigators will review and test the CDS firing to optimize the 
information displayed.  Provider training will inform providers of these limitations and offer strategies to 
further minimize these risks.  Throughout the implementation phase, the study team will request 
feedback from providers using the CDS to identify any issues and modify the CDS, if needed. 
Third, the CDS may be inappropriate for a given individual patient and, if applied without further 
checking the clinical status of a given patient, could lead to erroneous therapy, adverse events, 
disability, or death. However, the clinical recommendations are personalized based on the patient’s 
medical problem list, allergies and current medications. The risk of untoward consequences from such 
clinical actions is considered minimal. Moreover, this potential risk is routinely present in every clinical 
encounter in the health care system. Fourth, the potential shift in provider prescribing and/or pain 
management recommendations may also have unintended consequences on patients’ post-procedure 
pain management.  It is possible that this shift could cause under-controlled pain.  Providers encounter 
this in current dental practice and will address it in a similar fashion consistent with the reasonable 
standard of care. 
In addition to their providers being exposed to the CDS, patients in the CDS-E arm will also receive 
supplemental patient education.  To minimize the potential risk that intervention-related materials 
might conflict with clinical care recommendations, the supplemental patient education materials will 
not give any specific pain management recommendations.  Instead, the patient education materials will 

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offer information about pain management options and encourage them to talk with the providers.  
Patients may feel uncomfortable or awkward voicing their preferences about pain management options 
with their provider.  To minimize this potential risk, provider training will address this. 
2.3.2 KNOWN POTENTIAL BENEFITS  
Opioids are currently the most commonly prescribed class of medications for the treatment of acute 
pain in the United States. These medications make a significant contribution to our nation’s epidemic of 
overdoses and are a gateway to using other illicit drugs. The primary benefit of reducing the prescribing 
of opioids when not clinically necessary is reducing the likelihood of these outcomes for at-risk 
individuals.  For providers assigned to SP and their patients, a potential benefit is greater knowledge 
about whether usual care adequately manages patient-reported pain after a dental extraction, which 
based on current evidence is unknown. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The implementation of clinical decision support and patient education related to opioid prescribing after 
a dental extraction poses minimal risk to providers and patients.  The CDS does not explicitly make a 
recommendation about pain management options, but rather facilitates provider access to clinically 
relevant information.  Default messaging are consistent with current American Dental Association 
practice guidelines, suggesting NSAIDs as a first line treatment for post-extraction dental pain. The CDS 
display and intervention training will reinforce that pain management prescribing and recommendations 
should be based on provider judgement. Therefore, patients will be exposed to usual care.  The biggest 
known risk is the potential breach of privacy, for which appropriate measures have been taken to 
mitigate the possibility of such risk.  The potential for these interventions to reduce opioid prescribing 
among dental providers in terms of dose and number of pills has important public health implications 
that outweigh the potential risks.

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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To test the efficacy of two 
interventions (Clinical Decision 
Support with and without Patient 
Education), compared to treatment-
as-usual to decrease opioid 
prescribing for dental extractions. 
Differential pre- to post-intervention 
change by study arm in the 
percentage of extraction encounters 
with an opioid prescribed (during the 
day of the extraction encounter). 
A prescription is legally 
required for opioids to be 
dispensed. Prescriptions 
are reliably and routinely 
entered in the electronic 
health record. 
Secondary 
 
 
To test the efficacy of two 
interventions (Clinical Decision 
Support with and without Patient 
Education), compared to treatment-
as-usual to increase exclusive non-
opioid pain management for dental 
extractions. 
 
Differential pre- to post-intervention 
change by study arm in the 
percentage of extraction encounters 
at which a provider prescribed or 
recommended non-opioid analgesics 
(ibuprofen, naproxen, aspirin, or 
acetaminophen) and did not 
prescribe opioids (at the time of the 
extraction encounter). 
A discrete data element in 
the electronic health 
record exists for 
documenting a non-
opioid recommendation. 
Documentation standards 
ensure these are routinely 
documented. 
To compare the degree to which 
each of the 3 study arms (Clinical 
Decision Support with and without 
Patient Education, and treatment-
as-usual), facilitates shared provider 
and patient decision-making 
concerning pain management 
options for dental extractions. 
 
Study arm comparison of the mean of 
the patient-reported shared decision- 
making composite score (composite 
of 3 components concerning 
management of post-extraction pain 
options: effort to explain, to listen, 
and to personalize 3-6 days after the 
extraction encounter) 
Patient report best 
captures the patient 
experience of the 
encounter. This is a 
modification validated, 
succinct patient-reported 
outcome measure used to 
demonstrate the extent 
of shared decision 
making. 
To explore whether the study 
interventions lead to differences in 
patient experiences of post-
extraction pain. 
Study arm comparison of the average 
patient-reported pain following the 
extraction (3-6 days after the 
extraction encounter). 
Patient report best 
captures pain experience. 
The Numeric Rating Scale 
is a validated patient-
reported outcome 
measure used to measure 
pain level in research and 
clinical practice.  
 

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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
 
This study is a prospective, 3-arm, cluster randomized trial (Phase III) in which up to 60 dental providers 
(accrual goal: n=51) practicing at HealthPartners dental clinics are randomized in a 1:1:1 allocation ratio 
to either standard practice (SP) or one of two clinical decision support arms (CDS or CDS-E). Patients (up 
to n=8,400, accrual goal: n=6,900) are exposed to the study arm of their dental provider.  Opioid 
prescribing measured at the patient-level serves as the primary outcome. Opioid prescribing data for 
patients (up to n=8,400, goal: n=6,900) seen in the baseline period and unexposed to the intervention is 
utilized in the analysis to examine secular trends in opioid prescribing. Additional outcomes are also 
measured at the patient-level include: a recommendation or prescription for non-opioid analgesics from 
the electronic health record and patient reported outcomes about shared decision making and pain 
identified through surveys. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The cluster-randomized trial design randomizes dental providers to one of three study arms. This design 
maximizes the number of randomized units (providers) as compared to clinic- level randomization. 
Cluster randomization with providers as the unit randomized allows for techniques to balance attributes 
of providers and their patients across study arms. This design also solves the practical issue of providers 
floating across several clinics and different study arms that would occur in clinic- level randomization. 
Cluster randomization with providers as the unit randomized also has advantages over patient-level 
randomization because providers who are exposed to the interventions intermittently may change their 
usual practices in ways that would not occur naturally. Cluster randomization with providers as the unit 
randomized also matches the unit of randomization with the level at which the intervention is expected 
to have an effect, which is at the provider level. 
 
The Standard Practice (SP) arm was selected as a control to reflect care as it is currently performed and 
to serve as a comparison of secular trends in care, by contrasting such trends in a provider group that 
does not receive an intervention (SP), with those providers in the two active intervention arms (CDS, 
CDS-E).  
4.3 
JUSTIFICATION FOR DOSE 
Not applicable 
 
4.4 
END OF STUDY DEFINITION 
A provider participant is considered to have completed the study if they have completed the 
intervention period as shown in the Schedule of Activities (SoA), Section 1.3 or they leave employment 
at HealthPartners.  A provider participant will have the option to provide feedback about their 
experience during the intervention period in a sub-study evaluating the intervention. 
 
For a patient not selected to complete a survey, they are considered to have completed the study when 
regular dental care for their index extraction encounter is completed as shown in the Schedule of 
Activities (SoA), Section 1.3. 
 
For a patient participant selected to complete a survey, they are considered to have completed the 
study after completing the survey call as shown in the Schedule of Activities (SoA), Section 1.3. 

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The end of the study is defined as completion of the last procedure shown in the SoA in the trial 
globally.

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5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
Providers 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Have a current Drug Enforcement Administration (DEA) number allowing them to write 
prescriptions for controlled substances, including opioids, during the baseline period 
• 
Perform dental extractions of permanent teeth on a regular basis (a minimum of 6 extraction 
encounters during the baseline period) 
Patients 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Have a dental extraction of a permanent teeth performed by an eligible HealthPartners provider 
during the intervention period 
5.2 
EXCLUSION CRITERIA 
Patients 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Patients who have opted out of research at HealthPartners 
2. Patients under 16 years of age 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable 
5.4 
SCREEN FAILURES 
Implementation of the CDS is considered a HealthPartners Dental Group initiative in as a part of their 
strategy to reduce opioid prescribing. As such, providers are not consented for the study. Providers not 
eligible for the study will not be included in data collection activities and the data from their patients will 
not be included in the study. There will be no screen failures for providers. 
 
Patients will not be consented to the study for the primary study objective. Patients not eligible for the 
study or those who have opted out of research will not be included in the analysis. Patients who provide 
consent for the survey-based objective are known to be study eligible at the time their consent is 
requested. There will be no screen failures for patients.   
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Implementation of the CDS is considered a HealthPartners Dental Group initiative.  The project is being 
implemented with the aim of reducing opioid prescribing. Consent has been provided by dental 
leadership in accordance with HealthPartners practices. 
 
Providers randomized to the CDS or CDS-E will be exposed to the clinical decision support, integrated 
into the EHR.  Patients who receive care from providers randomized to the CDS-E arm will also be 
exposed to study-specific patient education. 
 
For the subset of patients eligible to receive a survey, patients will provide verbal consent for survey 
participation via telephone, which will be obtained by trained survey administrators. If a patient chooses 
not to participate, another patient will be sampled and called.   
 
Further information about the strategies for recruitment and retention are detailed in the Manual of 
Procedures.

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6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
The study intervention will be active within HealthPartners Dental Group for 12 months or until patient 
accrual goals are met.  After completion of the study, the HealthPartners Dental Group will decided 
whether to continue its activity, but this will be beyond the study’s scope. 
 
Standard Practice:  Providers will not receive point of care decision support, serving as the control group 
representing usual care.  Patients will receive usual dental care. 
 
CDS:  Providers will receive point of care decision support to guide pain management recommendations 
and prescribing for patients who receive dental extractions.  The clinical decision support will highlight: 
(1) potential medication interactions between the patient’s current medications and commonly 
recommended analgesics for patients following dental extractions; (2) relevant health conditions that 
may impact pain management strategies; and (3) automated access to the Prescription Drug Monitoring 
Program.  Patients will receive usual dental care [when implemented by HealthPartners Dental Group: 
access to the Prescription Drug Monitoring Program via the clinical decision support tool will be 
suspended to align with the organization approach via the electronic health record]. 
 
CDS-E:  Providers will receive point of care decision support to guide pain management 
recommendations and prescribing related to dental extractions.  The clinical decision support will 
highlight: (1) potential medication interactions between the patient’s current medications and 
commonly recommended analgesics for patients following dental extractions; (2) relevant health 
conditions that may impact pain management strategies; and (3) automated access to the Prescription 
Drug Monitoring Program [when implemented by HealthPartners Dental Group: access to the 
Prescription Drug Monitoring Program via the clinical decision support tool will be suspended to align 
with the organization approach via the electronic health record]. 
 
In addition, patients will receive an educational handout prior to the extraction procedure comparing 
effectiveness for managing pain, risks and benefits of non-opioid pain medications and opioid 
medications.  This handout intends to initiate a conversation between the patient and provider about 
patient needs, goals and preferences.  The patient will also receive an education handout about pain 
management after dental extraction for their reference. This handout intends to normalize the 
experience of some discomfort and to help patients decide about whether to contact their provider for 
additional help to manage their pain after extraction.  Patients will receive usual dental care. 
6.1.2 DOSING AND ADMINISTRATION 
 
Not applicable 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
Not applicable 
 

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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
The randomization of providers to study arm will utilize stratification on baseline factors in order to 
balance key provider factors evenly across study arms. Specific stratification factors to be utilized will be 
outlined in the Statistical Analysis Plan.  Providers will be randomly allocated 1:1:1 through a computer-
generated program to either Standard Practice, CDS, or CDS-E. Patients will be exposed to the 
intervention to which their provider has been randomized based on the provider they see at the index 
extraction visit. Systematic sampling with a variable sampling ratio by provider will be used to identify a 
sample of patients to receive the post-visit survey. This sampling strategy will approximate stratified 
random sampling and ensure roughly equal counts of patient surveys by provider and study arm. At 
each patient encounter, the CDS Web service will collect patient level data from the EHR (e.g., medical 
conditions, current medications, social history).  Providers assigned to the CDS or CDS-E arms will be 
able to access the information using the CDS tool. Providers assigned to the control arm will continue to 
use their usual methods to assess and address pain management for dental procedures without any 
effort to influence their prescribing of analgesics following the dental extraction. They will not be 
shielded from other outside influences.  
 
At the index encounter (the initial patient visit for a dental extraction during the intervention period 
where all the study criteria are met), the patient is assigned a unique study identifier that is used to link 
patient encounter data over time. All index and subsequent encounter data for eligible patients are 
stored in a limited de-identified analysis dataset. 
 
In order to minimize contamination across study arms, only providers in the CDS or CDS-E arms will be 
able to access the clinical decision support.  Similarly, patients who receive care from providers in the 
CDS-E arm will have access to supplemental patient education.  As such, both groups will know their 
assignment.  The study team will not disclose the study’s purpose, objectives, or outcomes measures 
directly to patients until after the encounter or after the participant has been surveyed about their 
experience, if selected. 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
The CDS is embedded into the existing EHR.  CDS use will be documented to monitor fidelity in the 
intervention arms.  Co-Investigators will regularly meet with study staff to discuss study progress and 
problem-solve potential issues. The purpose of these meetings is to focus on the day-to-day operations 
of the project (e.g., technical functionality) and to assure that all necessary tasks are completed in a 
timely fashion and strictly according to study protocol (e.g., integration into workflow and/or 
supplemental training). Quarterly meetings will include all co-investigators and will address any scientific 
issues (e.g., recruitment or enrollment) or safety issues (e.g., medication interactions) that may arise. 
 
6.5 
CONCOMITANT THERAPY 
 
Not applicable 
 
6.5.1 RESCUE MEDICINE 
 
Not applicable 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 

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7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Providers should exercise clinical judgment and can at their discretion disregard any information the CDS 
offers.  As such, patients will receive usual dental care, regardless of study arm. 
 
Hospitalizations documented within the HealthPartners electronic health record that occur within a 72-
hour window following the index extraction encounter will be chart reviewed for severity and 
relatedness on a quarterly basis during the intervention period by Co-investigator and/or PI D. Brad 
Rindal.  These hospitalizations rates will be compared at a frequency determined by the DSMB or 
quarterly whichever is greater. 
 
Based on the relevant data, the study team in consultation with the DSMB would determine whether 
the study intervention needed to be modified or discontinued. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Providers 
Providers may freely leave employment from HealthPartners.  The timing of their employment will 
impact whether or not they are randomized, whether or not they receive training, whether or not they 
are exposed to the intervention, and whether or not they are lost to follow-up.  
 
Patients 
For the sub-sample of patients who are selected for a survey, patients are free to withdraw from 
participation in the survey at any time upon request.  Patients may wish not to participate for any 
reason, including due to the perceived impact on their time or privacy.  Within the parameters detailed 
in the MOP, study staff will provide support and encouragement to participants in order to minimize 
withdrawal and attrition for survey participation. Withdrawal from survey participation will be tracked 
by the CESR staff in the centralized study database. 
 
7.3 
LOST TO FOLLOW-UP 
Providers 
Providers are considered lost to follow-up if: they do not complete at least 6 extraction encounters in 
the intervention period.  Providers lost to follow-up are not replaced and would be excluded from the 
analysis. 
 
Patients 
Patients are considered lost to follow-up if they meet any of the following criteria: (1) they withdraw 
from participation in the survey at contact or after completing any portion of the survey; (2) they cannot 
be reached after all call attempts have been made; (3) they cannot be reached within the defined survey 
window. Such patients would be excluded from the analysis for survey related objectives.  It is 
anticipated that patients will be lost to follow-up by the nature of survey data collection and sample size 
selection is made with attention to the anticipated size of this group. If more patients are lost to follow-
up than anticipated, additional patients will be sampled.

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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Primary Objective 
To test the efficacy of two interventions (Clinical Decision Support with and without Patient Education), 
compared to treatment-as-usual to decrease opioid prescribing for dental extractions. 
 
 
Data source:  HealthPartners electronic health record 
 
Procedures: 
 
1. Gather extraction procedure records performed prior to and post CDS implementation 
 
2. Gather opioid medication orders placed within 7 days of extraction procedure 
 
3. Retrieve patient and provider descriptive data 
 
Secondary Objectives 
To test the efficacy of two interventions (Clinical Decision Support with and without Patient Education), 
compared to treatment-as-usual to increase exclusive non-opioid pain management for dental 
extractions. 
 
Data source:  HealthPartners electronic health record 
 
Procedures: 
 
1. Gather extraction procedure records performed prior to and post CDS implementation 
 
2. Gather non-opioid medication recommendations given within 7 days of extraction procedure 
 
3. Gather patient and provider descriptive data 
 
To compare the degree to which each of the 3 study arms (Clinical Decision Support with and without 
Patient Education, and treatment-as-usual), facilitates shared provider and patient decision-making 
concerning pain management options for dental extractions. 
 
Data source:  Telephone administered patient survey responses 
 
Procedures: 
 
1. CESR staff will administer the survey by telephone 
 
2. CESR staff will input patient responses into RedCap 
 
3. Data will be exported and provided to the statistician 
 
To explore whether the study interventions lead to differences in patient experiences of post-extraction 
pain. 
Data source:  Patient survey 
 
Procedures: 
 
1. CESR staff will administer the survey by telephone 
 
2. CESR staff will input patient responses into RedCap 
 
3. Data will be exported and provided to the statistician 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
The study does not include objectives or endpoints concerning safety. However, the monitoring 
activities described below will be conducted to assess possible harm. 
 
Identify whether the CDS inappropriately fires or inappropriately offers considerations 
 
Data source:  Provider report to alert study team about potential issues or concerns 
 
Procedures: 
 
1. Providers randomized to an intervention arm will be offered training. 

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2. They will be instructed to notify the study team when clinical judgement differs from the CDS 
 
3.  Notification options: (a) Contact Co-Investigator Don Worley or PI D. Brad Rindal; (b) select a 
“feedback” button contained within the CDS  
 
Identify potential adverse events 
Data source:  HealthPartners electronic health record 
 
Procedures: 
 
1. Gather hospitalizations, emergency department visits, observational bed, and subsequent 
opioid prescribing made within 3 days post-extraction procedure 
 
 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
An adverse event is any untoward or unfavorable medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either of 
the co-PIs, it results in any of the following outcomes: (1) death, (2) a life-threatening adverse event, (3) 
inpatient hospitalization or prolongation of existing hospitalization, (4) a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or (5) a congenital 
anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 

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8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below.  
 
• 
Related (Possible, Probable, Definite) – The AE is known to occur with the study intervention, 
there is a reasonable possibility that the study intervention caused the AE, or there is a temporal 
relationship between the study intervention and event. Reasonable possibility means that there 
is evidence to suggest a causal relationship between the study intervention and the AE. 
• 
Not Related (Unlikely, Not related) – There is not a reasonable possibility that the 
administration of the study intervention caused the event, there is no temporal relationship 
between the study intervention and event onset, or an alternate etiology has been established. 
 
8.3.3.3 EXPECTEDNESS 
 
Adverse events will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the intervention. As the intervention for 
this study is a pain management clinical decision support module, inadequately managed pain, drug 
interactions or side effects related to pain medications are expected adverse events. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
Since there are no routine research contacts for all eligible patient participants, we will collect 
information from the electronic health record about hospitalizations, emergency department visits, 
observational bed, and subsequent opioid prescribing made within 3 days post-extraction procedure.  
This is consistent with the usual care delivery pathways and workflows related to dental procedures. 
 
For the sub-sample of patients reached as part of survey data collection, CESR staff provides information 
to call their dental provider with questions or concerns.  In this manner, the study team will not 
interfere with existing patient-provider communication, but rather support usual care. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
PI D. Brad Rindal or his designee will report necessary AEs in accordance with HPI Research Subjects 
Protection Program Standard Operating Procedures at the time of the event.  More details about 
reporting are outlined in the DIODE Data Safety Monitoring Plan. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
Any AE considered serious by a dental provider, study investigator, or PI, or which meets the definition 
of an SAE included in Section 8.3.2, Definition of Serious Adverse Events must be submitted to PI D. Brad 
Rindal, as soon as possible. 
 
PI D. Brad Rindal or his designee will report necessary SAEs in accordance with HPI Research Subjects 
Protection Program Standard Operating Procedures at the time of the event.  More details about 
reporting are outlined in the DIODE Data Safety Monitoring Plan. 

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8.3.7 REPORTING EVENTS TO PARTICIPANTS  
Not applicable 
8.3.8 EVENTS OF SPECIAL INTEREST  
Not applicable 
 
8.3.9 REPORTING OF PREGNANCY  
Not applicable 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 UNANTICIPATED PROBLEM REPORTING 
 
The study team member or dental clinic staff will report unanticipated problems (UPs) to Co-investigator 
Don Worley or PI D. Brad Rindal.  They will submit to Co-investigator Steve Asche to collect and to 
aggregate.  The PI D. Brad Rindal will be responsible for ensuring the assigned Institutional Review Board 
(IRB) receives notification in accordance with HPI Research Subjects Protection Program Standard 
Operating Procedures at the time of the event. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to NIDCR within one 
week of the investigator becoming aware of the event. 

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• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within one month of the IRB’s receipt of the report of the 
problem from the investigator. 
All unanticipated problems will be reported to NIDCR’s centralized reporting system via Rho Product 
Safety: 
(1) Product Safety Fax Line (US): 1-888-746-3293  
(2) Product Safety Fax Line (International): 919-287-3998  
(3) Product Safety Email: rho_productsafety@rhoworld.com  
General questions about SAE reporting can be directed to the Rho Product Safety Help Line (available 
8:00AM – 5:00PM Eastern Time):  
(1) US: 1-888-746-7231  
(2) International: 919-595-6486 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not applicable

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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
• 
Primary Efficacy Endpoint(s): 
 
H1 (alternative): Providers in the CDS and CDS-E strategy arms will reduce their likelihood of prescribing 
opioids for patients following extractions more than providers in the SP arm.  
 
H1 endpoint: Comparison across study arms of the differential change in percentage of permanent 
tooth extraction encounters having an associated opioid prescription on the day of the extraction 
encounter, from the one year prior to the intervention implementation to one year after the 
intervention implementation. 
 
• 
Secondary Efficacy Endpoint(s): 
 
H2 (alternative): Providers in the CDS and CDS-E strategy arms will increase their likelihood of 
prescribing or recommending non-opioid analgesics at the extraction encounter and not prescribing 
opioids for patients following extractions more than providers in the SP arm.  
 
H2 endpoint: Comparison across study arms of the differential change in percentage of permanent 
tooth extraction encounters having both 1) a prescription or recommendation in the treatment plan 
for non-opioid analgesics and 2) to not have an associated opioid prescription on the day of the 
extraction encounter, from the one year prior to the intervention implementation to one year after 
the intervention implementation. 
H3 (alternative): Patients will report higher levels of the extent of shared decision making in the CDS-E 
arm than the CDS or SP arms. 
H3 endpoint: Comparison across study arms of the mean of the 3-item composite of adapted 
Collaborate Shared Decision Making score reported by the patient.  
H4 (descriptive): Compare patient report of average pain in the week following extraction across the 3 
study arms.  
H4 endpoint: Comparison across study arms of the mean pain rating in the 3-6 days since the 
extraction encounter, self-reported by patients. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
• 
Primary Efficacy Endpoint(s):  
 
H1 (alternative): Providers in the CDS and CDS-E strategy arms will reduce their likelihood of prescribing 
opioids for patients following extractions more than providers in the SP arm.  
 
H1 patient-level endpoint: A binary code (0/1) indicating that a provider prescribed an opioid 
medication to the patient on the date of the index extraction encounter.  
 
Sample size and power: Preliminary data from 2018 indicates there will be 6,900 unique patients 
age 16 and higher with a permanent tooth extracted by 51 dental providers in the baseline period 
and also an estimated 6,900 unique patients age 16 and higher with a permanent tooth extracted by 
51 dental providers during the intervention period. The study analysis is expected to have at least 

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this many patients. Fully 40% of encounters in the baseline period with patients having a permanent 
tooth extraction included a prescription for opioid use, and the provider-level opioid use ICC=0.3. 
Assuming the use of a generalized linear mixed model, with alpha=0.05, two-sided tests , the 
planned analysis for H1 can detect a differential raw reduction of 23% from pre- to post-intervention 
opioid prescribing when comparing CDS or CDS-E patients (40% with opioid prescriptions pre-
implementation to 15% post-implementation) to SP patients (40% with opioid prescriptions pre-
implementation to 38% post-implementation) with 80% power. Power calculations were conducted 
with PASS v11 (NCSS Software). 
 
• 
 Secondary Efficacy Endpoint(s): 
 
H2 (alternative): Providers in the CDS and CDS-E strategy arms will increase their likelihood of 
recommending NSAIDs and/or APAP at the extraction encounter and not prescribing opioids for patients 
following extractions more than providers in the SP arm.  
 
H2 endpoint: A binary code (0/1) indicating that a provider both 1) prescribed or recommended in 
the treatment plan use of non-opioid analgesics and 2) did not prescribe an opioid prescription on 
the date of the extraction encounter. 
 
Sample size: This analysis will use the same analytic sample described for H1. The rate is unknown 
but will be lower than the percentage not prescribing opioids in H1 (60%) since the endpoint is a 
composite requiring no opioid prescription and also recommendation of non-opioid analgesic. 
H3 (alternative): Patients will report higher levels of the extent of shared decision making in the CDS-E 
arm than the CDS or SP arms. 
H3 endpoint: Mean of the 3-item composite of adapted Collaborate Shared Decision Making score 
reported by the patient within 3-6 days of the extraction encounter.  
Sample size: Survey materials will be sent to 1520 patients. The historical response rate for dental 
research surveys at the organization is 79%, yielding surveys returns from 1200 patients.  
H4 (descriptive): Compare patient report of average pain in the week following extraction across the 3 
study arms.  
H4 endpoint: Mean pain rating in the 3-6 days since the extraction encounter, self-reported by 
patients within 3-6 days of the extraction encounter.  
Samples size: This analysis will use the same analytic sample from the patient survey as described in 
H3. 
 
9.3 
POPULATIONS FOR ANALYSES 
Patient Encounter Study Population for H1, H2 
 
The analytic denominator for H1 and H2 will consist of up to 16,800 (8400 baseline and 8400 
intervention) first extraction encounters of patients aged 16 and higher and linked to a study-eligible 
provider, and who have a permanent tooth extraction during the year prior or year after the 
implementation of the strategies.  
 
Patient Study Population for H3, H4 
 

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The analytic denominator for H3 and H4 will start with the approximately 8,400 patients who meet the 
criteria for the analytic denominator during the intervention period for H1 and H2 above. This analytic 
dataset will be further reduced to the approximately 1,520 patients who are approached to complete 
and complete a patient survey within 6 days of the index encounter. Of the approximately 1,520 
patients approached it is expected that the analysis for H3 and H4 will include data from 1,200 patients.  
 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Baseline characteristics of study participants will be summarized with mean and standard deviation for 
interval data and proportions for categorical data. General and generalized linear mixed models will be 
used to test study arm differences in endpoints. Models will include terms for study arm, time (for 
models assessing change from pre- to post-intervention), and their interaction. Covariates to be 
included in models will be described in the Manual of Procedures (MOP). A random intercept for 
provider will be included in models to account for the cluster-randomized design with providers as the 
unit randomized.  Differential change will be compared for each study arm via a series of planned 
contrasts. Study arm contrasts will be tested at alpha=0.05 and all tests will be two-sided. Model-
predicted means and proportions along with 95% confidence intervals will be used to assess the 
magnitude, direction, and precision of intervention effects. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
H1: Providers in the CDS and CDS-E strategy arms will reduce their likelihood of prescribing opioids for 
patients following extractions more than providers in the SP arm. 
Analysis plan: Hypothesis H1a posits that patient encounters at which extractions are performed by 
dental providers in the CDS and CDS-E arms will have a larger reduction in the likelihood of receiving an 
opioid prescription at the index encounter than patient encounters in the SP arm when comparing 
independent samples of patient encounters before the implementation to patient encounters following 
the implementation. A generalized linear mixed-model regression with a logit link and binomial error 
distribution will be used to test the effects of the implementation strategies. The patient-level endpoint 
(patient received an opioid prescription at the index encounter) is coded as a binary outcome variable. 
This endpoint will be predicted by 2 fixed-effects terms for study arm of CDS (CDS vs. SP) and CDS-E 
(CDS-E vs. SP), year in which the patient has an extraction (post or pre-implementation), and by 
interaction terms of study arm and year. A random intercept for provider will be included in the model 
to accommodate the cluster-randomized design with providers as the unit randomized. Additional 
covariates to be included will be described in the MOP. Model-predicted proportions and confidence 
intervals of opioid prescribing will be summarized by time and study arm jointly. Contrasts will estimate 
differential reduction in the endpoint comparing CDS vs. SP and CDS-e vs. SP. This analysis will be 
conducted on the Intention to Treat Analysis Dataset. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
H2: Providers in the CDS and CDS-E strategy arms will increase their likelihood of satisfying the 
composite endpoint defined by: 1) prescribing or recommending non-opioid analgesics at the extraction 
encounter and 2) not prescribing opioids at the index encounter for patients following extractions more 
than providers in the SP arm. 
 

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Analysis plan: Hypothesis H2 posits that patient encounters at which extractions are performed by 
dental providers in the CDS and CDS-E arms will have a larger increase in the likelihood of receiving a 
prescription or recommendation for non-opioid analgesics and not prescribing opioid s at the index 
encounter than patient encounters in the SP arm when comparing independent samples of patient 
encounters before the implementation to patient encounters following the implementation. The same 
analytic strategy used for the primary endpoint will be used for this secondary endpoint and will be 
conducted on the Intention to Treat Analysis Dataset. 
H3 (alternative): Patients will report higher levels of the extent of shared decision making in the CDS-E 
arm than the CDS or SP arms. 
Analysis plan: Hypothesis H3 posits that patients will report higher levels of the extent of shared 
decision making in the CDS-e arm than CDS or SP arms during the strategies implementation time 
period. A general linear mixed-model regression with an identity link and normal error distribution will 
be used to test the effects of the implementation strategies. The patient-level endpoint is the score on 
the 3-item composite of adapted Collaborate Shared Decision Making, and is considered an interval-
level variable. This endpoint will be predicted by 2 fixed-effects terms for study arm of CDS (CDS vs. SP) 
and CDS-E (CDS-E vs. SP). A random intercept for provider will be included in the model. Additional 
covariates to be included will be described in the MOP. Model-predicted means and confidence intervals 
for the endpoint will be summarized by study arm. A contrast will estimate the difference in the mean of 
the endpoint for patients in the CDS-e arm vs. CDS and SP (pooled). This analysis will be conducted on 
the Intention to Treat Analysis Dataset. 
H4 (descriptive): Compare patient report of mean pain in the week following tooth extraction across the 
3 study arms. 
Analysis plan: This analysis is descriptive, and will comparison across study arms the mean pain rating in 
the 3-6 days since the extraction encounter, self-reported by patients within 6 days of the extraction 
encounter. A general linear mixed-model regression with an identity link and normal error distribution 
will be used to estimate the mean and 95% CI of the pain rating for each study arm. The model will 
include 2 fixed-effects terms for study arm of CDS (CDS vs. SP) and CDS-E (CDS-E vs. SP). A random 
intercept for provider will be included in the model. Additional covariates to be included will be 
described in the MOP. Model-predicted means and confidence intervals for the endpoint will be 
summarized by study arm. This analysis will be conducted on the subset of the Intention to Treat 
Analysis Dataset who complete a patient survey. 
 
 
9.4.4 SAFETY ANALYSES 
 
The study does not include objectives or formal endpoints concerning safety. However, potential harm 
monitoring activities will be conducted as described in section 8.2, and analysis activities conducted as 
described below. 
 
Identify whether the CDS inappropriately fires or inappropriately offers considerations 
The frequency of notifications and content areas (usability, potential safety, or other) will be 
summarized by study arm (CDE or CDS-E) and provider type. 
 
Identify potential adverse events 
 
Frequencies, proportions and 95% confidence intervals on proportions of patients having 
hospitalizations documented in the HealthPartners electronic health record within 72-hours of 
the extraction encounter deemed as adverse events will be summarized by study arm. The 

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patient encounter study population for H1 and H2 for patients seen following the 
implementation of the interventions will be used for this analysis. Events with non-overlapping 
confidence intervals on the proportions by study arm will prompt the study team to assess 
diagnostic codes related to the encounters from the electronic health record. Frequencies and 
proportions of diagnostic codes by study arm will be computed. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
The cluster-randomized design of the trial increases the probability of study arm imbalance on patient 
factors. Baseline patient factors will be summarized and compared across the three study arms using 
descriptive statistics (mean, SD, median, interquartile range, proportion) and confidence intervals. 
Results of statistical tests conducted on patient factors by study arm will not be used to inform covariate 
adjustment. Rather, in a-priori sensitivity analyses the models described in the analysis plan will include 
patient covariates of age, race, and public pay status. 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
There is no interim analysis planned for ending the study due to futility or efficacy. 
 
9.4.7 SUB-GROUP ANALYSES 
 
Not applicable 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Not applicable 
 
9.4.9 EXPLORATORY ANALYSES 
 
Not applicable

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
The following consent materials will be submitted with the IRB application: a phone script describing the 
study intervention, study procedures, and risks are given to the participant for verbal consent (patient 
participant survey call).   
 
Refer to the Schedule of Activities for clarity about timing and study population. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in and 
answer questions as part of the patient survey. Using an IRB-approved script, CESR staff will explain the 
research study to the participant and answer any questions that arise.  A verbal explanation will be 
provided in terms suited to the participant’s comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants will be informed that 
participation is voluntary and that they may withdraw from the study at any time. The rights and welfare 
of the participants will be protected by emphasizing to them that the quality of their medical care will 
not be affected if they decline to participate in this study. 
 
In addition to completion of training in practices of standardized telephone-administered survey 
research, CESR staff are trained in HIPAA and the responsible conduct of research through CITI. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  If the study is prematurely terminated or suspended, the PIs will promptly inform study 
participants, the IRB, and NIDCR and will provide written notification, including the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 

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Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the PIs, IRB and/or NIDCR. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators and their 
staff. This confidentiality is extended to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of the PIs. 
 
All research activities will be conducted in as private a setting as possible. 
 
The Data and Safety Monitoring Board, representatives of HealthPartners IRB, and/or regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants 
in this study. The clinical study site will permit access to such records, as required. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or NIDCR requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at HealthPartners Institute. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites and by HealthPartners research staff will be secured and password protected. At the end of 
the study, all study databases will be de-identified and archived at the HealthPartners Institute. 
 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
NIH.  This certificate protects identifiable research information from forced disclosure. It allows the 
investigator and others who have access to research records to refuse to disclose identifying 
information on research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from 
being compelled to disclose information that would identify research participants, Certificates of 
Confidentiality help achieve the research objectives and promote participation in studies by helping 
assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at HealthPartners Institute. After the study is 
completed, the de-identified, archived data will be transmitted to and stored at HealthPartners 
Institute, for use by other researchers including those outside of the study. 
 
When the study is completed, access to study data will be provided through HealthPartners Institute. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 

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10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise and selected by NIDCR. NIDCR will ensure that members of 
the DSMB are independent from the study conduct and free of conflict of interest, and/or establish 
measures to minimize perceived conflict of interest.  The DSMB will meet at least semiannually to assess 
safety and efficacy data on each arm of the study. The DMSB will operate under the rules of an 
approved charter that will be written and reviewed at the organizational meeting of the DSMB. At this 
time, each data element that the DSMB needs to assess will be clearly defined. The DSMB will provide its 
input to NIDCR.
Principal Investigator 
Principal Investigator 
Medical Monitor 
D. Brad Rindal, DDS 
Senior Investigator 
Shannon Gwin Mitchell, PhD 
Senior Research Scientist 
Kevin McBryde, MD 
HealthPartners Institute 
Friends Research Institute 
NIH, NIDCR  
8170 33rd Avenue South 
Bloomington, MN, 55425 
1040 Park Avenue, Suite 103, 
Baltimore, MD 21201 
 
952-967-5026 
410-837-3977 x238 
 
Donald.B.Rindal@HealthPartners.com smitchell@friendsresearch.org  

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10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, that the 
study is implemented in accordance with the protocol and/or other operating procedures, and that the 
quality and integrity of study data and data collection methods are maintained. Monitoring for this 
study will be performed by NIDCR’s Clinical Research Operations and Management Support (CROMS) 
contractor. The monitor will evaluate study processes and documentation based on NIDCR standards 
and the International Conference on Harmonisation (ICH), E6: Good Clinical Practice guidelines (GCP). 
 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) developed by 
the CROMS contractor, in collaboration with the NIDCR Office of Clinical Trials and Operations 
Management (OCTOM) and the NIDCR Program Official. The CMP will specify the frequency of 
monitoring, monitoring procedures, the level of clinical site monitoring activities (e.g., the percentage of 
subject data to be reviewed), and the distribution of monitoring reports. Some monitoring activities may 
be performed remotely, while others will take place at the study site(s). Staff from the CROMS 
contractor will conduct monitoring activities and provide reports of the findings and associated action 
items in accordance with the details described in the CMP. Documentation of monitoring activities and 
findings will be provided to the site study team, the study PIs, OCTOM, and the NIDCR. The NIDCR 
reserves the right to conduct independent audits as necessary. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The Co-PIs will provide overall oversight to quality assurance and quality control.  Project managers will 
support study staff with communicating any potential quality assurance or control issues to the Co-PIs.  
All Co-investigators will be involved with address scientific issues, including refinement of conceptual 
models, strategies to streamline and deploy the interventions efficiently and effectively, and strategies 
to maximize both recruitment and retention of study subjects, as well as methods to assure uniformity 
and fidelity to intervention protocols and data collection.  Study staff will collaborate to create regular 
reports related to subject accrual and data quality to assess the progress of the clinical study, any 
relevant safety data, and critical efficacy endpoints and provide recommendations to NIDCR. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
EHR records rely on usual care clinical and administrative data. 
All survey data will be reviewed for completeness and entered electronically within the centralized study 
database. Accuracy and completeness of the data is maximized through alerts and pop-ups if the data is 
inconsistent or not entered. 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained until at least 3 years have elapsed since the formal discontinuation 
of clinical development of the study intervention. These documents should be retained for a longer 
period, however, if required by local regulations.

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10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 15 days working days of identification of the protocol deviation, or within 15 days 
working days of the scheduled protocol-required activity.  All deviations must be addressed in study 
source documents, reported to National Institute of Dental and Craniofacial Research Program Official.  
Protocol deviations must be sent to the reviewing IRB per their policies. The site investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. Further details about the 
handling of protocol deviations will be included in the MOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals. 
 
A limited data set from this study may be requested from other researchers following the completion of 
the all analyses and related publications described in this protocol by contacting one of the study PIs.  
The request should include a 1-2 pages summary of the proposed secondary analysis. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The HealthPartners 
IRB, study leadership, and the National Institute of Dental and Craniofacial Research have established 
policies and procedures for all study group members to disclose all conflicts of interest and will establish 
a mechanism for the management of all reported dualities of interest. 

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10.2 ADDITIONAL CONSIDERATIONS 
Not applicable. 
10.3 ABBREVIATIONS 
 
ACE 
Affiliated Covered Entities  
ADL 
Activities of Daily Living 
AEs 
Adverse events / adverse experience 
APAP 
Acetyl-para-aminopheno (aka paracetamol or acetaminophen) 
CDS 
Clinical Decision Support  
CDS-E 
Enhanced Clinical Decision Support  
CESR 
Center for Evaluation and Survey Research 
CFR 
Code of Federal Regulations 
CITI 
Collaborative Institutional Training Initiative 
CMP 
Clinical Monitoring Plan  
CROMS 
Clinical Research Operations and Management Support  
DEA 
Drug Enforcement Administration 
DHHS 
Department of Health and Human Services 
DSMP 
Data and Safety Monitoring Plan 
DTA 
Data Transfer Agreement 
DUA 
Data Use Agreement 
EHR 
Electronic Health Record 
GCP 
Good Clinical Practice 
HCAHPS 
Hospital Consumer Assessment of Healthcare Providers and Systems 
HIPAA 
Health Insurance Portability and Accountability Act  
HPI 
HealthPartners Institute 
ICH 
International Conference on Harmonisation  
ID 
Identifier 
IRB 
Institutional Review Board 
MAR 
Missing at random 
MED 
Morphine Equivalent Dose 
MI 
Multiple imputation 
MOP 
Manual of Procedures  
NIDCR 
National Institute of Dental and Craniofacial Research, NIH, DHHS 
NIH 
National Institutes of Health 
NSAID 
Nonsteroidal anti-inflammatory drug 
OCTOM 
Office of Clinical Trials and Operations Management 
OHRP 
Office for Human Research Protections  
OTC 
Over-the-counter 
PDMP 
Prescription Drug Monitoring Program 
PHI 
Protected Health Information  
PI 
Principal Investigator 
REDCap 
Research Electronic Data Capture 
SAEs 
Serious adverse events 
SDM 
Shared Decision Making 
SoA 
Schedule of Activities 
SP 
Standard Practice 
UPs 
Unanticipated problems  
US 
United States 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
07Mar19 
Accepted all tracked changes in 
protocol development and 
versioned 
 
2.0 
19Dec19 
1.1 Synopsis 
Study population updated to 
reflect targeted recruitment 
numbers 
1.2 Schema 
Aligned the wording with the 
change described above related to 
permanent tooth extractions 
4.1 Overall design 
Study population updated to 
reflect targeted recruitment 
numbers 
8.3.4 Time Period and Frequency 
for Event Assessment and Follow-
Up 
Includes the visit types described 
elsewhere. 
 
Consistency 
5.1. Inclusion criteria 
Changed molars to permanent 
teeth 
Clinical relevance 
8.2 Safety and other assessments 
Expands safety-related data 
collection to more visit types, 
adding emergency department 
visits, observational bed, and 
subsequent opioid prescribing 
Alignment with DSMB 
recommendation 
8.4.2 Unanticipated Problem 
Reporting  
Non-serious UPs reporting will not 
be reported in an expedited 
fashion, so related text deleted. 
Alignment with funder 
requirements 
9.2 Sample size determination 
Sample size determination 
updated to reflect targeted 
recruitment numbers 
Alignment between sample 
size and targeted recruitment 
3.0 
10Mar20 
1.1 Synopsis 
Clarified the study population 
numbers  
4.1 Overall design 
Clarified the study population 
numbers 

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6.1 Study Intervention(s) 
Administration 
Noted the change to access 
the Prescription Drug 
Monitoring Program via the 
electronic health record 
rather than the clinical 
decision support 
6.3 Measures to Minimize Bias 
Clarified the approach taken 
to balance provider factors 
9.2 Sample Size Determination 
Clarified the study population 
numbers 
9.3 Populations for Analyses 
Clarified the study population 
numbers 
4.0 
13Apr20 
6.1.1 Study intervention description 
Timing of change to PDMP access 
changed to align with HealthPartners 
Dental Group planning 
Due to COVID-19, Epic Care 
updates at HealthPartners are on 
hold until further notice. 
 
 
8.3.3.2 Relationship to study 
intervention  
Added specification to the definition 
labels 
Recommended by Rho/NIDCR in 
feedback following Site Initiation 
Teleconference 
 
 
8.3.3.3 Expectedness  
Revised the definition of expectedness 
Recommended by Rho/NIDCR in 
feedback following Site Initiation 
Teleconference 
 
 
8.3.5 Adverse event reporting 
Referenced further specification about 
reporting in separate Data and Safety 
Monitoring Plan 
Consistency across protocol and 
DSMP 
 
 
8.3.6 Serious Adverse Events 
reporting  
Referenced further specification about 
reporting in separate Data and Safety 
Monitoring Plan 
Consistency across protocol and 
DSMP 
5.0 
28July20 
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
Clarified patient survey sampling 
strategy 
DSMB recommendation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Barry MJ, Edgman-Levitan S. Shared decision making--pinnacle of patient-centered care. N Engl J 
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Chapple H, Shah S, Caress AL, Kay EJ. Exploring dental patients' preferred roles in treatment 
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