Hybrid Effectiveness-Implementation Trial of Guided Relaxation and Acupuncture for Chronic Sickle Cell Disease Pain
Phase: PHASE2
Conditions: Sickle Cell Disease
Sponsor: University of Illinois at Chicago

 
 
Hybrid Effectiveness-Implementation Trial of Guided Relaxation and 
Acupuncture for Chronic Sickle Cell Disease Pain 
  
Protocol Number: 2021-0124  
National Clinical Trial (NCT) Identified Number: 04906447 
Contact Principal Investigator*: Dr. Ardith Doorenbos 
Office Telephone: (312) 996-2817 
Email: ardith@uic.edu 
 
Sponsor: University of Illinois Chicago 
Grant Title: Hybrid Effectiveness-Implementation Trial of Guided Relaxation and 
Acupuncture for Chronic Sickle Cell Disease Pain 
 
Grant Number*: UG3 AT011265 
Funded by: NCCIH 
Version Number:  v.11.0 
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NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by 
the recipient that no unpublished information contained herein will be published or disclosed without 
prior approval of the Principal Investigator or other participating study leadership and as consistent with 
the NIH terms of award.  
 

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 2 
1 
PROTOCOL SUMMARY ............................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................ 3 
1.2 
Schema ................................................................................................................................................. 3 
1.3 
Schedule of Activities .......................................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................................ 7 
2.1 
Study Rationale .................................................................................................................................... 7 
2.2 
Background........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................. 13 
2.3.1 
Known Potential Risks ................................................................................................... 13 
2.3.2 
Known Potential Benefits .............................................................................................. 13 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 13 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 13 
4 
STUDY DESIGN ........................................................................................................................................... 14 
4.1 
Overall Design .................................................................................................................................... 14 
4.2 
Scientific Rationale for Study Design.............................................................................................. 16 
4.3 
Justification for Intervention ............................................................................................................. 16 
4.4 
End-of-Study Definition ..................................................................................................................... 17 
5 
STUDY POPULATION ................................................................................................................................ 17 
5.1 
Inclusion Criteria ................................................................................................................................ 17 
5.2 
Exclusion Criteria ............................................................................................................................... 18 
5.3 
Lifestyle Considerations .................................................................................................................... 18 
5.4 
Screen Failures .................................................................................................................................. 18 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 18 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ............................................ 22 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ...................................... 22 
6.1.1 
Study Intervention or Experimental Manipulation Description ................................. 22 
6.1.2 
Administration and/or Dosing ....................................................................................... 22 
6.2 
Fidelity ................................................................................................................................................. 23 
6.2.1 
Interventionist Training and Tracking .......................................................................... 23 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 23 
6.4 
Study Intervention/Experimental Manipulation Adherence.......................................................... 24 
6.5 
Concomitant Therapy ........................................................................................................................ 24 
6.5.1 
Rescue Therapy ............................................................................................................. 25 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................................... 25 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................. 25 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 26 
7.3 
Lost to Follow-Up ............................................................................................................................... 26 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 27 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 27 
8.2 
Safety Assessments .......................................................................................................................... 28 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 28 
8.3.1 
Definition of Adverse Events ........................................................................................ 28 
8.3.2 
Definition of Serious Adverse Events .......................................................................... 28 

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8.3.3 
Classification of an Adverse Event .............................................................................. 28 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 29 
8.3.5 
Adverse Event Reporting .............................................................................................. 30 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 30 
8.3.7 
Reporting Events to Participants ................................................................................. 30 
8.3.8 
Events of Special Interest ............................................................................................. 30 
8.3.9 
Reporting of Pregnancy ................................................................................................ 30 
8.4 
Unanticipated Problems .................................................................................................................... 30 
8.4.1 
Definition of Unanticipated Problems .......................................................................... 30 
8.4.2 
Unanticipated Problems Reporting .............................................................................. 31 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 31 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 32 
9.1 
Statistical Hypotheses ....................................................................................................................... 32 
9.2 
Sample Size Determination .............................................................................................................. 32 
9.3 
Populations for Analyses .................................................................................................................. 34 
9.4 
Statistical Analyses............................................................................................................................ 34 
9.4.1 
General Approach .......................................................................................................... 34 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 35 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 35 
9.4.4 
Safety Analyses .............................................................................................................. 35 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 35 
9.4.6 
Planned Interim Analyses ............................................................................................. 36 
9.4.7 
Sub-Group Analyses ..................................................................................................... 36 
9.4.8 
Tabulation of Individual Participant Data .................................................................... 36 
9.4.9 
Exploratory Analyses ..................................................................................................... 36 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 37 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 37 
10.1.1 
Informed Consent Process ........................................................................................... 37 
10.1.2 
Study Discontinuation and Closure ............................................................................. 37 
10.1.3 
Confidentiality and Privacy ........................................................................................... 38 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 39 
10.1.5 
Key Roles and Study Governance .............................................................................. 39 
10.1.6 
Safety Oversight ............................................................................................................. 39 
10.1.7 
Clinical Monitoring .......................................................................................................... 40 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 40 
10.1.9 
Data Handling and Record Keeping ............................................................................ 41 
10.1.10 
Protocol Deviations ........................................................................................................ 41 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 42 
10.1.12 
Conflict of Interest Policy .............................................................................................. 43 
10.2 
Additional Considerations ................................................................................................................. 43 
10.3 
Abbreviations and Special Terms ................................................................................................... 43 
10.4 
Protocol Amendment History ........................................................................................................... 45 
11 
REFERENCES ............................................................................................................................................. 47 
 

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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) and the following:  
 
• 
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).  
 
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 IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. 
All changes to the consent form(s) 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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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this study 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, as described in the Statement of Compliance above. 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name*:  Ardith Z. Doorenbos 
 
Title*: Professor 
Investigator Contact Information 
Affiliation*: College of Nursing, UIC 
Address: 845 S Damen Ave 
Office Telephone: 1-(312) 996-2817 
Email: ardith@uic.edu 
Duke University Site Investigator:  
Signed: 
 
Date: 
 
 
Name:  
 
Title: 
 
 
Affiliation: 
University of Florida Site Investigator:  
Signed: 
 
Date: 
 
 
Name:  
 
Title: 
 
 
Affiliation: 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Hybrid Effectiveness-Implementation Trial of Guided Relaxation and 
Acupuncture for Chronic Sickle Cell Disease Pain 
Grant Number: 
UG3 AT011265 
Study Description: 
This pragmatic randomized clinical trial will explore the effectiveness of 
two complimentary integrative therapies, acupuncture and guided 
relaxation, for helping reduce chronic pain in individuals living with 
sickle cell disease. As a pragmatic trial, this study will also assess the 
implementation barriers and facilitators of including these interventions 
in real world healthcare settings.  
Objectives*: 
 
Primary Objective: Determine if each intervention reduces pain impact 
compared to usual care based on Pain Impact Scores 
Secondary Objectives: Determine the impact of each intervention on 
all other patient reported outcomes, including opioid use, anxiety, 
depression, sleep, quality of life, pain catastrophizing, pain self-efficacy, 
patient activation, as well as measuring patient experience with the 
interventions. 
Endpoints*: 
Primary Endpoint: Change in pain impact score and PEG 
Secondary Endpoints: Opioid Use, Anxiety, Depression, Sleep, Pain 
catastrophizing, Global impression of change, Substance use, and 
Constipation 
Study Population: 
366 people, aged 18 and up, living with chronic pain resulting from 
Sickle Cell Disease 
Phase* or Stage: 
Phase 2  
Description of 
Sites/Facilities Enrolling 
Participants: 
 
The study sits will include 3 university hospital systems in the US, 
University of Illinois Hospital & Health Sciences System, Duke 
University Health System and University of Florida Health.   
Description of Study 
Intervention/Experimental 
Manipulation: 
The study interventions are acupuncture and guided relaxation. 
Participants randomized to the acupuncture group will receive 
treatments on-site twice a week for 10 sessions for 30 minutes per 
session, and the guided relaxation group will use a web-based app 
remotely on a daily basis with sessions ranging from 2 to 20 minutes 
each.  
Study Duration*: 
41 months 
Participant Duration: 
24 Weeks 
1.2 
SCHEMA  
 
 
 

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Flow Diagram Pragmatic Randomized Clinical Trial 
 
 
 
 

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1.3 
SCHEDULE OF ACTIVITIES  
 
Construct 
Operational Measure 
Time Point 
 
 
 
 
Pre-screen Baseline 
 
Day 1 
Week 6 
(mid-point) 
Day 42 ±7 days 
 
Week 12 
(intervention 
end) 
Day 84 ±7 days 
 
Week 24 
(follow-up) 
Day 168 ±7 
days 
 
Source 
EHR for screening 
 
 
 
 
 
 
 
Informed Consent  
 
 
 
 
 
 
 
PRIMARY OUTCOME (PAIN) 
Pain impact score A composite measure of PEG average 
pain intensity, pain interference 4a, and 
function 6b 
 
 
 
 
 
SRS 
 
SECONDARY OUTCOMES (MENTAL AND PHYSICAL WELL-BEING AND SATISFACTION WITH CARE) 
PEG 
0-10 rating on pain intensity, enjoyment 
of life and general activity  
 
 
 
 
 
SRS 
Opioid use, 
morphine 
milligram 
equivalent 
(MME) 
Based on participant report of # opioid 
pills per day using Timeline Followback 
method with a 14-day look-back period 
(pill number will be converted to 
MME/day)  
 
 
 
 
 
SRS 
Opioid MME 
change 
(continuous) 
Change from baseline to 12 and 24 
weeks 
 
 
 
 
 
Calculated 
Opioid MME 
change 
(categorical) 
Movement from high (> 90 MME), to 
medium (90–50 MME), to low (< 50 
MME), to off opioids 
 
 
 
 
 
Calculated 

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Anxiety 
GAD–7  
 
 
 
 
 
SRS 
Depression 
PHQ-9 
 
 
 
 
 
SRS 
Sleep  
PROMIS sleep disturbance 8a and sleep 
duration question 
 
 
 
 
 
SRS 
Pain 
catastrophizing  
Pain Catastrophizing Scale (PCS)  
 
 
 
 
 
SRS 
Global impression 
of change 
PGIC 
 
 
 
 
 
SRS 
Substance use 
screener 
TAPS1 
 
 
 
 
 
SRS 
Constipation 
PROMIS GI Constipation 9a 
 
 
 
 
 
SRS 
 
OTHER MEASURES 
Clinical data 
Hospitalizations and length of stay 
 
 
 
 
 
SRS, 
confirm 
with EHR 
Demographic 
data 
Age, sex, race, employment status, 
comorbidities, marital status, number of 
household members, annual income, 
educational attainment 
 
 
 
 
 
SRS 
Other 
Use of non-study behavioral or other 
non-pharmacologic treatment for pain 
 
 
 
 
 
SRS 
Implementation 
Survey 
 
 
 
 
(Intervention 
arms only) 
 
SRS 
Randomization 
 
 
 
 
 
 
 
See specific intervention tables for schedules of events 

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ACUPUNCTURE 
INTERVENTION 
First 
randomization 
Second 
randomization 
Session 1 
Day 3±1 
Day 43±1 
Session 2 
Day 7±1 
Day 47±1 
Session 3 
Day 10±1 
Day 50±1 
Session 4 
Day 14±1 
Day 64±1 
Session 5 
Day 17±1 
Day 67±1 
Session 6 
Day 21±1 
Day 71±1 
Session 7 
Day 24±1 
Day 74±1 
Session 8 
Day 27±1 
Day 77±1 
Session 9 
Day 31±1 
Day 81±1 
Session 10 
Day 34±1 
Day 84±1 
 
GUIDED 
RELAXATION 
INTERVENTION 
First 
randomization 
Second 
randomization 
Intro video 
Day 2 
Day 43 
Pre-video stress 
and pain 
tracking 
Day 3-42 
Day 44-83 
Video session 
Day 3-42 
Day 44-83 
Post-video 
stress and pain 
tracking 
Day 3-42 
Day 44-83 
 
QUALITATIVE 
INTERVIEWS 
First focus group 
Second focus group 
Third focus group 
Final focus group 
Hospital Staff 
6 months after study 
initiation 
12 months after study 
initiation 
18 months after study 
initiation 
24 months after study 
initiation 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Nearly 100 people die every day from a prescription opioid overdose in the United States (US). Over-
reliance on opioids for those with chronic pain is one of the factors that led to this crisis. Pain, both 
acute and chronic, that is so severe that it requires opioids to attempt to keep it to tolerable levels, is a 
constant companion to the 100,000 people in the United States, mostly of African and Hispanic 
background, and millions more worldwide living with sickle cell disease (SCD). Pain is SCD’s hallmark 
symptom and is the leading cause for almost 200,000 annual emergency department (ED) admissions 
and most hospitalizations, with estimated annual health care costs in the US of $2.4 billion. We will 
conduct a hybrid type 1 effectiveness implementation trial to assess the effectiveness of acupuncture 

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and guided relaxation on 366 people with SCD while observing and gathering information on 
implementation in three health systems: University of Illinois Hospital & Health Sciences System, 
University of Florida Health, and Duke University Health Systems. Each serves a large population with 
SCD, uses EPIC as their electronic health record, and has a Clinical and Translational Science Award 
(CTSA), which will help speed the translation of discovery into improved patient care. UG3 1-year 
Planning Phase: Year 1 comprises milestone-driven planning to prepare the three health systems for the 
subsequent pragmatic clinical trial (UH3). During the UH3 Implementation Phase, our 3-arm, 3-site 
randomized controlled trial will follow a quantitative Sequential, Multiple Assignment, Randomized 
Trials (SMART) design, a pragmatic trial that evaluates adaptive interventions where our guided 
relaxation and acupuncture interventions responds to patients’ characteristics and evolving pain status. 
We rely on the Consolidated Framework for Implementation Research (CFIR) to plan, execute, and 
evaluate associated implementation processes. The use of complementary and integrative (CIH) 
therapies by those with SCD to reduce pain, opioid use, and enable themselves to better cope with their 
pain is well known, but there are few studies that evaluate the effectiveness of these therapies, and 
none that also evaluates the implementation across multiple health care systems and patient 
populations as this study will. 
2.2 
BACKGROUND  
Chronic pain and the opioid epidemic are recognized as public health crises with chronic pain affecting 
11% of adults in the US. In 2016 chronic pain was estimated to have an annual cost of $635 billion.1 
While chronic pain is frequently treated with opioid medication, long-term opioid therapy is of 
questionable benefit for it.2,3 Unfortunately, the dramatic increase in opioid prescribing for chronic pain 
has not been associated with measurable decreases in the prevalence of chronic pain or pain-related 
disability. Since 1999, overdose deaths involving prescription opioids have risen along with total opioid-
related deaths.4,5 In 2017, the U.S. Department of Health and Human Services declared the opioid 
epidemic a public health emergency and outlined 5 key strategic priorities, including supporting 
research on pain and addiction and advancing better practices for pain management.6 In light of the 
generally unfavorable risk-benefit profile of long-term opioid therapy, consensus guidelines promote 
increasing pain self-management strategies and non-opioid pain care.7,8 There is now urgent need to 
evaluate novel treatment interventions.  
Potential Harms from Long-Term Opioid Therapy   
While we are acutely aware of the dangers of opioid therapy for pain, including the lack of significant 
improvement in pain, the potential for addiction, overdose, death, and multiple other side effects also 
can occur, and may be dose limiting. These include opioid induced hyperalgesia,9 tolerance, 
hypogonadism, infection,10 osteoporosis, falls, fractures, motor vehicle accidents, opioid use disorder, 
intermittent withdrawal symptoms,11 glycemic control in diabetics,12 cognitive dysfunction,13 
somnolence and sleep disordered breathing,14 to name just some. Critically, many of these occur with 
other medical conditions that are increase in prevalence, as is pain, increasing the possibility of additive 
or more effect. Clearly effective opioid sparing therapies are need.  
Sickle Cell Disease and Pain Management   
The term SCD refers to several hemoglobin disorders that have in common a mutation in the -
hemoglobin chain. It is the most common lethal genetic blood disorder in the world. In the US, 
approximately 100,000 people, mainly of African and Hispanic background have it, but there are millions 
with it worldwide.15 Pain is a constant companion for those with SCD. They are so intertwined, that 

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ancient African tribal words are onomatopoeic for it.16 Pain is the most common admitting diagnosis to 
both the Emergency Department (ED), as well as to the hospital. In 2009, the annual medical care costs 
for SCD in the US were estimated at $2.4 billion.17 For many years, SCD disease pain was thought to be 
only acute; it has now become increasingly clear that adults with SCD also experience chronic pain,18,19 in 
addition to acute worsening of their pain. Pain in sickle cell disease is a complex process and is often 
associated with anxiety. In order to attempt to keep their chronic pain to acceptable levels, those with 
SCD require opioid therapy. One study reported that in a sample of 219 adult patients with SCD during 
the study period, 78% of the patients used opioids. These included both long acting with or without 
short acting opioid (38.8%), as well as 47% used only short-acting opioids. Only about 10% used only 
non-opioid analgesics, and about 5% used no analgesics.20 In another study of adults with SCD, 85% 
were taking step 2 opioids, and 65% were taking step 3. This study also reported pain barrier scores 
similar to or greater than those reported by people with cancer.19The evaluation of alternative therapies 
that reduce chronic pain and the need for opioid medication among individuals with SCD, and to enable 
patients to better cope with pain, is critically needed to address the lack of adequate pain control, high 
opioid use, and their negative sequelae.  
Safe and Effective Complementary and Integrative Health (CIH) Therapies and Pain Management   
The National Pain Strategy has called for a cultural shift in how chronic pain is managed.21 The use of 
complementary and integrative health (CIH) therapies is widespread in the US, with a significant 
increase in its use for common chronic conditions over a 7-year time span.22 The last updated National 
Health Interview Survey (2008) reported that 38% of Americans use some type of CIH therapy.23 The 
research literature also indicates that there is use of CIH among SCD patients.24 
Due to the chronicity of pain in SCD and concerns with opioid therapy, patients and families with SCD 
often attempt to control pain and other symptoms with traditional medicine or CIH therapies.25 Studies 
have reported that 89% to 92% of patients with SCD use CIH therapies or cognitive behavioral therapy to 
control pain, with use higher among females, singles, and patients with more education and higher 
household income.26 Prayer and meditation, relaxation techniques, massage, herbal products, heat 
application, and alternative medical systems are the leading therapies used by people with SCD, 
followed by warm baths, exercise, and mind-body interventions.26–28 Since many SCD patients try using 2 
or more therapies, there is also a need to rigorously test the effects of adding another therapy when the 
first does not produce the desired outcomes in a given period of time. This study will assess the 
outcomes of sequencing 2 evidence-based CIH therapies among SCD patients treated in real-world 
health care systems.  
Selection of Therapies 
The National Center for Complementary and Integrative Health29 identified 5 areas for investigation: 
mind-body therapies; body-based therapies; biologically based therapies; energy therapies; and 
alternative medical systems. For this study, we selected one body-based therapy (acupuncture) and one 
mind-body therapy (guided relaxation), because these 2 therapy groups are the most widely used by 
patients,30 and there is evidence that the therapies are safe and effective for reducing pain.   
Acupuncture 
Acupuncture use is on the rise in the United States. In 2012 (last updated), Americans received 
3,484,000 acupuncture sessions, which was a significant increase from the years 2002 to 2007.31 There is 
also evidence of its efficacy for pain conditions. American men and women frequently seek acupuncture 

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for pain whether or not they tell their physicians; almost 8% of those using CIH do not tell their 
physicians.32 Acupuncture has demonstrated physiologic analgesic effects. It has been shown to help 
relieve pain by (1) deactivating the limbic-paralimbic-neocortical network system;33 (2) activating mu 
opioid receptors;34 (3) increasing serum β endorphins;35 (4) down-regulating M1 macrophages, 
interleukin-1β, interleukin-6, interleukin-18, and tumor necrosis factor;36 and (5) regulating central and 
peripheral blood flow.37  
Rationale for acupuncture to address pain 
A meta-analysis of 39 high-quality randomized trials of acupuncture examined 20,827 patients for the 
treatment of 4 chronic pain conditions: nonspecific musculoskeletal pain, osteoarthritis, chronic 
headache, and shoulder pain. Study designs included acupuncture needling versus either sham 
acupuncture or no acupuncture as a control. Results indicated that acupuncture was superior over sham 
acupuncture or usual care for reduction of pain in all 4 pain conditions (all p < .001).38 A second meta-
analysis examined duration of the acupuncture treatment effect.39 Long-term follow-up data was 
analyzed for 20 of the aforementioned trials with 6,376 patients.39 In trials comparing acupuncture to no 
acupuncture, effect sizes were reduced by a nonsignificant 0.011 SD per 3 months post acupuncture 
completion (95% CI, -0.014 to 0.037, p = 0.4). In trials comparing acupuncture to sham acupuncture, 
effect sizes were reduced 0.025 SD per 3 months post acupuncture completion (95% CI, 0.000–0.050, p 
= 0.050). The central estimate suggested that approximately 90% of the acupuncture effect as compared 
to usual care and approximately 50% of the acupuncture effect versus sham acupuncture would be 
sustained at 12 months post acupuncture completion. A third 2019 systematic review and meta-analysis 
examined acupuncture and/or acupressure for reducing cancer pain.40 Seventeen randomized controlled 
trials (RCTs) of 1,111 patients for the systematic review and 14 RCTs of 920 patients for the meta-
analysis compared acupuncture to sham control, analgesic therapy, and usual care for reducing cancer 
pain. The primary outcome was pain intensity as measured by the Brief Pain Inventory (BPI), a numerical 
rating scale, a visual analog scale, or a verbal rating scale. In 7 sham controlled RCTs, verum (traditional) 
acupuncture as compared to sham acupuncture was found to be associated with reduced pain intensity 
(mean difference [MD], −1.38 points, 95% CI, −2.13 to −0.64 points, I2 = 81%).  
Acupuncture and/or acupressure were combined with analgesic therapy for reducing pain intensity in 6 
RCTs (MD, −1.44 points; 95%CI, −1.98 to −0.89; I2 = 92%) and for reducing opioid dose in 2 RCTs (MD, 
−30.00mg morphine equivalent daily dose; 95%CI, −37.5mg to −22.5mg). These 3 large meta-analyses 
examining acupuncture for the treatment of 4 chronic pain conditions establish the effectiveness of 
acupuncture for the treatment of other chronic pain conditions including SCD. In summary, acupuncture 
treats a wide range of pain conditions within the body therapy category and was selected because it (1) 
has been a highly utilized CIH therapy and (2) is effective in reducing pain.  
Acupuncture for the treatment of SCD 
There have been 5 studies of acupuncture for the treatment of SCD. Three were pediatric studies: a case 
study,41 a study of 2 patients,42 and a retrospective uncontrolled trial of 12 patients.43 Two additional 
studies examined the use of acupuncture for the treatment of adults with SCD. One study, which was an 
uncontrolled retrospective review, treated a total of 24 inpatient and outpatient adults during acute 
vaso-occlusive crisis with individualized acupuncture point prescriptions.44 In this study, 9 inpatients 
received a median of 3 treatments and had a reduction in pain of 2.1 on a 0–10 pain rating scale, and 15 
outpatients received a median of 4 treatments and had up to a 75% reduction in pain. Another 
uncontrolled study treated 10 adults with a total of 16 acute vaso-occlusive crises; participants reported 
a decrease in pain in 15 of 16 acute vaso-occlusive crises.45 All studies reported pain reduction, and 

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several examined the implementation effect of acupuncture for the treatment of SCD.44–46 In summary, 
acupuncture is a significant body-based therapy selection because it: (1) is low risk; (2) does not 
interfere with any other treatment the patient is receiving; and (3) is proven popular, acceptable, and 
effective. 
Guided Relaxation 
Mind-body therapies such as guided relaxation use the mind to reduce pain, promote well-being, and 
improve physical function. Guided relaxation is a state of concentration and focused attention that gives 
people more control over their pain experience and its impact and an increased sense of well-being.47  
Rationale for guided relaxation to address pain 
Systematic reviews and meta-analyses reviewing over 48 RCTs have demonstrated that guided 
relaxation reduces chronic pain,48–50 as well as reducing acute pain following surgical procedures.48 
Guided relaxation has also been shown to help with sleep,51 anxiety,52 and reduce cardiac events.53 
Guided relaxation that is delivered via web app can be provided in any location at any time, so it is less 
costly and more convenient than delivery by an experienced clinician. In a systematic study of eHealth 
interventions for SCD published in 2018, the authors found studies that evaluated guided relaxation as a 
stand-alone therapy showed intervention participants had lower current anxiety and pain scores and 
continued reductions in pain at follow up.54 
Guided relaxation for treatment of SCD 
Our previous studies have demonstrated that guided relaxation is an effective CIH therapy for reducing 
pain.55 The goals for the first feasibility study were to determine (1) acceptability, (2) frequency and 
issues related to tablet use, (3) data completion rates, and (4) attrition rate. The study also explored the 
potential efficacy of the intervention on pain, among people with SCD ≥18 years old with a moderate to 
severe level of pain (>3 on a 0–10 scale). Participants were stratified by worst pain intensity and 
randomly assigned to either control or guided relaxation. The tablet-based guided relaxation 
intervention included a 12-minute guided relaxation video that was administered at baseline, plus 6 
additional video clips ranging from 2 to 20 minutes. All video clips had similar content. Participants were 
asked to watch any of the video clips at least once daily. Of the eligible patients who were approached, 
59% agreed to be part of the study, and of these, 96% completed the study. Participants receiving the 
guided relaxation intervention, 72% (n = 20) used the tablet daily during the 2-week intervention period. 
The guided relaxation lowered current pain [mean = -1.8, 95% CI (−3.3, −0.4)] at immediate posttest. 
Guided relaxation also demonstrated short-term effects (Day 14) where the intervention group had 
lower chronic pain scores [mean = -9.0, 95% CI (−17.9, −0.4)] than the control group.56 Further, we 
evaluated the proportion of patients who reported a clinically significant reduction in pain, defined as a 
2-point reduction on a 0–10 scale, and found that 36% of intervention and 17% of control group patients 
had a clinically significant reduction in pain over a 2-week period. In a confirmatory study conducted in 
different geographic region using the same guided relaxation protocol, we found that in immediate 
posttest, guided relaxation exercises significantly reduced current pain by 1.1 on a scale of 0–10 in the 
intervention group compared to the attention control group.55 At the 2-week posttest, the guided 
relaxation group had significantly lowered composite pain index scores. These findings demonstrate the 
feasibility of implementing a guided relaxation intervention among adults with SCD experiencing pain 
and indicate that a tablet-based guided relaxation intervention is effective in reducing pain. In summary, 
guided relaxation represents a wide range of options within the mind-body therapy category and was 

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selected because it (1) has been a highly utilized CIH therapy, (2) has been shown to reduce pain, and (3) 
can be economically delivered and is feasible for adults with SCD to use on their own.  
Rationale for Sequencing of the 2 Therapies  
Our past work has demonstrated significant improvement in pain from both acupuncture and guided 
relaxation. While there are likely several contributing physiological mechanisms involved, the benefits 
derived from acupuncture as a direct body therapy are primarily physically mediated, whereas the 
effects derived from guided relaxation are cognitively mediated. In this study we will test one strategy, 
and if it is inadequate, randomize to continue with that therapy or switch to the other therapy, 
recognizing that benefits may be cumulative alone or by targeting another pathway and be synergistic to 
the sought benefits. Given potential beneficial systemic effects, the benefits of acupuncture and guided 
relaxation are not limited to immediate results and may be cumulative over time. The use of 2 therapies 
that reduce pain via different pathways optimizes the potential for therapeutic benefit. In addition, 
some people may prefer a mind-body strategy over direct physical contact, and the optimal intervention 
choice and sequencing may need to account for individual differences. A critical step to determine how 
to integrate these therapies into evidence-based practice is to complete a pragmatic clinical trial. This 
trial can inform clinicians, patients, administrators, and policymakers about integrating guided 
relaxation and acupuncture into real-life clinical settings to increase access to non-opioid treatments, 
decrease opioid need, and improve health outcomes. 
Implementation Science Using the Consolidated Framework for Implementation Research (CFIR)  
The development of our implementation protocol (UG3) and its execution and evaluation (UH3) 
combine our team’s clinical and research experience to advance implementation science by identifying 
barriers to and facilitators that affect the integration of effective CIH therapies into health systems 
under real-world conditions. Our study relies on the Consolidated Framework for Implementation 
Research (CFIR) to inform implementation across the 5 years of the UG3/UH3: planning, execution, and 
evaluation. This is a novel approach that goes beyond examining effectiveness to also document what 
affects implementation in 3 different health care systems.57,58  
We will use CFIR tools, such as interview guides and outcome metrics to guide implementation and 
increase the potential for scalability from launch to execution and evaluation. The CFIR is a conceptual 
framework developed to guide multilevel assessment of factors that may influence an intervention’s 
implementation and effectiveness. The core CFIR domains are (1) intervention characteristics; (2) inner 
setting (i.e., implementing organization); (3) outer setting (i.e., external environment); (4) individual 
characteristics (i.e., knowledge and beliefs of the individuals involved in the implementation); and (5) 
process (i.e., strategies and tactics used in the implementation). Within each domain, specific constructs 
may influence implementation. The final product of the UG3 milestones is a flexible and evidence-based 
implementation blueprint prototype that will guide and support each health system’s capacity to 
implement the intervention.59,60 Technical assistance and support by the research team will gradually 
decrease as each health care system builds capacity to sustain these therapies at the local level. Our 
blueprint can then be used by others to integrate these and other evidence-based CIH therapies into 
health care systems. This study is the first to assess these interventions in 3 hospital systems among SCD 
patients with chronic pain. We will analyze key implementation facilitators and challenges and link these 
to effectiveness. This work will result in an evidence-based set of recommendations to guide future 
implementation across different health care settings, with the long-term goal of establishing CIH 
therapies as part of the standard of care.   

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2.3 
RISK/BENEFIT ASSESSMENT  
 
2.3.1 KNOWN POTENTIAL RISKS  
 
These are low risk interventions, but as with all research, there are potential risks.  
• 
Emotional Distress. During the study, participants will be asked to answer questions about 
sensitive topics that may be upsetting.  
• 
Acupuncture. The risks from acupuncture needle insertions include soreness, minor 
bleeding, bruising after acupuncture needle removal, and fatigue after acupuncture.  
• 
Loss of confidentiality.  
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
There are no guaranteed benefits for being in the research study; however, it is possible that 
participants will experience a reduction in pain as part of this study.  
Participation in this research study may also contribute to the development of treatments for chronic 
pain management in sickle cell disease patients and may benefit the future health of the community at 
large. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Emotional distress. The research team will help in identifying additional care, if needed. It will also be 
emphasized that they have to right to withdraw from the study at any point in time without any 
negative impact on their healthcare or relationship with the hospital system.  
 
Acupuncture. Participants will be encouraged to rest if necessary and will be provided with a light snack 
or juice following the acupuncture session.  
 
Loss of confidentiality will be mitigated through methods outlined through the protocol, including 
hosting the survey data on REDCap, an encrypted server, storing physical files in a locked cabinet and 
locked office at each site, among others outlined in Section 10.1.3.  
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
Test effectiveness of 2 non-
pharmacological 
interventions (Guided 
Relaxation and Acupuncture) 
Pain impact at 6 weeks is the 
primary endpoint. 
 
Secondary outcomes include 
opioid use, PEG, sleep, 
Both guided relaxation and 
acupuncture have shown positive 
changes in pain impact at 6 weeks 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
compared to usual care for 
treatment of sickle cell pain 
 
anxiety, depressive symptoms, 
and pain catastrophizing 
 
Secondary 
 
 
Identify the best sequence of 
interventions over a 12 week 
interval, allowing for 
adaptation for participants 
not showing adequate 
response. 
Same primary and secondary 
outcomes measured at 12 
weeks. 
 
Pain impact will determine the 
effectiveness of intervention 
sequences.  Secondary outcomes 
may show improvements, possibly 
as sequelae related to pain relief.  
Treatment sequence, i.e., initial 
treatment and second line 
treatment if poor response, will 
comprise 4 options (see design) and 
usual care, will be the independent 
variable of interest. 12 weeks is the 
amount of time needed to complete 
two treatment sequences.  
Tertiary/Exploratory  
 
 
Explore characteristics to 
understand differential 
treatment response. 
Pain Impact is the primary 
endpoint 
Moderators of treatment response 
will be explored from among age, 
sex, and initial treatment 
assignment 
Patient CIH Therapy 
Experience 
Following completion of the 
24 week follow up, patient 
participants from either of the 
intervention arms will be 
interviewed to gain feedback 
on barriers and facilitators 
These qualitative data will be used 
to better inform how these 
therapies might be successfully 
introduced in hospital settings   
 
4 
STUDY DESIGN 
 
4.1 
OVERALL DESIGN 
 
This Phase 2 pragmatic trial is for the purpose of determining the effectiveness of CIH therapies to 
reduce pain in SCD patients. Following Baseline data collection (see above table for an outline of all 
measures), participants will be randomized into one of three arms: usual care, acupuncture or 
guided relaxation (see Section 4.3 for a fuller description of these interventions). At 6 weeks, 
participants complete the midpoint assessment. Utilizing a SMART design (discussed in more detail 
in Section 4.2), we will be able to test for the most effective sequence of intervention, as 
participants in either of the intervention arms who are not showing improvement in pain scores will 
be re-randomized to either continue with the CIH therapy they were initially assigned or to switch to 
the other intervention. At 12 weeks, all participants will complete another assessment (see above 
for all measures collected at this time point).  A final assessment will occur at 24 weeks. Each of the 

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follow up assessments (6 weeks, 12 weeks and 24 weeks) will occur online through REDCap. As the 
study continues, we anticipate having the ability to capture patient-reported outcomes in EPIC.  
 
Aim 1: Determine the effectiveness of guided relaxation and acupuncture as compared to usual care 
in decreasing pain and opioid use for SCD patients. Hypothesis: At 6 weeks, SCD patients 
randomized to either CIH intervention will have a greater decrease in pain, opioid use, sleep, 
anxiety, depressive symptoms, and pain catastrophizing compared to SCD patients randomized to 
usual care.  
Aim 2: Identify the best adaptive intervention for improved outcomes by documenting outcomes 
among adaptive intervention sequences: (1) initiate guided relaxation and switch to acupuncture for 
non-responders at midpoint; (2) initiate guided relaxation and continue with guided relaxation for 
non-responders at midpoint; (3) initiate acupuncture and switch to guided relaxation for non-
responders at midpoint or (4) initiate acupuncture and continue with acupuncture for non-
responders at midpoint.  
Aim 3: Explore differences in response to the adaptive interventions by age and sex.  
Aim 4: Identify implementation facilitators, challenges, and solutions for structures and processes 
that contribute to the seamless integration of CIH therapies into the 3 health systems by conducting 
individual interviews with participants in the intervention group who responded to the intervention 
and those who did not. We will also conduct focus groups with hospital personnel at 4 timepoints. 
 
Randomization 
We will use the REDCap randomization module to manage randomizations within site, stratified 
on PROMIS pain interference and opioid use. The study statistician will create the allocation 
schedule for each site using permuted blocks of six within each stratum. Staff can randomize 
participants by entering the answers to stratification questions and pushing a button. This 
approach conceals the upcoming treatment arm assignments from staff, and the study 
statistician will remain blinded to the meaning of treatment arm indicators within the REDCap 
data management system. We will randomize one-third of participants to the usual care arm 
and one-third of participants to each intervention arm. If randomization is warranted due to non-
response at week 6, a re-randomization form is completed in REDCap. 
 
Planned Interim Analysis 
Use of the SMART design provides an interim measure of study outcome.  We will summarize the 
number of participants requiring an additional six weeks of intervention due to non-response.  
Other planned analyses will include enrollment progress, adherence and protocol deviations, and 
a summary of adverse events.  
 
To assess implementation barriers and facilitators (Aim 4), 2 non-responder patient participants and 
2 responder patient participants at each site will be interviewed about their experiences with CIH 
therapies, and focus groups involving hospital personnel will occur every 6 months after initiation of 
the trial to determine if issues have come up and how they were resolved. In addition, all 
participants will complete an implementation survey assessing technology ownership, use, and 
acumen as well as previous exposure to acupuncture/guided relaxation, and insurance status.  The 
survey will be administered through REDCap at Baseline for all participants, and at the 12-week 
timepoint for those participants in either intervention arm. 
 

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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Pragmatic trials are designed to maximize external validity to determine effectiveness of interventions 
in real-world settings while also providing information about the generalizability of an intervention 
within the context of routine practice. Pragmatic trials and implementation research designs are useful 
for testing flexible and broadly applicable evidence-based interventions across multiple settings and 
within diverse populations. In keeping with the intent of this HEAL initiative: Pragmatic and 
Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM), we are 
determining the effectiveness of two CIH therapies, guided relaxation and acupuncture to improve outs 
of adults with SCD. The PRECIS 2 was used to guide the design of the proposed research, which 
measures the relationship of the intervention, setting, and study design with the health care systems 
where the intervention will be delivered. 
 
This study uses a hybrid type 1 effectiveness-implementation research design. The RCT will follow a 
quantitative SMART design, to which we will add a qualitative implementation research component. 
SMART design results in pragmatic trials that evaluate adaptive interventions where the selection of 
interventions responds to the patient’s characteristics and evolving clinical status. Using this design, the 
study team will make the following determinations: 
(1) the relative effectiveness of guided relaxation and acupuncture;  
(2) the subgroups of patients who do and do not respond to each Stage 1 intervention;  
(3) the most effective intervention sequences; and  
(4) methods for identifying moderators to operationalize the choice of which intervention to apply at 
each stage for each individual. 
 
The primary objectives of the trial are (a) to compare guided relaxation with usual care and (b) to 
compare acupuncture with usual care, rather than to compare guided relaxation to acupuncture. This is 
our rationale for choosing, as the primary objective, to determine whether either intervention has 
benefit rather than comparing the effectiveness of the 2 interventions: 
(1) There is strong evidence for the effects of each intervention, but it is not yet known whether either 
intervention can be implemented in the context of SCD clinical care. 
(2) Outside of the trial setting, the infrastructure and/or personnel required for implementing each 
intervention differ and may not be uniformly available. Thus, knowing whether each intervention is 
effective will allow post-trial implementation to be based on available resources. 
(3) Outside of the trial setting, the uptake of the interventions may depend on patient preferences. 
Thus, knowing if an intervention has benefit may be more important than knowing if it is more effective 
than an alternative that might not be as appealing to an individual patient. 
 
If the effectiveness of guided relaxation and acupuncture is confirmed in this pragmatic trial, then our 
findings could change practice for treating adults with SCD by reducing prescription of drugs, including 
opioid, in favor of referral for CIH interventions like guided relaxation and acupuncture with far fewer 
adverse effects. 
4.3 
JUSTIFICATION FOR INTERVENTION 
Acupuncture intervention.  
In Traditional Chinese Medicine, qi is the vital energy flowing within and surrounding the body. The 
channels through which qi and blood flow in the body are called meridians. Disorders of qi and disorders 
of blood, whether deficiency or excess (stagnation or obstruction), can result in pain. Acupuncture 

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needles are inserted into acupuncture points that access the meridians (pathways for the flow of qi) and 
promote the circulation of qi and blood, which reduces pain. In acupuncture, a set of standardized 
points is referred to as a point prescription. Dr. Schlaeger has developed this standardized and 
efficacious point prescription through her Traditional Chinese Medicine assessments of SCD patients. 
This point prescription can be easily replicated by any acupuncturist and can be used nationally and 
internationally for the treatment of SCD pain. The needles will be retained (left in place) for 30 minutes. 
All needles will be evenly rotated to stimulate the movement of qi every 10 minutes. Participants will 
receive 2 acupuncture treatments each week for 5 weeks, for a total of 10 treatments. While a full 
treatment would be 10 sessions, our other work has shown that participants can experience some 
reduction in pain after 7 sessions.  
 
Guided relaxation intervention.  
The video clips were developed and validated in psychoneuroimmunology studies in patients with 
cancer or HIV. The video includes colorful smoke-like images that slowly change shapes against a dark 
background. The guided relaxation intervention includes a 12-minute guided relaxation video 
(administered at baseline) and 6 additional video clips ranging from 2 to 20 minutes. All video clips have 
similar content, with longer ones having more repetitions of the same content. For example, the clip on 
Breathing out worry, breathing in light begins with  
 
“Notice the cloud-like formations on the screen. Observe how the images drift and change. As 
you breathe deeply, your concerns and tensions, which worry you, go out into the atmosphere 
where they can dissolve just as the cloud-like formations on the screen dissolve and vanish from 
view. It is all right to let go of your worries. In fact, it is important to your health that you do so. 
Just breathe out problems and worries. See them drift off, walking by and off the screen, no 
longer a part of you.” 
 
The video a participant selects will only play after the pain score has been entered. Participants will be 
encouraged to watch at least one of the 6 video clips daily for the first two weeks. In on our previous 
work, after 2 weeks utilizing these videos, a reduction of pain ratings occurred. Ideally, a participant 
would complete the guided relaxation sessions daily until the assessment. As this is a pragmatic trial, we 
will also be assessing the use of these interventions in real world conditions, which might mean that a 
participant does not complete all the sessions leading up to the assessment. 
4.4 
END-OF-STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed the baseline, 6 week, 
12 week and 24 weeks assessments. 
 
The end of the study is defined as completion of the final assessment at 24 weeks of our final enrolled 
participant (n=366), as shown in the Schedule of Activities (SoA), Section 1.3. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
Patient-Participants: 

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In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Age ≥ 18 years old  
3. Has SCD diagnosed by hemoglobin electrophoresis 
4. Ability to speak/understand English 
5. Chronic pain defined as a response of “Most days”,“Every day”, or “Some days” to the question, 
“In the past 3 months, how often have you had pain?” (Answer options: Never, Some days, Most 
days, Every day)   
6. Current pain interference using the general activity question from PEG, score ≥3 on 0-10 scale 
 
Hospital personnel focus group participants: 
1. Currently employed in the health system in a capacity that interfaces with SCD patients 
2. Able to speak/understand English 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Had a stem cell transplant for sickle cell disease 
2. A known diagnosis of moderate or severe opioid use disorder by Diagnostic and Statistical Manual of 
Mental Disorders-5 criteria  
3. Current incarceration 
4. Patients who are on a chronic transfusion/exchange program 
5. Any other condition that the investigator considers precludes participation in the clinical trial 
 
Hospital staff participants: 
1. Any concerns that the investigator considers would preclude or bias participation 
5.3 
LIFESTYLE CONSIDERATIONS 
 
N/A 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently assigned to the study intervention or entered in the study. Individuals who do not meet 
the criteria for participation in this trial (screen failure) because of meeting one or more exclusion 
criteria will not be able to participate. We will collect demographic information on these screen failures 
to determine if there are any common factors among those who do not meet study criteria. Individuals 
who do not meet the eligibility criteria for one or more reasons can be screened again after 30 days. 
There is no limit to the number of times an individual can be screened for participation in the trial. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
  

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Total Recruitment: 366 participants, 122 per arm after randomization. We anticipate a 5% attrition at 6 
weeks and 10% attrition by end of study. Our anticipated enrollment table: 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian 
or Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian 
or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
199 
132 
10 
7 
348 
White 
0 
0 
0 
0 
0 
More than One 
Race 
10 
7 
1 
0 
18 
Total 
209 
139 
11 
7 
366 
 
 
Anticipated accrual over time: 
 
 
 
Recruitment Strategy. Study participants will be recruited from the population of patients with sickle 
cell disease with pain who are receiving care at the University of Illinois Hospital & Health Sciences 
System, the Duke University Health System, and the University of Florida Health. At the time of each 
patient’s clinical visit, the health care provider will determine if the patient is a candidate for non-
pharmacological pain care (both acupuncture and guided relaxation). Providers will be encouraged to 
Cum. Accrual
6
12
19
26
33
40
50
60
70
80
90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 310 320 330 340 350 360 366
Recruitment
6
6
7
7
7
7
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
6
Study Month
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
0
50
100
150
200
250
300
350
400
Sep-21
Oct-21
Nov-21
Dec-21
Jan-22
Feb-22
Mar-22
Apr-22
May-22
Jun-22
Jul-22
Aug-22
Sep-22
Oct-22
Nov-22
Dec-22
Jan-23
Feb-23
Mar-23
Apr-23
May-23
Jun-23
Jul-23
Aug-23
Sep-23
Oct-23
Nov-23
Dec-23
Jan-24
Feb-24
Mar-24
Apr-24
May-24
Jun-24
Jul-24
Aug-24
Sep-24
Oct-24
Nov-24
Dec-24
Jan-25
Feb-25
Cumulative Enrollment

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refer patients to this project using flyers in each provider exam room. There will also be flyers in the 
waiting room, as well as research staff who will be present in the waiting room to answer any questions 
about the study. The study will also utilize printed materials in public spaces, including ads posted on 
public transportation. Additionally, patients of the sickle cell clinics will be contacted through MyChart 
ahead of a scheduled appointment or by mail for those not enrolled in MyChart with permission from 
their provider. Patients who express an interest in the study will meet with the research assistant, who 
will explain the study and answer any questions. Additionally, patients will be shown an informational 
website and research assistants will provide the participants with the URL. Since the website is publicly 
available potential participants will also be able to navigate there via search engines (i.e. Google, Duck 
Duck Go, Yahoo), review the site, and complete a contact form enabling a member of the research team 
to answer any questions. 
Patients who meet study eligibility criteria will be offered the opportunity to be randomized to either 
the acupuncture or guided relaxation interventions. The research assistant will emphasize the 
importance of participating in the full intervention or interventions, and the data collection. Participants 
will be asked to mark their personal calendar for intervention days and times and data collection dates. 
These strategies have worked well in our ongoing trials to keep attrition below 20%. 
Participants will be assured of the confidentiality of all information and that refusing to participate will 
not alter their care. Participants will continue to receive standard medical care while participating in the 
study, so if any health care problems arise, they may seek care from their providers. For patients who 
refuse the study, the research assistant will seek consent to review their record for demographics and 
ask the reason for refusal. These data will help us understand who declines and will contribute to 
external validity and generalizability of the findings. 
Research assistant training will occur during the first six months of the study and will include didactic 
information, role-playing, reviewing problem cases, and return-demonstrations. The research assistant 
will introduce the study to patients using a script that includes (1) initial randomization to acupuncture 
or guided relaxation, and the possibility of being re-randomized after 5 weeks of receiving the first 
intervention to either continuing the same intervention or switching interventions; (2) the complete 
study lasting a total of 6 months to include all data collection; (3) both interventions being designed to 
help reduce symptoms and improve physical function and quality of life; and (4) a review of potential 
risks and benefits. 
Strategies to enhance recruitment. Although we will be using the electronic health record to initially 
identify eligible patients, using personalized, face to face recruitment methods by research staff and 
providers have been found to produce the best results in recruiting Black/African American participants. 
Additional strategies to be used to increase our recruitment will include: 1) establishing contact with any 
Black/African American or female health care providers located in the sickle cell clinic to gain their 
support to encourage their patients to participate; 2) reviewing training and recruitment materials to 
assure that language used is culturally sensitive, clear and simple; and 3) making every effort to hire 
research staff of female gender and/or Black/African American. We will work to develop a list of 
benefits, as well as barriers to participating in the research study. This list of benefits can be 
communicated to potential participants, and specific benefits can be emphasized when speaking to 
different audiences. A frequently asked questions sheet will be created addressing potential concerns in 
order to clear up misconceptions. 
Participant Retention Strategies. An important retention strategy is to engage the participants as active 
partners in the research through their understanding of the importance of their contribution. We will 

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build on existing trusting relationships with the community, as well as encouraging our patients to 
engage with their networks about the study. We will schedule data collection at times convenient to 
participants and at a time of day with fewer competing activities. We will collect multiple types of 
contact information (email, cell phone, and home phone) to maximize our ability to contact participants 
with reminders the day before and the day of their study appointments. We will also send a thank-you 
letters upon completion to acknowledge the participant’s contribution to the research. Importantly, the 
implementation side of this study will include patient interviews to gain insight on what barriers and 
facilitators they observed in participation in the study. 
Participants will receive a total of $100 for participation in each of the 4 data time points for Aims 1-3. 
Participant compensation will be greatest at the end as another mechanism for encouraging continued 
participation. Participant compensation is as follows: 
• 
Baseline: $20 
• 
6-week assessment: $20 
• 
12-week assessment: $20 
• 
Final assessment: $40 
Because participants randomized to the acupuncture group will have to go to a clinic site to receive their 
intervention treatments, people in this arm will receive regionally specific amounts to cover travel costs. 
Participants at UIHealth and Duke University will receive $10 per session; those at the University of 
Florida will receive $20 per session, as they have to travel a greater distance to the acupuncture site on 
average.  
Strategies to enhance retention.  
1) Research staff will emphasize the importance of participating in the full intervention and the data 
collection.  
2) Patients will be asked to mark their home calendar for study contact times.  
3) Patients are called regularly so that the contact is maintained for the entire study and study staff will 
be flexible when scheduling appointments. 
4) Several phone numbers for participants will be obtained for follow up.  
5) Along with incentives, participants will be sent small tokens of appreciation that will remind them of 
the study: birthday cards, thank you cards, etc.  
6) Study updates and results will be shared with participants, families of participants, participating 
practitioners and the Black/African American community.  
These strategies have worked well in our completed and ongoing trials. Our training of study staff 
includes topics often expressed by Black/African American people approached for research including: 1) 
mistrust, 2) the inability to see a clear personal benefit, and 3) a lack of understanding about the 
purpose of the research. We will also observe for evidence of cultural stereotyping and gender biases in 
our training session. We will provide booster sessions on sensitivity training as needed and reassess any 
personnel who appear to need improvement in this area. Recruitment of women will be tracked to 
ensure adequate recruitment milestones are met. If adequate recruitment milestones are not met, 
focus groups will be conducted to assess the needs and preferences of potential participants. 

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6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
 
Acupuncture. In Traditional Chinese Medicine, qi is the vital energy 
flowing within and surrounding the body. The channels through which 
qi and blood flow in the body are called meridians. Disorders of qi and 
disorders of blood, whether deficiency or excess (stagnation or 
obstruction), can result in pain. Acupuncture needles are inserted into 
acupuncture points that access the meridians (pathways for the 
flow of qi) and promote the circulation of qi and blood, which reduces 
pain. In acupuncture, a set of standardized points is referred to as a 
point prescription. Dr. Schlaeger has developed this standardized and 
efficacious point prescription through her Traditional Chinese 
Medicine assessments of SCD patients. This point prescription can be 
easily replicated by any acupuncturist and can be used nationally and 
internationally for the treatment of SCD pain.  
 
Guided Relaxation. Mind-body therapies such as guided relaxation use the mind to reduce pain, 
promote well-being, and alter physical function. Guided relaxation is a state of concentration and 
focused attention that gives people more control over their pain experience and its impact and an 
increased sense of well-being. Systematic reviews and meta-analyses reviewing over 48 RCTs have 
demonstrated that guided relaxation reduces chronic pain. Previous work by Dr. Ezenwa has developed 
a protocol for Guided Relaxation that has shown to help with the management of chronic pain in sickle 
cell disease patients.  
6.1.2 ADMINISTRATION AND/OR DOSING 
 
Acupuncture. Participants will receive the acupuncture treatments in a clinical space designated at each 
of the study sites. Treatments will be administered by a trained acupuncturist. The needles will be 
retained (left in place) for 30 minutes. All needles will be evenly rotated to stimulate the movement of qi 
every 10 minutes. Participants will receive 2 acupuncture treatments each week for 5 weeks, for a total 
of 10 treatments. 
 
Guided Relaxation. On the first day of the intervention, participants will complete a pain and stress 
tracking, watch a 12-minute introductory video, and complete the pain and stress tracking again on the 
first day of the intervention. Every day following, participants will complete the pain and stress tracking, 
watch one of 6 videos (ranging in duration from 2 to 20 minutes each), and complete the stress and pain 
tracking again. Sessions are self-initiated and accessed remotely.  
 

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6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
Research team training will be provided for team members who recruit participants, collect data, 
provide the guided relaxation and acupuncture interventions, and conduct interviews. Training will 
include didactic information, written protocols, role-playing, demonstrations, and return 
demonstrations, based on our study-specific criteria.  
Guided Relaxation. Dr. Ezenwa has developed a protocol for the guided relaxation intervention, which is 
delivered via web app. The research specialist will be trained on this protocol and will practice explaining 
how to access the app to participants with other team members.  
Acupuncture. Dr. Schlaeger will train the licensed acupuncturists, who will be given the acupuncture 
protocol with written instructions and diagrams. Dr. Schlaeger has also developed a proficiency checklist 
for the acupuncture protocol that will be used to determine if the acupuncturists are adhering to the 
protocol.  
Additional checklists will be used to determine if research staff assisting with and monitoring the 
intervention are demonstrating protocol proficiency of greater than 90%, both before they begin and as 
they continue to approach patients and collect data. There will be a refresher training for research staff 
every 6 months during the data collection and intervention period. Role-playing will be used to ensure 
that team members understand the protocols for interacting with participants. All contact with 
participants by research specialists will be scripted and will be randomly taped and regularly reviewed 
by Dr. Doorenbos. 
Sickle cell clinic physicians and staff will be oriented at one of their respective monthly meetings by Dr. 
Schlaeger via Zoom. The orientation will include a short introduction to the philosophy of Traditional 
Chinese Medicine and acupuncture, our sickle cell feasibility study results, a brief overview of the GRACE 
study acupuncture protocol, and logistics of how and where to refer potential participants for 
acupuncture. Reorientations to the study will be administered by Dr. Schlaeger as needed. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Team Member 
Role 
Blinding Status 
Dr. Ezenwa and Dr. 
Schlaeger 
Directly managing elements of 
intervention 
Unblinded 
All other PI’s and Co-Is 
Management of higher level 
study activities at recruitment 
sites and meeting overall 
research goals 
Blinded 
Statistician 
Statistical analysis of primary 
and secondary aims 
Blinded 
Data Collection Staff 
Remote follow-up 
Blinded 
Site Researcher Managers 
Recruitment, randomization, 
coordinating intervention 
Unblinded 

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Acupuncturists 
acupuncture 
Unblinded 
Data Manager 
Manage collected data, run 
reports 
Unblinded 
 
Intervention assignments will not be masked to participants or research managers because of (1) 
impracticability, and (2) an interest in implementing the interventions as they would be implemented 
outside of a trial setting. The trial includes a control group that does receive an educational intervention 
beyond usual clinical care; however, as the educational intervention is written material, it will not be fully 
possible to determine whether changes observed in the active treatment groups are the result of the 
interventions or the result of either the increased attention that accompanies trial participation or the 
natural history of the condition. Bias will be minimized by performing randomization after collection of 
baseline data, concealing the allocation order, and ascertaining the patient-reported outcomes, including 
the primary outcome, using standardized, centrally administered questionnaires. PI’s and Co-I’s will be 
blinded unless responsible for directly implementing components of the interventions (for clarification, 
see table above). Staff assisting with data collection, such as following up with participants who do not 
complete emailed surveys, will be blinded to treatment arm assignment. An unblinded data manager will 
address issues with randomization and any unblinded reports or other data needs. After the REDCap 
randomization module is set up with the allocation schedule an independent staff will assign a label to 
the group assignment number (e.g., 1= control, 2= guided relaxation, etc.).  For each randomization, the 
research staff will enter stratification information and push a button to reveal group assignment.  We will 
restrict access to treatment arm assignment for all blinded personnel, including the statistician, by user 
right settings within the REDCap system.  After the data freeze, the point at which no further data are 
collected, the statistician will be aware of group numbers (e.g., 1, 2, or 3) but blinded to the meaning of 
the assignment labels during analyses. An independent statistician will be enlisted to help with DSMB 
unblinded reports, if requested.   
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
Treatment delivery will be monitored by tracking length, frequency, and intensity of all interventions 
(e.g., guided relaxation and acupuncture sessions tracked for length and intensity). Should any technical 
difficulties present (e.g., issues with downloads of guided relaxation recordings), the participant will be 
contacted by phone or email; all technical problems will be resolved. 
Receipt of treatment for the guided relaxation intervention will be assessed by the research team 
tracking participants’ use and duration of the guided relaxation recordings. Adherence will be based on 
the number of guided relaxation sessions completed (out of 42 prescribed sessions) and categorized as 
minimal (<14 sessions), some (14–28 sessions), and most (over 28 sessions). For the acupuncture 
intervention, the treatment dose will be assessed by monitoring participants’ acupuncture 
appointments. Regular interactions between the acupuncturists and Dr. Schlaeger will occur, during 
which any issues will be reviewed. 
6.5 
CONCOMITANT THERAPY 
The following approach will be taken regarding concomitant therapies: 
 
1)  Doses and frequency of use of non-opioid analgesics, antidepressants, and anxiolytic and 
sedative/hypnotic medications will be recorded at baseline, Week 6, Week 12, and Week 24. 
 

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2) Use of non-study behavioral therapy or any other non-pharmacological therapy for pain (e.g., physical 
therapy) will be recorded at baseline, Week 6, Week 12, and Week 24. 
 
3) For the duration of the study, the study team members will encourage patients to seek treatment of 
co-existing depression and/or anxiety if indicated. They will inform the primary care providers and other 
relevant clinicians about any mental health symptoms, such as depression and/or anxiety, discovered 
during study assessments and will develop a collaborative plan, maximizing safety and efficacy of any 
prescribed medications. Details of such study recommendations and resulting medication orders will be 
recorded during the 24-week study period. 
 
4) Opioid dose reduction or discontinuation will not be protocolized. The study team will provide 
information and general recommendations to the participants opioid prescriber, but decisions to 
prescribe or change opioids will be up to the treating clinician and participant. If a participant develops a 
new indication for pain medication (e.g., new fracture, dental procedure) during the study intervention 
period, there may be a need to initiate or increase the dose of an opioid medication. Opioid use during 
this period will be considered as rescue medication and recommendations for opioid tapering may be 
put on hold. Once the acute event subsides (based on clinical judgment), the recommendations for 
opioid tapering will be resumed, as deemed appropriate. The duration of rescue periods will be 
recorded. 
6.5.1 RESCUE THERAPY 
N/A 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
When a subject discontinues from acupuncture or guided relaxation but not from the study, remaining 
assessments will be completed as indicated by the study protocol. If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods for 
determining the need to discontinue. 
• 
If the participant is due to complete assessments within 2 weeks of being discontinued from the 
study intervention, those assessments will be administered at the time of discontinuation; if the next 
scheduled assessments are more than 2 weeks from the discontinuation date, the discontinued 
participant will wait for the next scheduled assessment. Thereafter, the participant will be included in all 
future scheduled assessments, even though not participating in the intervention. 
 

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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. If a 
participant indicates a desire to withdraw, the study team will discuss the request with the participant 
and determine whether the participant is willing to allow ongoing data collection for outcomes or 
adverse event monitoring. 
 
An investigator may discontinue a participant from the study for the following reasons: 
 
• 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up 
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced. Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are discontinued from 
the study, will be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she cannot be contacted and fails to respond to 
complete consecutive assessments (6 week, 12 week and 24 week time point) through the end of the 
study.  
 
The following actions must be taken if a participant fails to return to the clinic for an acupuncture 
appointment: 
 
• 
The site will attempt to contact the participant, offer to resend the link to complete the 
assessment online or over the phone, counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or should continue in 
the study 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 5 telephone calls (including 3 
voicemail messages left) and, if necessary, a certified letter to the participant’s last known 
mailing address. These contact attempts will be documented in the participant’s medical record 
or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up 
 
The amount of missing data will first be quantified, using the approach recommended by Glick 

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et al. where possible.61 We propose to use mixed effects regression models which allow all observed 
data to be included in the analysis under the assumption that data are missing at random (MAR), 
essentially providing a full information maximum likelihood solution to missing outcome data.62 We will 
incorporate covariates that have predicted missingness in our previous studies to support the validity of 
the MAR assumption. If substantial missing data occurs, multiple imputation will be used with 
subsequent sensitivity analyses to explore the impact of imputation on results.63 Sensitivity analyses 
such as pattern mixture models will be employed if data are suspected to be missing not at random. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
Participants will be identified through a diagnosis of SCD in their medical record, making sure to exclude 
those with chronic transfusion/exchange program and other exclusionary conditions determined by the 
PIs.  
 
Those identified through the medical record will be approached in clinic settings. We will also be posting 
flyers for recruitment in clinic spaces. Interested people will then be asked our screening questions, 
which include:  
• 
In the past 3 months, how often have you had pain? Never, Some days, Most days, or Every 
day? 
• 
Chronic pain defined as a response of “Most days”,  “Every day”, or “Some days” 
• 
PEG pain interference on general activity (0-10 scale) of ≥3 
Participants will be enrolled within one week of answering screening questions. Once enrolled and 
consented, participants will complete the Baseline Assessment, which consists of questionnaires, 
including the following: 
• 
Demographic 
• 
PROMIS Pain Interference 
• 
PROMIS Physical Function 
• 
PEG 
• 
Opioid use (will also be confirmed via EHR)  
• 
GAD-7 
• 
PHQ-9 
• 
PROMIS Sleep Disturbance 8a and sleep disturbance question 
• 
Pain Catastrophizing Scale 
• 
PGIC 
• 
TAPS1 
• 
PROMIS GI Constipation 9a 
• 
Clinical data regarding hospitalizations (will also be confirmed via EHR) 
• 
Use of non-study behavioral or other non-pharmacologic treatment for pain 
 
Once participants complete the Baseline Assessment, they will be randomized into one of the three study 
arms (acupuncture, guided relaxation or standard care).  
 

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No physical assessments are conducted as part of this study.  
8.2 
SAFETY ASSESSMENTS 
N/A 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS 
 
This protocol uses the definition of adverse event from the IRB at the University of Illinois at Chicago, 
the reviewing IRB site: An untoward physical or psychological occurrence in a human subject 
participating in research which occurs during the study having been absent at baseline or, if present at 
baseline, appears to worsen.  The event may be any unfavorable outcome, including abnormal 
laboratory result, symptom, disease or injury.  Adverse events may be expected or unexpected, may not 
necessarily be caused by the research, and may be serious or not.  Adverse events that are 
unanticipated, related to the research and serious or involve risks to subjects or others qualify as a 
subset of unanticipated problems. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
 
A serious adverse event (SAE) is any AE that is: 
• fatal or results in death 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• results in congenital anomalies or birth defects 
• an important medical event* 
*Important medical events are those that may not be immediately life threatening but are clearly of 
major clinical significance. 
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. 

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• 
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”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
All adverse events (AEs) will have their relationship to study procedures, including the intervention, 
assessed by an appropriately-trained clinician based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below.  
 
• 
Definitely Related – The AE is known to occur with the study procedures, there is a reasonable 
possibility that the study procedures caused the AE, or there is a temporal relationship between 
the study procedures and the event. Reasonable possibility means that there is evidence to 
suggest a causal relationship between the study procedures and the AE. 
• 
Possibly Related –Though the AE is not known to occur with the interventions, it cannot be 
ruled out that it is related. 
• 
Not Related – There is not a reasonable possibility that the study procedures caused the event, 
there is no temporal relationship between the study procedures and event onset, or an 
alternate etiology has been established. 
 
8.3.3.3 EXPECTEDNESS  
 
A clinician with appropriate expertise in sickle cell disease will be responsible for determining whether 
an adverse event (AE) is expected or unexpected. An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously described for 
the study procedures. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report form 
(CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study procedures (assessed only by those with the training and authority to 
make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study will 
be documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 

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Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 
The PI will record events with start dates occurring any time after informed consent is obtained until 7 
(for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At each study visit, 
the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed 
for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
We do recognize that participants in this research are individuals living with advanced, progressive 
chronic disease who have pain. It is possible that during the active intervention period of the study they 
may have health issues requiring hospitalization unrelated to this research. As eligibility criteria require 
that participants have advanced, progressive chronic disease, hospitalization during the intervention 
period is possible but also an expected natural progression of their underlying disease. The MPIs will 
evaluate all hospitalizations or other reported issues to determine whether there is a relationship 
between the reported issue and the procedures involved in the research. All events determined as not 
related will be noted and reported to the IRB in the annual report, and research activities will continue 
as scheduled.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The PI will be responsible for conducting an evaluation of a serious adverse event and shall report the 
results of such evaluation to the NIH and the reviewing Institutional Review Board (IRB) as soon as 
possible, but in no event later than 7 calendar days after the investigator first learns of the event. SAE 
forms can be completed by research coordinators but must be signed by a health care system MPI. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
N/A 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 

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This protocol uses the definition of Unanticipated Problems as defined by the Office for Human Research 
Protections (OHRP).  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 PROBLEMS REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). 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 the DCC/study 
sponsor/funding agency within 7 days of the investigator becoming aware of the event.  
• 
Unexpected fatal or life-threatening AEs related to the intervention will be reported to the NCCIH 
Program Officer and the DSMB within 3 days of the investigator becoming aware of the event  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor/funding agency within 14 
days of the investigator becoming aware of the problem  
• 
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 14 days of the IRB’s receipt of the report of the 
problem from the investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
N/A 

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9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Endpoint and Secondary Outcomes at 6 weeks:  
 
Primary: At 6 weeks, SCD patients randomized to either CIH intervention will have a greater 
decrease in pain impact compared to SCD randomized to usual care arm.  
 
Secondary: At 6 weeks, SCD patients randomized to either CIH intervention (acupuncture, 
guided relaxation) will have greater decrease in opioid use, PEG, sleep, anxiety, depression, pain 
catastrophizing, global impression of change, substance use and constipation compared to SCD 
patients randomized to usual care. 
 
 
 
 
Aim 2: Identify the best adaptive intervention for improved outcomes by documenting 
outcomes among adaptive intervention sequences: (1) initiate guided relaxation and switch to 
acupuncture for non-responders at midpoint; (2) initiate guided relaxation and continue with 
guided relaxation for non-responders at midpoint; (3) initiate acupuncture and switch to guided 
relaxation for non-responders at midpoint or (4) initiate acupuncture and continue with 
acupuncture for non-responders at midpoint.  
 
From our model we will estimate the adjusted mean outcome for each embedded sequence and 
control condition at 12 weeks and compare using contrast statements to select the sequence 
with the greatest improvement. 
 
Aim 3: Explore differences in response to the adaptive interventions by age and sex.  
We will explore moderating variables such as, age, sex, and response to Stage 1 treatment using 
a Q-learning approach. Although our SMART results will provide evidence for a best sequence, 
Q-learning can be used to develop decision rules for more extensive tailoring if the response 
differs by sex or age, for example. This approach uses regression models and will involve 2 
stages for the proposed study design. Working backward from the final outcome, we can 
explore variables that predict the best response to the Stage 2 interventions among the non-
responders to Stage 1. The goal is to determine explicit decision rules for assigning the Stage 2 
intervention by predicting the best outcome based on baseline patient characteristics, Stage 1 
treatment, and initial response to the Stage 1 intervention at Week 6. The next step examines 
moderators of response for the Stage 1 intervention, controlling for the optimal Stage 2 
intervention for non-responders. Confidence intervals estimated for the predicted response will 
suggest which tailoring decisions will lead to reliable differences in outcomes. We will explore 
the quality of these decision rules for the pain impact outcome at Week 12 (end-of-intervention) 

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and Week 24 follow-up in order to recommend additional tailoring for the combinations of 
guided relaxation and acupuncture tested by this SMART design. These analyses will be 
implemented in SAS PROC QLEARN, developed by Murphy and colleagues. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Power Considerations. Our goal is to recruit 366 and retain 330 participants accounting for 10% attrition 
by end of study. At 6 weeks we anticipate 5% attrition based on our previous work yielding a sample size 
of 116 per treatment arm. The table below shows the most conservative minimal detectable differences 
in group means (standard deviation units) for the two primary endpoint comparisons using a two-sided 
test and alpha=0.025 for our proposed sample size of 116 per group, adjusting for clustering effects due 
to acupuncturists. We adjusted the variance of the treatment arm using a range of plausible intraclass 
correlations (ICC) and average group sizes per acupuncturist. Pragmatic trials commonly have ICCs 
ranging from 0.01-0.05. We assumed a range of 6 to 9 acupuncturists across the three sites; more than 9 
acupuncturists are possible further increasing study power. Based on a published effect size of 0.5 for 
acupuncture and 0.57 for our previous work, we estimate this sample size will have adequate power to 
detect a true difference between groups. Power will be enhanced if pre-post measures are correlated 
greater than r=0.5. These minimum detectable differences are based on a single primary outcome (PIS) 
measured at 6 weeks. 
 .  Power 
N per 
group 
Participants per 
Acupuncturist 
ICC 
Minimal Detectable 
Difference 
0.90 
116 
13-19 
0.005 
0.47 
0.90 
116 
13-19 
0.01-0.02 
0.48-0.50 
0.85 
116 
13-19 
0.03-0.04 
0.48-0.50 
0.85 
116 
13-15 
0.05-0.06 
0.49-0.51 
0.80 
116 
13-19 
0.05-0.06 
0.46-0.50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Aim 2 power considerations. Aim 2 proposes to identify the best treatment sequence among the 4 
embedded sequences in this trial.  We have planned that a sample of 220 will be available to test this 
aim.  Based on the web-based calculator (http://methodologymedia.psu.edu/smart/samplesize), we 
determined the sample size of 205 will yield a probability of .85 for choosing the best strategy from 
among 4 embedded treatment sequences given an effect size of 0.3 between the strongest two 
sequences.  The table below varies the probability and effect size to show the effect on sample size. 
 
Probability of detecting best 
treatment sequence π 
Effect size between two 
strongest sequences δ 
Sample size needed 
0.8 
0.3 
161 
0.85 
0.3 
205 
0.9 
0.3 
269 
0.85 
0.4 
117 
0.85 
0.2 
465 
 
 
Minimum Detectable Differences for Research Questions Based on Target Sample Size 
Assumes 80% power, 5% type I error 
 
Minimum Detectable Difference 
Research Question 
Expected N 
Cohen’s D 
Pain Impact 
Aim 1 RCT Main effect comparing each CIH control at 6 
weeks 
330 
0.38 
2.4 
Choose best treatment sequence* 
220 
0.30 
1.9 
Main effect of initial treatment on 12 week outcome 
220 
0.38 
2.4 
Main effect of secondary treatment for non-responders^ 
144 
0.61 
3.8 
*85% probability http://methodologymedia.psu.edu/smart/samplesize 
^Assumes 40% respond to initial treatment, a higher response rate will result in less power (exploratory 
question) 
Crivello AI, Levy JA, Murphy SA. Statistical Methodology for a SMART Design in the Development of Adaptive 
Treatment Strategies. (Tech. Rep. No. 07-82). University Park, PA: The Pennsylvania State University, The 
Methodology Center. 2007. 
Crivello AI, Levy JA, Murphy SA. Evaluation of Sample Size Formulae for Developing Adaptive Treatment 
Strategies Using a SMART Design. (Tech. Rep. No. 07-81). University Park, PA: The Pennsylvania State 
University, The Methodology Center. 2007. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
We will conduct Intention to Treat and Per Protocol Analysis for Aim 1.  Per protocol will include 
participants receiving 70% or more of the intended intervention.   
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Categorical and continuous data will be summarized using frequencies, percentages, means with 
standard deviations or median and interquartile depending on the distributions. Inferential tests will be 
two-tailed, presenting actual p-values, and will use alpha=.05 as the type I error rate unless otherwise 
indicated. Covariates will include stratification variables; others will be defined in a subsequent SAP. 

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Variables that are do not conform to assumptions for normal distribution of residuals in multivariable 
models will be transformed to improve the distribution.   
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
Aim 1 analyses of the primary endpoint and secondary outcomes will use the same modeling approach. 
All are interval level measures that will be measured at baseline and 6 weeks. We will investigate mean 
differences at 6 weeks controlling for the baseline level of the outcome and stratification variables used 
for randomization, use of opioids and PROMIS pain interference. Clustering due to common 
acupuncturists will be addressed by including indicators for each acupuncturist as a repeated factor in a 
GEE model.. We are unable to determine the number of participants per acupuncturist given the 
logistical differences at each site but the desired range is 13-19 for the initial randomization We will 
attempt to balance caseloads of acupuncturists and will seek to add acupuncturists if the maximum (19) 
is approached, by site.  Least square (adjusted) means will be estimated for each treatment arm as well 
as standard errors and 95% confidence intervals. Analyses will be repeated for intention to treat and per 
protocol population subsamples. All variables will be assessed for amount of missing, and predictors of 
missingness. Models will be estimated using full information maximum likelihood to retain all 
participants and utilize all available data. Among secondary outcomes, a Benjamini Hochberg approach 
will be applied using a false discovery rate of 0.05.64 
In the context of the model, i.e., yi2 = β0 + β1x1 + β2yi1 + ei , testing for group differences while 
adjusting for the baseline measure of the outcome: 
α=.05 
H0:  β1a=0 
H1:  β1a≠0 
 
H0:  β1b=0 
H1:  β1b≠0 
 
 
Note:  β1 is a vector of 2 parameters for three initial treatment arms.     
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Aim 2 analyses will be finalized with guidance from the Collaboratory Biostatistics Core and published in 
the SOP. 
 
9.4.4 SAFETY ANALYSES 
 
N/A 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Treatment arms will be compared on their baseline demographic and clinical characteristics using 
descriptive statistics.  Categorical and continuous data will be summarized using frequencies, 

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percentages, means with standard deviations or median and interquartile depending on the 
distributions. Inferential statistics will not be used. 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Use of the SMART design provides an interim measure of study outcome. We will summarize the 
number of participants requiring an additional six weeks of intervention due to non-response. Other 
planned analyses will include enrollment progress, adherence and protocol deviations, and a summary 
adverse events.  
9.4.7 SUB-GROUP ANALYSES 
We will explore moderating variables such as, age, sex, and response to Stage 1 treatment using a Q-
learning approach. Although our SMART results will provide evidence for a best sequence, Q-learning 
can be used to develop decision rules for more extensive tailoring if the response differs by sex or age, 
for example. This approach uses regression models and will involve 2 stages for the proposed study 
design. Working backward from the final outcome, we can explore variables that predict the best 
response to the Stage 2 interventions among the non-responders to Stage 1. The goal is to determine 
explicit decision rules for assigning the Stage 2 intervention by predicting the best outcome based on 
baseline patient characteristics, Stage 1 treatment, and initial response to the Stage 1 intervention at 
Week 6. The next step examines moderators of response for the Stage 1 intervention, controlling for the 
optimal Stage 2 intervention for non-responders. Confidence intervals estimated for the predicted 
response will suggest which tailoring decisions will lead to reliable differences in outcomes. We will 
explore the quality of these decision rules for the pain impact outcome at Week 12 (end-of-intervention) 
and Week 24 follow-up in order to recommend additional tailoring for the combinations of guided 
relaxation and acupuncture tested by this SMART design. These analyses will be implemented in SAS 
PROC QLEARN, developed by Murphy and colleagues. 
 
Race will not be investigated with this approach because the participants will be predominantly African 
American. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
N/A 
9.4.9 EXPLORATORY ANALYSES 
 
Duration of effect will be examined using Model from Aim 2 using outcomes at 24 weeks. Additional 
analyses will explore dose response and sensitivity of findings to additional covariate adjustment if we 
observe imbalance in baseline characteristics despite randomization or attributes associated with 
attrition.  
 
We will also conduct analyses to examine the treatment sequence effects (Aim 2) among non-responders, 
however, this will likely be underpowered and shall be presented as exploratory. 
 

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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 
 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to the 
participant and written documentation of informed consent will be completed prior to starting the study 
intervention.   
 
The following consent materials are submitted with this protocol: 
• 
Informed consent document for patient participants for Aims 1 through 3 
• 
Informed consent for staff/provider focus groups 
• 
Recruitment flyer 
• 
Recruitment script for patient participants 
• 
Recruitment email for staff/provider focus groups 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
The consenting process will be performed by a qualified investigator or study site designee. The study 
team member will discuss the study goals and procedures with the potential participant and assess 
understanding of the content in the consent form before obtaining written informed consent from the 
participant. 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 have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants will also have the opportunity to discuss the study with family 
members or surrogates, and to fully consider the decision to participate or not. A signed copy of the 
informed consent form will be stored in a locked cabinet in a locked office.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor/funding 

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agency and will provide 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 of study staff to the protocol (ie, significant protocol violations) 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the funding agency, sponsor, IRB, Food and Drug Administration (FDA), or other 
relevant regulatory or oversight bodies (OHRP, DSMB). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a specific 
study participant will be held in strict confidence within the research team. No personally-identifiable 
information from the study will be released to any unauthorized third party without prior written 
approval of the sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor or funding agency, representatives 
of the Institutional Review Board (IRB), regulatory agencies or representatives from companies or 
organizations supplying the product, 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. 
 
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 sponsor/funding agency 
requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the UIC College of Nursing. 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 UIC College of Nursing 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 UIC College of Nursing. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  

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It is NIH policy that the results and accomplishments of the activities that it funds should be made 
available to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms 
used to share data will include proper plans and safeguards for the protection of privacy, confidentiality, 
and security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not 
be traceable to a specific study participant). Plans for archiving and long-term preservation of the data 
will be implemented, as appropriate.  
 
Certificate of Confidentiality  
To further protect the privacy of study participants, the Secretary, Health and Human Services (HHS), 
has issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, 
clinical or other human subjects research funded wholly or in part by the federal 
government.  Recipients of NIH funding for human subjects research are required to protect identifiable 
research information from forced disclosure per the terms of the NIH Policy (see 
https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 75.303(a) and NIHGPS Chapter 
8.3, recipients conducting NIH-supported research covered by this Policy are required to establish and 
maintain effective internal controls (e.g., policies and procedures) that provide reasonable assurance 
that the award is managed in compliance with Federal statutes, regulations, and the terms and 
conditions of award. It is the NIH policy that investigators and others who have access to research 
records will not disclose identifying information except when the participant consents or in certain 
instances when federal, state, or local law or regulation requires disclosure. NIH expects investigators to 
inform research participants of the protections and the limits to protections provided by a Certificate 
issued by this Policy. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
N/A 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Contact Principal Investigator 
Dr. Ardith Doorenbos, PhD, RN, FAAN 
University of Illinois at Chicago  
845 S Damen Ave 
Chicago, IL 60612 
312-996-2817 
ardith@uic.edu 
 
10.1.6 SAFETY OVERSIGHT 
 
The DSMB is an independent group of experts that advises the study investigators. All regular members 
of the DSMB for the trial will be eligible for service as voting members of the DSMB. 
 
No members of the DSMB may have any conflicts of interest (financial, regulatory, or professional) with 
the study. At the beginning of every DSMB meeting, the Executive Administrator or the DSMB Chair will 

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reconfirm that no conflict of interest exists for DSMB members. Members will disclose potential conflicts 
of interest prior to any discussion. The DSMB will determine how to handle such potential conflicts. The 
DSMB may require that a member with a potential conflict not vote or it may take other actions or 
decisions deemed appropriate. 
 
The primary responsibilities of the DSMB are to 1) perform periodic reviews of accumulated study data 
and evaluate them for participant safety, study conduct and progress, and efficacy, and 2) make 
recommendations to the study investigators concerning the continuation, modification, or termination of 
the trial. The DSMB will consider study-specific data, as well as relevant background knowledge about 
the diseases, interventions, and/or patient population under study. The DSMB will maintain the 
confidentiality of its internal discussions and activities, as well as the contents of reports provided to it. 
 
Prior to study implementation the DSMB will review the protocol and define its deliberative processes, 
including stopping guidelines, unmasking (unblinding), event triggers that would call for an unscheduled 
review, and voting procedures. The Executive Administrator will take notes and provide administrative 
support during the meetings. 
 
Following study initiation, the DSMB will review data on safety, study conduct, and scientific validity and 
integrity of the trial every 12 months. The DSMB will also assess the performance of overall study 
operations and any other relevant issues at each meeting. The DSMB will likely meet 5 times during the 
study to review data. 
10.1.7 CLINICAL MONITORING 
 
N/A 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion. All sites will follow a common quality management plan. 
 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process as well 
as a percentage of the completed consent documents.  This review will evaluate compliance with GCP, 
accuracy, and completeness.  Feedback will be provided to the study team to ensure proper consenting 
procedures are followed.  
 
Source documents and the electronic data --- Data will be initially captured on source documents (see 
Section 10.1.9, Data Handling and Record Keeping) and will ultimately be entered into the study 
database.  To ensure accuracy site staff will compare a representative sample of source data against the 
database, targeting key data points in that review. 
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking.  

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Protocol Deviations – The study team will review protocol deviations on an ongoing basis and will 
implement corrective actions when the quantity or nature of deviations are deemed to be at a level of 
concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all trial related 
sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection will occur online through REDCap, a HIPAA-Compliant database. Participants will be able 
to access their surveys online. Acupuncture visit tracking will be entered into REDCap by each site’s 
research specialist.  
 
Usage tracking of the Guided Relaxation intervention is held on the secure University of Florida servers.  
 
Hardcopies of the signed consent forms will be kept in a locked cabinet in a locked officed designated at 
each site.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system provided by the UIC College of Nursing. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents will be retained for a minimum of 3 years after completion of study activities. These 
documents should be retained for a longer period, however, if required by local regulations. No records 
will be destroyed without the written consent of the sponsor/funding agency, if applicable. It is the 
responsibility of the sponsor/funding agency to inform the investigator when these documents no 
longer need to be retained. 
10.1.10 
PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
International Council 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 will be developed by the site and 
implemented promptly.  
 
These practices are consistent with ICH GCP:  

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• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
 
It will be the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 10 working days of identification of the protocol deviation, or within 10 working days 
of the scheduled protocol-required activity. All deviations will be addressed in study source documents, 
reported NIH Program Official and the UIC. Protocol deviations will be sent to the reviewing Institutional 
Review Board (IRB) per their policies. The site investigator will be 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.  
 
In addition, this study will follow the HEAL Public Access and Data Sharing Policy, which prioritizes 
expedient and transparent data sharing to combat the public health crisis of the opioid misuse, 
addiction, and overdose. To this end, this study will share Underlying Primary Data, which will include 
self-reported demographics, self-reported questionnaires, and interviews. Underlying Primary Data will 
be stripped of identifiers according to the Health Insurance Portability and Accountability Act (HIPAA) 
Privacy Rule. Participants will be notified prior to providing their informed consent that de-identified 
study data will be shared. 
The data and associated documentation will be made available to users only under a data-sharing 
agreement that provides for (a) a commitment to using the data only for research purposes and not to 
identify any individual patient; (b) a commitment to securing the data using appropriate computer 
technology; and (c) a commitment to destroying or returning the data after analyses are completed. 
Such a data-use agreement will be executed through the PIs and the University of Illinois at Chicago 
College of Nursing. The database can then be accessed via our secure website, in a format that can be 
used by a variety of statistical software packages. We will make our data and results publicly available 
(predominately online), so that they can easily be found. 
 
We will publish our results in open-source manuscripts that will be available to the public. Electronic 
copies of publications will be deposited in PubMed Central with proper tagging of metadata to ensure 
online discoverability and accessibility within four weeks of acceptance by a journal. Publications will be 
published under the Creative Commons Attribution 4.0 Generic License (CC BY 4.0) or an equivalent 
license, or otherwise dedicated to the public domain (e.g., Creative Commons public domain tool, CC0). 
To the extent feasible, Underlying Primary Data will be shared simultaneously with the publication and 
made immediately accessible through release under the Creative Commons Attribution 4.0 Generic 

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License (CC BY 4.0) or an equivalent license, or otherwise dedicated to the public domain (e.g., Creative 
Commons public domain tool, CC0). Before submitting Underlying Primary Data, we will work with our 
Institutional Review Board (IRB) and Data Safety and Monitoring Board to assess the informed consent 
materials and to determine whether the Underlying Primary Data may be shared as contemplated in this 
policy. 
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 study leadership 
in conjunction with the NCCIH has 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. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
N/A 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CIH 
Complementary and Integrative Health 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  

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IB 
Investigator’s Brochure 
ICH 
International Council on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCD 
Sickle Cell Disease 
SMART 
Sequential, Multiple Assignment, Randomized Trials 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SRS 
Self-report Survey 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
0.1 
2/1/2021 
Initial Draft 
Not applicable; this is the first 
version of the protocol. 
0.2 
4/1/2021 
Changes throughout document in 
response to review 
Response to reviewer 
comments of Initial Draft 
0.3 
6/10/2021 
-NCT number added (registration 
approved since last protocol version) 
-study measure and blinding 
procedure questions clarified 
-inserted blinding table 
Response to NIH review 
comments 
0.4 
7/12/2021 
Changes in response to NIH review 
comments regarding blinding and 
limiting the number of participants 
per acupuncturist 
NIH review comments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.  
Pitcher MH, Von Korff M, Bushnell MC, Porter L. Prevalence and Profile of High-Impact Chronic 
Pain in the United States. J Pain. 2019;20(2):146-160. doi:10.1016/j.jpain.2018.07.006 
2.  
Krebs EE, Gravely A, Nugent S, et al. Effect of opioid vs nonopioid medications on pain-related 
function in patients with chronic back pain or hip or knee osteoarthritis pain the SPACE 
randomized clinical trial. JAMA - J Am Med Assoc. 2018;319(9):872-882. 
doi:10.1001/jama.2018.0899 
3.  
Busse JW, Wang L, Kamaleldin M, et al. Opioids for Chronic Noncancer Pain: A Systematic Review 
and Meta-analysis. JAMA - J Am Med Assoc. 2018;320(23):2448-2460. 
doi:10.1001/jama.2018.18472 
4.  
Seth P, Scholl L, Rudd R, Bacon S. Overdose Deaths Involving Opioids, Cocaine, and 
Psychostimulants — United States, 2015–2016. MMWR Morb Mortal Wkly Rep. 2018;67:349–
358. doi:http://dx.doi.org/10.15585/mmwr.mm6712a1 
5.  
Seth P, Rudd RA, Noonan RK, Haegerich TM. Quantifying the epidemic of prescription opioid 
overdose deaths. Am J Public Health. 2018;108(4):500-502. doi:10.2105/AJPH.2017.304265 
6.  
Balon R. The opioid epidemic and us. Ann Clin Psychiatry. 2017;29(1):1-2. Accessed November 8, 
2020. https://europepmc.org/article/med/28207911 
7.  
Dowell D, Haegerich T, Chou R. CDC guideline for prescribing opioids for chronic pain—United 
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