Acupuncture Treatment for Chronic Post-traumatic Headache in Individuals With Mild Traumatic Brain Injury
Phase: NA
Conditions: Chronic Post-traumatic Headache, Mild Traumatic Brain Injury
Sponsor: HealthPartners Institute

 
 
Acupuncture Treatment for Chronic Post-traumatic 
Headache in Individuals with Mild Traumatic Brain 
Injury. 
  
Protocol Number: Version 11 
National Clinical Trial (NCT) Identified Number: NCT04369911 
Principal Investigator: Amanda A. Herrmann, PhD 
Site/Sponsor: HealthPartners Neuroscience Center, HealthPartners Clinic St. 
Paul Como, and Healing Response Acupuncture & Functional 
Neurology/HealthPartners Institute 
Institutional Review Board Number: A19-094 
Funded by: Minnesota Office of Higher Education 
03 March 2023 
 

 
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recipient that no unpublished information contained herein will be published or disclosed without prior 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 
terms of the award. 
 
 

 
Protocol Amendment Version 3:  
Summary of changes to the protocol due to the COVID-19 Pandemic 
 
This protocol has been amended to account for changes due to the COVID-19 pandemic, which has 
resulted in increased health and safety concerns for study participants and clinical research staff. 
Specifically, the risks are primarily due to how easily the virus can be transmitted with person-to-person 
contact. 
 
The specific changes to the protocol are summarized below. The primary rationale for these changes is 
to reduce contact time between patients and study staff, while maintaining their health and safety. 
 
• 
Addition of 3 healthy volunteer practice participants. Previously, we obtained IRB approval to test 
our protocol on 3-5 healthy volunteers. Because we tested all 5 practice participants prior to the 
pandemic, we are requesting an additional 3 volunteer participants. Practicing the protocol on 3 
additional participants will ensure that the acupuncturists have recent protocol training prior to 
recruitment and will allow them to practice under the new COVID-19 policies and procedures (e.g. 
utilizing appropriate PPE under COVID-19 guidelines). 
• 
Study visits completed via phone. All study visits, except for the acupuncture treatment visits, will 
be converted to phone visits. This will be done to decrease study staff and patient exposure time. 
• 
Informed consent and study assessments completed electronically. Informed consent for the study 
will be obtained through a phone call with study staff and electronically through a Research 
Electronic Data Capture (REDCap) survey sent via e-mail. All study assessments will be obtained 
through REDCap surveys sent via e-mail. 
• 
Appropriate COVID-19 screening procedures and personal protective equipment (PPE) will be 
utilized for all acupuncture treatment visits. We will screen participants for COVID-19 by phone 1-2 
days before each scheduled acupuncture treatment visit and also the day of the clinic visit. If a 
patient screens positive for COVID-19, study visits will be postponed for the appropriate amount of 
time per current guidance, and we will follow the current clinic site process for COVID-19 positive 
screens, as defined by the medical group. This study will also align with the HealthPartners 
Neuroscience Center policies regarding PPE for in-person visits. This will be done to ensure the 
safety of patients and study staff. 
• 
Finally, this study will align with HealthPartners Neuroscience Center’s COVID-19 policies and 
procedures. 
Protocol Amendment Version 4: 
Summary of changes to the protocol due to the COVID-19 Pandemic 
• 
Addition of COVID-19 Questions. The addition of questions related to COVID-19 will be done to 
potentially explore whether acupuncture has an effect on post-COVID-19 symptoms. The questions 
below will be asked at 2 time points: at the beginning of first acupuncture appointment and at the 4-
week post-treatment visit (4 weeks after the last acupuncture treatment). They will be collected 
electronically via REDCap. As an exploratory analysis, patients who report post-COVID-19 symptoms 
will be identified using the additional COVID-19 set of questions. Types and severity of post-COVID-
19 symptoms present within the group will be described. The t-test or non-parametric equivalent 
will be used to determine whether acupuncture had an effect on post-COVID symptoms. The 
protocol has been updated to reflect the changes and the questions are listed below. 

 
Questions: 
1) Have you previously received a positive test for COVID-19? (yes/no) 
2) Were you exposed to someone with a positive test, subsequently developed symptoms, but 
did not get a COVID-19 test? (yes/no) 
3) Are you currently experiencing any of the following post-COVID-19 symptoms? 
(Drop down list with most common symptoms, select all that apply) 
a. Fatigue 
b. Difficulty breathing 
c. Joint pain 
d. Chest pain 
e. Brain fog, including an inability to concentrate and impaired memory 
f. Loss of taste and/or smell 
g. Sleep issues 
h. Other: Specify – (free text to type in) 
4) If a participant answers yes to any of the symptoms: How would you rate your symptoms? 
a. Mild: you have symptoms, but they are not a problem 
b. Moderate: your symptoms limit your normal daily activities 
c. Severe: your symptoms make normal daily activities challenging or impossible 

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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 ............................................................................................................... 8 
2.1 
Background & Study Rationale................................................................................... 8 
2.2 
Risk/Benefit Assessment........................................................................................... 9 
2.2.1 
Known Potential Risks............................................................................... 9 
2.2.2 
Known Potential Benefits .........................................................................11 
2.2.3 
Assessment of Potential Risks and Benefits .................................................11 
3 
OBJECTIVES AND ENDPOINTS............................................................................................11 
4 
STUDY DESIGN................................................................................................................12 
4.1 
Overall Design ........................................................................................................12 
4.2 
Scientific Rationale for Study Design..........................................................................12 
4.3 
Justification for Intervention ....................................................................................12 
4.4 
End-of-Study Definition ...........................................................................................13 
5 
STUDY POPULATION ........................................................................................................13 
5.1 
Inclusion Criteria ....................................................................................................13 
5.2 
Exclusion Criteria ....................................................................................................13 
5.3 
Lifestyle Considerations...........................................................................................13 
5.4 
Screen Failures .......................................................................................................13 
5.5 
Strategies for Recruitment and Retention ..................................................................14 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ...........................................14 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration...........................14 
6.1.1 
Study Intervention or Experimental Manipulation Description .......................14 
6.1.2 
Administration and/or Dosing ...................................................................15 
6.2 
Fidelity..................................................................................................................15 
6.2.1 
Interventionist Training and Tracking .........................................................15 
6.3 
Measures to Minimize Bias: Randomization and Blinding .............................................16 
6.4 
Study Intervention/Experimental Manipulation Adherence ..........................................16 
6.5 
Concomitant Therapy..............................................................................................16 
6.5.1 
Rescue Therapy ......................................................................................16 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..............................................................................................16 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ................................17 
7.2 
Participant Discontinuation/Withdrawal from the Study ..............................................17 
7.3 
Lost to Follow-Up ...................................................................................................17 
8 
STUDY ASSESSMENTS AND PROCEDURES............................................................................18 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................18 
8.2 
Safety Assessments.................................................................................................18 

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8.3 
Adverse Events and Serious Adverse Events ...............................................................19 
8.3.1 
Definition of Adverse Events .....................................................................19 
8.3.2 
Definition of Serious Adverse Events ..........................................................19 
8.3.3 
Classification of an Adverse Event .............................................................19 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ..................20 
8.3.5 
Adverse Event Reporting ..........................................................................21 
8.3.6 
Serious Adverse Event Reporting ...............................................................21 
8.3.7 
Reporting Events to Participants................................................................21 
8.3.8 
Events of Special Interest .........................................................................21 
8.3.9 
Reporting of Pregnancy............................................................................21 
8.4 
Unanticipated Problems ..........................................................................................22 
8.4.1 
Definition of Unanticipated Problems ........................................................22 
8.4.2 
Unanticipated Problems Reporting ............................................................22 
8.4.3 
Reporting Unanticipated Problems to Participants .......................................22 
9 
STATISTICAL CONSIDERATIONS ..................................................................................23 
9.1 
Statistical Hypotheses .............................................................................................23 
9.2 
Sample Size Determination ......................................................................................23 
9.3 
Populations for Analyses..........................................................................................24 
9.4 
Statistical Analyses .................................................................................................24 
9.4.1 
General Approach ...................................................................................24 
9.4.2 
Analysis of the Primary Endpoint(s) ...........................................................24 
9.4.3 
Analysis of the Secondary Endpoint(s) ........................................................24 
9.4.4 
Safety Analyses.......................................................................................25 
9.4.5 
Baseline Descriptive Statistics ...................................................................25 
9.4.6 
Planned Interim Analyses .........................................................................25 
9.4.7 
Sub-Group Analyses ................................................................................25 
9.4.8 
Tabulation of Individual Participant Data ....................................................25 
9.4.9 
Exploratory Analyses ...............................................................................25 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..................26 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..............................................26 
10.1.1 
Informed Consent Process........................................................................26 
10.1.2 
Study Discontinuation and Closure ............................................................26 
10.1.3 
Confidentiality and Privacy .......................................................................27 
10.1.4 
Future Use of Stored Specimens and Data ..................................................28 
10.1.5 
Key Roles and Study Governance...............................................................28 
10.1.6 
Safety Oversight .....................................................................................28 
10.1.7 
Clinical Monitoring ..................................................................................28 
10.1.8 
Quality Assurance and Quality Control .......................................................28 
10.1.9 
Data Handling and Record Keeping ............................................................29 
10.1.10 
Protocol Deviations .................................................................................29 
10.1.11 
Publication and Data Sharing Policy ...........................................................29 
10.1.12 
Conflict of Interest Policy .........................................................................29 

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10.2 
Additional Considerations ........................................................................................30 
10.3 
Abbreviations and Special Terms ..............................................................................30 
10.4 
Protocol Amendment History ...................................................................................31 
11 
REFERENCES...................................................................................................................32 
 

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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).  
 
Investigators and clinical trial site staff who are responsible for the conduct, management, or oversight of 
clinical trials have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and participant materials will be 
submitted to the Institutional Review Board (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:  Amanda A. Herrmann, PhD 
Title: 
Research Fellow 
 
Investigator Contact Information 
Affiliation: HealthPartners Neuroscience Center 
Address: 295 Phalen Blvd. 
       St. Paul, MN 55130 
   Mailstop 41200A 
Telephone: (651) 495-6356 
Email: Amanda.A.Herrmann@HealthPartners.com 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Acupuncture Treatment for Chronic Post-traumatic Headache in 
Individuals with Mild Traumatic Brain Injury. 
IRB Number: 
A19-094 
Study Description: 
The purpose of the study is to determine the effect of a low vs. high 
dose of acupuncture treatment in individuals with chronic post-
traumatic headache (CPTH). A total of 40 people with mild traumatic 
brain injury (mTBI) suffering from CPTH will be enrolled in this study to 
receive acupuncture treatment for 5 weeks. Participants will be 
randomized into two groups: 1) Low Acupuncture group (5 treatments) 
and 2) High Acupuncture group (10 treatments). We hypothesize that 
both treatment groups will have decreased headaches, but that 10 
treatments will greater alleviate headaches when compared to 5 
treatments. 
 
Specific Aims: 
 
Specific Aim 1: To determine the effect of a low versus high dose 
acupuncture treatment on number of headache days for individuals 
suffering from CPTH. 
Specific Aim 2: To determine the safety and tolerability of acupuncture 
on CPTH in individuals with mTBI. 
Specific Aim 3: To explore the effects of acupuncture on sleep, quality 
of life (QOL), headache outcomes, and medications in individuals 
with mTBI who suffer from CPTH. 
Endpoints: 
Primary Endpoint: Number of headache days over 4 weeks 
Secondary Endpoints: 1) Adverse or Serious Adverse Events and 2) 
Completion of treatment durations and sessions 
Exploratory Endpoints: 1) Sleep, 2) Quality of life, 3) Headache 
Outcomes, and 4) Medications 
Study Population: 
40 individuals aged 18-70 with a diagnosis of mTBI suffering from CPTH 
will be recruited for this study. 
Description of 
Sites/Facilities Enrolling  
Participants: 
 
Participants will be enrolled at HealthPartners Neuroscience Center, 
and will be treated at the Neuroscience Center, HealthPartners Clinic 
St. Paul Como, or Healing Response Acupuncture & Functional 
Neurology. 
Description of Study 
Intervention/Experimental 
Manipulation: 
 
Acupuncture treatment will be administered by a licensed 
acupuncturist for a duration of 5 weeks. One treatment group will 
receive 5 treatments and the other will receive 10 treatments. 
Study Duration: 
The duration of this study is 2 years.  
 
Participant Duration: 
Participants should complete all study-related tasks within 176 days 
(approximately 6 months). 
1.2 
SCHEMA  

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Visit 7 [Arm 1] 
 Visit 12 [Arm 2] 
(Day 71-106 + 7) 
Visits 2-6 [Arm 1] 
Visits 2-11 [Arm 2] 
(Days 29 + 14 to  
64 + 14) 
  
Visit 1 
(Day 1) 
  
Pre-screening  
Phone Call 
  
Visit 8 [Arm 1]  
Visit 13 [Arm 2] 
(Day 127-169 + 7) 
Pre-screen potential participants by inclusion and 
exclusion criteria. 
Schedule Pre-treatment Visit. 
Pre-treatment Visit 
Conduct informed consent process. Perform baseline assessments: 
•
Pittsburgh Sleep Quality Index (PSQI) 
•
Traumatic Brain Injury-Quality of Life (TBI-QOL) short forms 
•
Medication Review 
Randomize N = 36 
Arm 1 
N = 18 
Study intervention (Low Dose) 
•
Acupuncture treatment  
       1x/week for 5 weeks (5 total) 
•
Completed Headache Diary 
•
Adverse Events Reporting 
•
Medication Review 
•
Treatment Adherence 
Study intervention (High Dose) 
•
Acupuncture treatment  
       2x/week for 5 weeks (10 total) 
•
Completed Headache Diary  
•
Adverse Events Reporting 
•
Medication Review 
•
Treatment Adherence 
4-week Post-treatment Visit 
Perform assessments: 
•
Completed Headache Diary 
•
Adverse Events Reporting  
•
Medication Review 
•
PSQI 
•
TBI-QOL short forms 
12-week Post-treatment Visit 
Perform final assessments: 
•
Completed Headache Diary 
•
Adverse Events Reporting 
•
Medication Review 
•
PSQI 
•
TBI-QOL short forms 
Arm 2 
N = 18 

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1.3 
SCHEDULE OF ACTIVITIES 
 
 
 
VISIT SCHEUDULE DESCRIPTION 
 
All in-person visits will take place at: HealthPartners Neuroscience Center, 295 Phalen Boulevard, St. 
Paul, MN, 55130, or HealthPartners Clinic St. Paul Como, 2500 Como Ave, St. Paul, MN 55108, or 
Healing Response Acupuncture & Functional Neurology, 1940 Greeley St. S, Suite 108, Stillwater, MN 
55082. 
 
1. Pre-screening Phone Call 
• 
Duration: Approximately 30 minutes 
• 
Research staff will: 
o Provide potential participants information about the study and ask whether 
they are interested in participating. 
o Determine whether they meet the inclusion/exclusion criteria for the study. 
o Ask participants for permission to communicate through e-mail for the study 
(e.g. send them study documents and surveys to complete). 
 
Pre-screening 
Phone Call 
Pre-treatment 
Visit 
Study 
Intervention 
4-week Post-
treatment Visit 
12-week Post-
treatment Visit 
Arm 1:  
5 Treatments 
Visit 0 
Visit 1 
Visit 2-6 
Visit 7 
Visit 8 
Arm 2:  
10 Treatments 
Visit 2-11 
Visit 12 
Visit 13 
Review Eligibility 
X 
 
 
 
 
Informed 
Consent 
 
X 
 
 
 
Demographics 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
Medication 
Review 
 
X 
X 
X 
X 
Completed 
Headache Diary 
 
 
X 
X 
X 
Pittsburgh Sleep 
Quality Index 
(PSQI) 
 
X 
 
X 
X 
Traumatic Brain 
Injury-Quality of 
Life (TBI-QOL) 
short forms 
 
X 
 
X 
X 
Adverse Events 
(AE) Reporting 
 
 
X 
X 
X 
Treatment 
Adherence 
 
 
X 
 
 

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o Assist participants with setting up an e-mail account, if they do not have one. 
o Schedule Pre-treatment Visit if the person is eligible for the study and e-mail the 
person the Informed Consent, Health Insurance Portability and Accountability 
Act (HIPAA), and HealthPartners non-discrimination forms. 
 
2. Pre-treatment Visit 
• 
Duration: Approximately 1 hour via phone 
• 
Research staff will:  
o Review the Informed Consent and HIPAA documents with potential participants. 
o Answer any questions of potential participants and ensure they understand the 
expectations of the study.  
o Ask participants to electronically sign the Informed Consent and HIPAA 
documents via REDCap and provide them electronic copies for their records. 
o Complete the Demographics and Medication Reviewshort forms in the relevant 
electronic case report forms (eCRFs) in Research Electronic Data Capture 
(REDCap), a secure web-based system. 
o E-mail the Pittsburgh Sleep Quality Index (PSQI) and Traumatic Brain Injury-
Quality of Life (TBI-QOL) surveys to the patient for completion. Ask patients to 
complete the surveys prior to their first acupuncture visit. During the reminder 
call for the acupuncture visit, patients will be reminded to complete the surveys 
if they have not yet completed them. 
o Provide participants instructions regarding the Headache Diary REDCap survey 
(example script below): 
1. “You will receive a Headache Diary survey via e-mail once a week for the 
next 4 weeks. Each survey will ask questions about your headaches over 
the last week. What is most important for you to remember is the 
number of headaches you had. The rest of the information is also 
helpful.” 
2. Provide participants a paper diary and ask them to use it to keep track 
of their headaches during the week. Instruct participants that they 
should use it to fill out the weekly e-mail survey. 
3. Show participants an example of the REDCap survey. 
 
3. Study Intervention 
• 
Duration: Each visit approximately 1 hour 
• 
A study acupuncturist will:  
o Complete the Adverse Events (AE) Reporting, Medication Review, and 
Treatment Adherence in the relevant eCRFs in REDCap. 
o Perform the acupuncture treatment. 
• 
Only at the LAST acupuncture visit, a study acupuncturist will: 
o Provide participants instructions regarding the Headache Diary REDCap survey 
(example script below): 
1. “Like you experienced before, you will receive a Headache Diary survey 
via e-mail once a week for the next 4 weeks. Each survey will ask 
questions about your headaches over the last week. What is most 
important for you to remember is the number of headaches you had. 
The rest of the information is also helpful.” 

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2. Provide participants a paper diary and ask them to use it to keep track 
of their headaches during the week. Instruct participants that they 
should use it to fill out the weekly e-mail survey. 
3. Show participants an example of the REDCap survey. 
 
4. 4-week Post-treatment Visit 
• 
Duration: Approximately 30 minutes via phone 
• 
Research staff will:  
o Complete the AE Reporting and Medication Review forms in the relevant eCRFs 
in REDCap. 
o E-mail the PSQI and TBI-QOL surveys to the patient for completion. Ask patients 
to complete the surveys within one week. Five days after the visit, patients will 
receive a reminder call if they have not yet completed the surveys. 
o Provide participants instructions regarding the Headache Diary REDCap survey 
(example script below): 
1. “Like you experienced before, you will receive a Headache Diary survey 
via e-mail once a week for the next 4 weeks. Each survey will ask 
questions about your headaches over the last week. What is most 
important for you to remember is the number of headaches you had. 
The rest of the information is also helpful.” 
2. Provide participants a paper diary and ask them to use it to keep track 
of their headaches during the week. Instruct participants that they 
should use it to fill out the weekly e-mail survey. 
3. Show participants an example of the REDCap survey. 
 
5. 12-week Post-treatment Visit 
• 
Duration: Approximately 30 minutes via phone 
• 
Research staff will:  
o Complete the AE Reporting and Medication Review forms in the relevant eCRFs 
in REDCap. 
o E-mail the PSQI and TBI-QOL surveys to the patient for completion. Ask patients 
to complete the surveys within one week. Five days after the visit, patients will 
receive a reminder call if they have not yet completed the surveys. 
 
 

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2 
 
INTRODUCTION 
2.1 
BACKGROUND & STUDY RATIONALE 
 
Chronic post-traumatic headache (CPTH) after a mild traumatic brain injury (mTBI) is extremely 
debilitating, dramatically impacts function and quality of life, and is the most frequent type of chronic 
pain reported after injury.1 It has been estimated that approximately 17.1 million Americans suffer a 
traumatic brain injury (TBI) each year,2 with CPTH estimated to occur in 57.8% of these individuals.3 CPTH 
presents as: 1) tension-like (mild-moderate dull pain), 2) migraine headache (moderate-severe throbbing 
pain), or 3) combined tension-like and migraine headache.1 On average, the number of reported headache 
days each month for individuals suffering from CPTH is 26,4 which is almost daily. Individuals suffering 
from CPTH are more likely to have post-traumatic stress disorder, cognitive symptoms, and somatic 
symptoms.4 They are also more likely to perceive difficulties in their physical and social function.4 
Consequently, it is not surprising that CPTH is extremely agonizing and frustrating for individuals with 
mTBI. 
 
There are currently no FDA approved pharmacological treatments specifically for CPTH and the long-term 
effects of pharmacologic treatments on recovery after TBI are unclear.5 Thus, individuals are typically 
prescribed medications that target the particular type of headache (e.g. triptan for a migraine headache).5 
Non-narcotic analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and triptans are often prescribed 
for headache and migraine treatment and have been recommended to be coupled with non-
pharmacological treatments, such as physical therapy, biofeedback, and relaxation training.6 However, 
because the long-term effects of pharmacologic treatments on recovery after TBI are unclear, non-
pharmacologic or behavioral treatments for CPTH are very appealing.5 
 
As an alternative, acupuncture is a non-pharmacologic treatment that has been explored for CPTH. 
Acupuncture has been practiced in Chinese medicine for over 4,000 years.7 It is a technique where fine 
needles are inserted into specific areas of the body to achieve a therapeutic benefit.7 Historically, 
acupuncture is based on a Chinese/East Asian medical theory that acupuncture restores normal function 
to the body by balancing Qi.7 Although the mechanism of acupuncture is not fully understood, previous 
research has shown that it has a regulating effect on the nervous system8 and it has been effective for 
treating a wide range of chronic pain conditions, including headaches and migraines.9 
 
Acupuncture has been shown to be safe and effective treatment for individuals suffering from headaches 
and migraines. Acupuncture has been used and reported by physicians in the United States as early as the 
1600s and has been researched since the 1800s. Most of the early reports were of individual patient cases, 
whereas the first randomized controlled trial of acupuncture treatment was published in 1975.10 While 
there are still many theories regarding the mechanism of acupuncture, research has provided evidence 
for the benefits of acupuncture in several medical indications, including for migraine and tension 
headache. Acupuncture has been shown to be efficacious for both acute migraine treatment, migraine 
prophylaxis, and tension headache treatment.11 In addition, acupuncture has been shown to be more 
effective than, or as effective as pharmacotherapy with fewer side effects.11-13 It has also been shown to 
decrease migraine11,12 and tension headache11 frequency, reduce pain intensity,11,12,14 decrease the use of 
acute medication,14 and improve quality of life.12 Importantly, the safety of acupuncture has been well 
documented. Although both minor and serious adverse events (AEs) have been reported, serious 
complications related to acupuncture are rare.15 
 

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While acupuncture is currently well-accepted as a behavioral treatment for individuals with chronic pain, 
headaches, and migraines,9 it has not been extensively examined in individuals with CPTH. Although there 
have been studies as early as the 1980s that have shown improvements in headache symptoms with 
acupuncture for individuals who have suffered from mTBI,16,17 there have been a limited number of 
studies since. In two recent case reports, acupuncture combined improved acute post-traumatic 
headache symptoms in an individual who suffered a mTBI.18,19 In another recent study, acupuncture 
improved headache-related quality of life and reduced overall pain in adult service members with mild-
to-moderate TBI suffering from CPTH.20 Therefore, although there is a paucity of research examining 
acupuncture for CPTH, it has shown efficacy in patients with chronic headaches and migraines,11 and 
researchers have suggested that it be investigated and considered for treatment of CPTH.21 In addition, 
while they did not examine CPTH specifically, four randomized controlled trials investigated acupuncture 
treatment in individuals with TBI and reported no AEs.22 Thus, acupuncture could potentially be a safe and 
viable alternative to medication for individuals with mTBI suffering from CPTH. 
 
Because acupuncture for CPTH has not been extensively examined, there is also no consensus on the 
number of acupuncture sessions that are necessary for improvement. In the study of service members 
with mild-to-moderate TBI suffering from CPTH, 10 sessions of acupuncture were administered over 6 
weeks.20 Because the two case studies were examining acupuncture for acute post-traumatic 
headache,18,19 the specific treatment methods may not be applicable for CPTH. In a recent review of 
acupuncture for chronic headaches and migraines, 6-10 weekly or twice-weekly acupuncture sessions 
were reported to be most effective.21 However, the amount of acupuncture necessary for improvement 
in individuals suffering from CPTH is unclear. Thus, the primary goal of this study is to determine the effect 
of a low versus high dose of acupuncture treatment on number of headache days for individuals suffering 
from CPTH. 
 
2.2 
RISK/BENEFIT ASSESSMENT  
2.2.1 KNOWN POTENTIAL RISKS  
 
Acupuncture Treatment 
Reported Side Effects23: 
 
Common 
1-10 out of 100 people 
Uncommon 
1-10 out of 1,000 people 
Rare 
1-10 out of 10,000 people 
Very Rare 
<1 out of 10,000 people 
Bleeding 
Inflammation/swelling  Local infection 
Palpitations 
Hematoma (bleeding 
outside of vessels) 
Bruising 
Redness 
Constipation 
 
Pain during needling 
Itching 
Diarrhea 
Local muscle pain 
Sweating 
Gastrospasm  
(stomach spasm) 
Nerve irritation or 
injury 
Decrease/increase of 
blood pressure 
Enterospasm  
(spasm of the intestine) 
Headache 
Unconsciousness 
Weight loss 
Fatigue 
Tachycardia 
Circulatory disturbance 
Dizziness 
Breathing difficulties 
Lesion of blood vessels 
Nausea 
Vomiting 
Systemic infection 

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Exacerbation of 
symptoms that led to 
treatment 
Worsening health state 
Euphoria 
 
Generalized muscle pain 
Nightmares 
Restricted movement 
Poor concentration 
Joint problems 
Imbalance 
Feeling of coldness 
Disturbance of speech 
Menstrual problems 
Disorientation 
Depressive mood 
Shivering 
Anxiety 
Eye irritation 
Sleep disturbance 
Broken (retained) 
needles 
Restlessness/nervousness Organ puncture/ 
Pneumothorax 
Disturbed vision 
Injury of the central 
nervous system  
Tinnitus 
Injury of the 
pericardium 
 
Additional potential risks specific to electroacupunture treatment and minimization of these risks 
Potential risks24: 
• 
Increased depth and altered angulation of needles to ensure needles can support the weight of 
the leads and clips. 
o We plan to use microclips, which are much lighter than alligator clips, so this risk will be 
dramatically minimized. 
• 
Vigorous muscle contraction causing needle movement (e.g. need drawn deeper into the body). 
o The goal of acupuncture treatment in this study is not to illicit a muscle twitch. The goal 
is to induce a mild level of sensation, which typically does not cause muscle contraction. 
Thus, we do not anticipate vigorous muscle contractions or unsafe needle movement. 
• 
Minor risks have been reported for acupuncture treatment of the abdominal muscles, over the 
rib cage, the carotid sinus, the laryngeal muscles, and the vagus nerve. 
o For this study, we will not be performing acupuncture treatment in any of these areas, so 
we do not anticipate these risks. 
• 
Risk of cardiac arrest with excessive current (risks reported around 50mA).  
o The Pantheon Research 8c.Pro stimulator we will use for this study has a current range of 
0-15 mA, therefore we will be simulating with a current that is much lower than the range 
for this risk. 
o There is also a risk of excessive current if electrostimulation devices are plugged into the 
main electrical supply. The Pantheon Research 8c.Pro stimulator that we will use for this 
study is battery operated, therefore we do not anticipate this risk. 
• 
Interference with implantable cardioverter defibrillators, pacemakers, or other implantable 
devices. 
o We have minimized this risk for our study by excluding anyone with a history of cardiac 
arrhythmia or current pacemaker, neurostimulator, or other implanted stimulation 
device. 
• 
Seizures 
o We have minimized this risk for our study by excluding anyone with a history of seizures. 

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o In addition, there have not been any reports linking electroacupuncture to seizures. 
 
Assessments/Questionnaires (Headache Diary, PSQI, & TBI-QOL) 
Participants will be asked to complete a headache diary 3 times, each time for a duration of 4-weeks. This 
may be difficult or tiring for participants. The PSQI and the Traumatic Brain Injury-Quality of Life (TBI-QOL) 
are standardized questionnaires that will measure personal perception of life and sleep quality. The 
questions on these assessments may make participants feel uncomfortable because some parts may be 
easy to answer, while some parts may be difficult or tiring. Filling out the questionnaires may also cause 
individuals to feel uncomfortable or upset. 
 
Loss of Confidentiality 
There may be a slight possibility of breach of confidential information that was collected. However, the 
following procedures will be implemented to reduce this risk: 
• 
Data collection and reporting tools will be developed and stored internally. 
• 
Data collected and stored electronically will remain confidential and secure (e.g. secured server 
and password protected files [REDCap]).  
• 
Study binders will be stored in a locked file cabinet within a locked office. 
• 
After the study is closed, all subject identifiers will be destroyed. 
 
2.2.2 KNOWN POTENTIAL BENEFITS  
 
Acupuncture has been shown to be a safe and effective treatment for individuals suffering from headache 
and migraines. Although there is less evidence for individuals with mTBI suffering from CPTH, acupuncture 
treatment may provide headache relief to patients. 
 
2.2.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
We believe the potential risks to the participants in this study are minimal and that the benefit of 
understanding how much acupuncture treatment is needed for headache relief in individuals with CPTH 
outweighs the potential risks. 
 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To determine the effect of a low versus high dose 
of acupuncture on number of headache days per 
month in individuals with mTBI suffering from 
CPTH.  
Number of headache days over 4 weeks 
Secondary 
 
To determine the safety and tolerability of 
acupuncture on CPTH in individuals with mTBI. 
1. Adverse or Serious Adverse Events 
2. Completion of treatment durations and 
sessions 
Exploratory  
 
To explore the effects of acupuncture on sleep, 
quality of life, headache outcomes, and 
1. Pittsburgh Sleep Quality Index 
2. Traumatic Brain Injury-Quality of Life 

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OBJECTIVES 
ENDPOINTS 
medications in individuals with mTBI who suffer 
from CPTH. 
3. Headache Outcomes 
4. Medications 
 
4 
STUDY DESIGN 
 
4.1 
OVERALL DESIGN 
 
Study Design: 
This study is an unblinded, uncontrolled randomized, 2-arm clinical trial. 
 
Hypotheses: 
Primary Hypothesis: We hypothesize that both treatment groups will have decreased headaches. 
Secondary Hypothesis: We hypothesize that acupuncture will be safe and tolerated in both groups. 
 
Randomization: 
Prior to the first acupuncture treatment visit, participants will be randomized into two treatment groups. 
Randomization is explained in Section 6.3. 
 
Acupuncture Treatment Groups: 
 
Group 1: 18 participants will receive acupuncture treatment 1x per week for 5 weeks = 5 total. 
 
Group 2: 18 participants will receive acupuncture treatment 2x per week for 5 weeks = 10 total.  
 
Study Intervention: 
Acupuncture treatment will consist of a standardized treatment protocol designed for this study. 
Specifically, 18 needles will be inserted into specific areas of the body for a duration of 30 minutes. 
Additional details of the treatment are discussed in Section 6.1. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Justification for an unblinded study: Because it will be clear to both study personnel and participants who 
is receiving 5 vs. 10 treatments, neither will be blinded in this study. This will be reported as a limitation 
of the study. 
 
Justification for an uncontrolled study with no control group: Because there is already evidence that 
acupuncture treatment improved headache-related quality of life and reduced headache pain in 
individuals suffering from CPTH20, the goal of this study was to provide treatment to both groups and to 
determine whether a low or high dose of treatment is more effective. 
 
4.3 
JUSTIFICATION FOR INTERVENTION 
 
Acupuncture is a treatment that has been practiced for over 4,000 years and is well-accepted by many 
cultures. Although the mechanism is not well understood, acupuncture has been shown to be safe and 
effective at treating headaches and migraines. The number of treatments will be examined to determine 
whether 5 or 10 treatments is more effective at treating CPTH. The 30-minute treatment duration was 
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4.4 
END-OF-STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed study/treatment visits 
and assessments. Study withdrawals are described in Section 7. The end of the study is defined as 
completion of the 12-week post-treatment visit shown in the Schedule of Activities, Section 0. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• Ability to provide and provision of signed and dated informed consent form 
• Age 18-70 
• Diagnosis of mTBI (as defined by ICHD-3; a. Either no loss of consciousness, or loss of 
consciousness of <30 minutes duration, b. Glascow Coma Scale (GCS) ≥ 13, and c. Symptoms 
and/or signs diagnostic of concussion)25 
• Diagnosis of mTBI ≥3 months and ≤2 years at the time of study enrollment 
• Suffering from CPTH of any etiology (e.g. tension or migraine), with chronic defined as 
developed within 7 days after injury and lasting ≥3 months from the time of injury25 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
• 
Non-English speaking 
• 
Participation in acupuncture treatment outside of the study, while enrolled 
• 
History of pre-existing primary headache, defined as more than 12 days of tension-type headache 
annually and/or more than one migraine attacks per month in the last year4 
• 
History of any other serious neurological, psychiatric, chronic pain disorders, or seizures 
• 
History of bleeding diathesis, other bleeding disorders, or syncope with needle puncture 
• 
History of cardiac arrhythmia or current pacemaker, neurostimulator, or other implanted 
stimulation device 
• 
Recent or active substance use disorder 
• 
Women who are currently pregnant, lactating, or planning to become pregnant during the study 
• 
Any other medical conditions that could affect their ability to participate in acupuncture 
treatments for the study duration (as determined by study investigators) 
• 
Active participation or past participation ≤3 months in any other interventional study. 
• 
Unwilling to participate in all study related activites 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
N/A  
5.4 
SCREEN FAILURES 
 
Pre-screening Phone Call: 

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All potential participants will undergo a pre-screening phone call to determine whether they meet the 
inclusion/exclusion criteria. Patients will be considered ineligible if they do not meet one or more of the 
inclusion/exclusion criteria during pre-screening. We will collect information on why participants are 
ineligible or decide not to move forward with the trial. 
 
Pre-treatment Visit: 
Screen failures are defined as participants who are considered eligible during the pre-screening phone 
call, but it was subsequently determined that they do not meet one or more of the inclusion/exclusion 
criteria at or after the Pre-treatment (baseline) visit. We will collect information on why participants 
screen fail or decide not to move forward with the trial.  
 
Rescreening Patients: 
Individuals who do not meet the criteria for participation in this trial (ineligible or screen failure) because 
of meeting one or more exclusion criteria that are likely to change over time may be rescreened up to one 
time. Examples include: successful treatment for a substance use disorder; women who are no longer 
pregnant, lactating, or planning to become pregnant; or participation in an interventional study ≥3 months 
prior. Rescreened participants will be assigned a new participant number. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment: Individuals with mTBI suffering from CPTH will be recruited by physician and therapist 
referrals from HealthPartners’ clinics. We will also advertise our research study by distributing flyers to 
HealthPartners’ physicians and throughout HealthPartners’ clinics. Recruitment flyers will also be 
provided to our community partners for example, the Minnesota Brain Injury Alliance, TRIA, and Allina 
Health. If we encounter difficulties with recruitment, we plan to submit an amendment to the IRB to 
contact HealthPartners patients and members and invite them to participate. 
 
To reach our target enrollment, we anticipate that we will need to screen 100 people, of those 50 
individuals will sign the informed consent, and of those 40 individuals will be randomized to treatment 
groups. We expect that we will enroll approximately 35% (~13) women and 65% (~23) men, primarily 
between the ages of 41-84, and approximately 80% will be white. Values are based on our Regions 
Hospital Rehabilitation census data. 
 
Remuneration: Participants will be provided gift cards totaling $50 per person for completing certain time 
points of the research study. Specifically, after completing all acupuncture treatment visits, participants 
will receive a $25 gift card. After completion of the 12-week post-treatment visit (end of study visit) 
participants will receive another $25 gift card. 
 
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 
 

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The study intervention for both groups is acupuncture treatment. Acupuncture is a treatment where fine 
needles are inserted into specific areas of the body to achieve a therapeutic benefit. The treatment 
regimen is described next in more detail. 
6.1.2 ADMINISTRATION AND/OR DOSING 
 
Acupuncture Treatment Methods:  
Group 1 will receive weekly acupuncture and Group 2 will receive twice-weekly acupuncture over five 
weeks. Acupuncture treatments will be separated by a minimum of 2 days and a maximum of 14 days, 
unless a participant has an illness, such as COVID-19. In this case, additional time may be allowed, as 
determined by the investigator. Treatment methods will be identical for both groups and are described 
below. 
Standard, sterile stainless-steel, disposable needles (DongBang™ Corporation, Spring Ten 0.25x30mm; 
Boryeoung, Republic of Korea) will be inserted in the acupuncture point locations (described below), with 
a total of 18 needles used for each treatment session. The depth of the needle insertion will be 
approximately 10-20mm, depending on the region of the body undergoing treatment. Needle reaction 
(soreness, numbness or distended feeling around the point, also known as a Deqi sensation) will occur 
during the initial insertion. Following 10 minutes of retention, all needles (except points St36 and LI4 under 
electrostimulation, and auricular points SM and PtZ) will be rotated in order to maintain Deqi sensation. 
Maintaining Deqi sensation has been shown to increase the effectiveness of acupuncture.26,27 All needles 
will be left in place for a total of 30 minutes, which is a typical duration in acupuncture practice. It also is 
a common duration of previously reported clinical trials of acupuncture for headaches and 
migraines.11,12,28 
 
Acupuncture points were selected for their classical indications, anatomical locations, effect on pain 
networks29,30 and influence on cerebral blood flow.31 The anatomical location for each point will be based 
on the World Health Organization’s acupuncture point guideline.32 Electroacupuncture will be 
administered with Pantheon Research electrostimulation 8c pro machines (Pantheon Research Inc; 
Huntington Beach, CA), with a continuous milliampere wavelength of 2Hz at stomach 36 (ST36) and large 
intestine 4 (LI4). The intensity will be gradually increased to a comfortable level that participants can 
tolerate, without the sensation of pain. Traditional Chinese manual acupuncture will be used at eight 
acupuncture points: yin tang (YT) and Du20 and bilateral acupuncture of liver 3 (LV3), urinary bladder 2 
(UB2), small intestine 19 (SI19), extra point Anmian (EX-22), and two auricular points Shen Men (SM) and 
point zero (PtZ). During treatment, acupuncture needles or electrical stimulation can be removed due to 
extreme pain or discomfort, so as not to exceed the removal of more than 2 of the 18 needles. 
6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
 
Acupuncturists: 
Acupuncture treatments will be administered by MN licensed acupuncturists with a Master’s degree level 
of training in acupuncture (or higher) from accredited institutions, and five or more years of clinical 
experience. Prior to enrolling participants, the acupuncturists will complete practice sessions together of 
the treatment protocol and methods of administration to ensure consistency between providers 
 
Training: 

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Following IRB approval and prior to recruitment and enrollment, the study acupuncturists will complete 
10 practice sessions. For the training, we will seek 12 volunteers who will sign a volunteer consent form 
prior to participating. The purpose of training will be to ensure consistency in intervention procedures 
and further standardized treatment methods. This includes, but is not limited to: needle location (18 
points), needle depth, time of first and last needle placement, total treatment duration, and pre-defined 
electro-acupuncture settings.  
 
Tracking: 
All practice sessions will be documented on a training log. This will include dates and times of the trainings, 
names of the volunteers, and printed names and signatures of the study acupuncturists. We will also keep 
a record of the volunteers’ signed treatment release forms. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Randomization:  
Randomization will be performed with a 1:1 allocation ratio. Balanced treatment assignments will be 
achieved using permuted block randomization with random block sizes stratified by gender. This decision 
was based on evidence that females in this population reported higher rates of headaches.33 The study 
biostatistician will generate a randomization schedule using the SURVERYSELECT procedure in SAS. 
Assignments will not be seen by other study personnel in advance and will not be changed after 
randomization. 
 
Blinding:  
Study personnel will be unblinded to the randomization, as it will be clear the number of participants who 
receive 5 acupuncture treatments versus those that receive 10. In addition, it will be clear to participants 
which treatment group they are in and it will be impossible to blind them from this information. 
 
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
Participants will be asked to adhere to study visits and to complete study assessments. Participants will 
remain active unless withdrawn from the study (see Section 7). We will track participants’ adherence to 
study visits, as well as completion of the assessments. These will be documented in the relevant eCRF. 
 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, participants may use non-opioid analgesics for pain control, including over-the-counter 
medications and dietary supplements, and prescribed medications. This includes use for rescue therapy 
in the event of exacerbation of symptoms due to acupuncture treatment. Medication usage will be 
assessed at each study visit and documented in the relevant eCRF. 
 
6.5.1 RESCUE THERAPY 
 
Any medications used for rescue therapy will be recorded in the Headache Diary. 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 

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7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
When a participant who signed the consent form chooses to discontinue participation in the study or 
study intervention, or if the principal investigator and co-investigators determine that a participant should 
discontinue participation, they will be withdrawn from the study. A withdrawal will either be defined as 
‘Patient Withdrawal’ or ‘Principal Investigator Withdrawal’. The participant will be asked to complete an 
early withdrawal phone call 7-14 days from the date the intervention was discontinued. The purpose of 
the phone call will be to record any AEs or serious adverse events (SAEs) that may have occurred after the 
discontinuation of treatment. Research staff will attempt to call the participant up to 3 times. 
 
The data that will be collected at the time of study withdrawal will include the following: 
• 
The reason(s) for discontinuation of the study intervention 
 
The data that will be collected during the early withdrawal phone call will include the following: 
• 
AEs or SAEs that occurred since the time of withdrawal 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
1. Participant has not completed an acupuncture treatment for > 14 days, unless a participant has 
an illness, such as COVID-19. In this case, additional time may be allowed, as determined by the 
investigator. 
2. Significant study intervention non-compliance  
3. Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
4. 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 
5. 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 relevant 
eCRF. 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 not 
be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to attend any scheduled study visit and 
study staff are unable to contact the participant after at least 5 attempts, while maintaining the 14 day 
maximum between visits. 
 
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• Study staff will attempt to contact the participant, reschedule the missed visit, 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, telephone calls or e-mail – if no 
answer leave a voicemail on the first and last attempt). These contact attempts will be 
documented. 
• 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. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
Demographics: Demographic information will be collected, including: gender, age, race, ethnicity, 
language, height, weight, marital status, employment status, date of TBI, date of CPTH diagnosis, and e-
mail address for Headache Diary surveys (discussed below). 
 
Medication Review: Medication data will be used for exploratory purposes for Specific Aim 3. 
 
Headache Diary: Participants will be sent an e-mail REDCap survey to complete and asked to record 
headache information for three 4-week time periods. During each 4-week period, they will receive the e-
mail once per week. They will be provided paper headache diaries (Appendix 1-3) to keep track of their 
headaches and will be asked to complete each e-mail survey they receive. The headache diary survey will 
include: how many headaches occurred each week during the 4-week period, duration, pain intensity (0-
10 scale), type (e.g. tension), and name of medication taken and dosage (if applicable). The outcome 
measure for Specific Aim 1 is number of headache days over 4 weeks; other variables will be exploratory. 
 
Treatment Adherence: The participant’s treatment adherence will be measured to determine tolerability 
of acupuncture. We will record the number of attended acupuncture sessions. We will also record 
participants’ ability to maintain the acupuncture duration of 30 minutes per session.  
 
Sleep: Participants will be asked to complete the Pittsburgh Sleep Quality Index (PSQI), which contains 
questions about one’s usual sleep habits during the past month. 
 
Quality of Life: Participants will be asked to complete the TBI-QOL short forms. The TBI-QOL includes the 
following domains: ability to participate in social roles and activities, anger, anxiety, attention-
concentration, cognition-general concerns, communication, depression, emotional behavior dyscontrol, 
executive function, fatigue, grief-loss, headache pain, independence, learning-memory, mobility, pain 
interference, positive affect and well-being, resilience, satisfaction with social roles and activities, self-
esteem, stigma, and upper extremity. 
 
8.2 
SAFETY ASSESSMENTS 
 
Assessment of Adverse and Serious Adverse Events: 

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AEs and SAEs will be monitored by acupuncturists during acupuncture treatment sessions, and by study 
staff during the 4-week and 12-week post-treatment visits. The acupuncturists and research staff will 
immediately notify the Principal Investigator and utilize the eCRF to record any AEs or SAEs. The PI and 
the study physician will review and categorize all AEs or SAEs and report them accordingly, as discussed 
below. 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS 
 
This protocol uses the definition of AE from 21 CFR 312.32 (a): any untoward medical occurrence 
associated with the use of an intervention in humans, whether or not considered intervention-related. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
 
This protocol uses the definition of SAE from 21 CFR 312.32 (a): An AE or suspected adverse reaction is 
considered "serious" if, in the view of either the investigator or study clinician, it results in any of the 
following outcomes: Death, a life-threatening AE, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity.  
 
1. Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
2. Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
3. 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 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.  
 

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• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study procedures administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study procedures should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study procedures, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal.  
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of study procedures). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study procedures administration makes a causal relationship improbable 
(e.g., the event did not occur within a reasonable time after administration of the study 
procedures) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study procedures administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.  
8.3.3.3 EXPECTEDNESS  
 
A clinician with expertise in TBI, CPTH, and acupuncture will be responsible for determining whether an 
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 AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate eCRF. 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. 
 
Study staff will record events with start dates occurring any time after the first acupuncture treatment 
session until the 12-week post-treatment visit. At each acupuncture treatment visit (after the 1st) and the 
4-week and 12-week post-treatment visits, study staff will inquire about the occurrence of AE/SAEs since 
the last visit. All reported events will be monitored until the 12-week post-treatment visit. Any reported 
event that is definitely or probably related to the intervention will be followed until resolution or 
stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
In consultation with the Principal Investigator (PI) and the study clinician, a trained member of the study 
team will be responsible for conducting an evaluation of an AE and shall report the results of such 
evaluation to the reviewing IRB either at the time of continuing review or within 10 working days of 
becoming aware of the event if the event is considered to be serious or meets the definition of an 
unanticipated problem involving risks to study subjects or others. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
In consultation with the PI and the study clinician, a trained member of the study team will be responsible 
for conducting an evaluation of a SAE and shall report the results of such evaluation to the reviewing IRB 
as soon as possible, but in no event later than 10 working days after the investigator first learns of the 
event. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Following IRB review of any AEs or SAEs, the PI will follow the IRB’s recommended actions. This may 
include, but is not limited to, modifying the informed consent document or process, re-consenting current 
participants, providing information to past or current participants (e.g. whenever the information may 
relate to the participant’s willingness to continue participants), and modifications to the 
protocol/research plan. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
 
Women who are currently pregnant, lactating, or planning to become pregnant during the study are 
excluded from this study. This is due to the hormonal changes that may alter headache patterns. If any 
participant who is still undergoing acupuncture treatment expectedly or unexpectedly becomes pregnant 
while active in the trial, the participant will be withdrawn from the study by the Principal Investigator. The 
participant will be asked to complete an early withdrawal phone call in 7-14 days from the date the 
intervention was discontinued for safety follow-up. 
 

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If any participant who has completed all acupuncture treatment sessions expectedly or unexpectedly 
becomes pregnant, the participant may remain in the study until study completion. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
 
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: 
 
1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being 
studied; 
2. 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 
3. 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 PI will report unanticipated problems (UPs) to the reviewing IRB. 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 will be reported to the IRB as soon as possible, but no later than 10 working days after the 
investigator first learns of the event 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Following IRB review of any unanticipated problems, the PI will follow the IRB’s recommended actions. 
This may include, but is not limited to, modifying the informed consent document or process, re-
consenting current participants, providing information to past or current participants (e.g. whenever the 
information may relate to the participant’s willingness to continue participants), and modifications to the 
protocol/research plan. 
 

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9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Endpoint: Number of headache days over 4 weeks 
We hypothesize that 10 treatments will greater alleviate headaches when compared to 5 
treatments over a 5-week treatment period. We also hypothesize that both treatment groups will 
have decreased headaches. Alternatively, our null hypothesis is that there will be no difference 
between 5 and 10 treatments. 
 
• 
Secondary Endpoints: 1) Adverse or Serious Adverse Events and 2) Completion of treatment 
durations and sessions 
We hypothesize that acupuncture will be safe and tolerated in both groups. 
 
• 
Exploratory Endpoints: 1) Sleep, 2) Quality of life, 3) Headache Outcomes, and 4) Medications 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
We require 18 subjects in each study group to achieve 80% power at a 5% significance level for our primary 
hypothesis (PASS software version 11). The primary analysis is a a two-sided two-sample t-test comparing 
the mean number of headache days over 4 weeks from a parallel-group design. We hypothesize that, 
while both groups will have decreased headaches, 10 treatments will greater alleviate headaches when 
compared to 5 treatments over a 5-week treatment period. For analysis purposes, we will analyze the 
data such that the opposite could be shown (5 treatments better reduces headaches). The null hypothesis 
is that there will be no difference between treatment groups. To conduct the power calculation, we 
assumed an equal standard deviation of 4.47,33 equivalence limits of ±1 SD, and a true difference between 
means of 0. No interim analyses are planned. The potential effect on our power if our estimates for the 
effect size are inaccurate are displayed in the table below. 
 
N 
δ 
Σ 
Power 
Alpha 
36 
4 
4.5 
0.742 
0.05 
36 
4.5 
4.5 
0.835 
0.05 
36 
5 
4.5 
0.903 
0.05 
N = total sample size; δ = treatment effect (change);  
σ = standard deviation.  
 
Based on preliminary estimates, we do not anticipate difficulty recruiting 40 subjects. HealthPartners 
Physical Medicine and Rehabilitation physicians see approximately 25 individuals with CPTH per month at 
the Neuroscience Center. Therefore we will need a 16% enrollment rate to reach our recruitment goal in 
the allotted time frame. In addition, we also plan to recruit and enroll from other HealthPartners clinics 
and within the community. If we see a 20% reduction in sample size due to dropout, withdrawal, or 
missing data, our power will be 75.8% to detect a similar effect size. This, and other possible changes in 
power due to attrition, are listed in the table below.  
 
N 
μ1 
μ2 
δ 
σ 
Power 
Alpha 
28 
26 
21.5 
4.5 
4.5 
0.727 
0.05 

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30 
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21.5 
4.5 
4.5 
0.758 
0.05 
32 
26 
21.5 
4.5 
4.5 
0.787 
0.05 
36 
26 
21.5 
4.5 
4.5 
0.835 
0.05 
N = total sample size; μ1 = mean of 5 treatment group; μ2 = mean of 10 
treatment group; δ = treatment effect (change); σ = standard deviation. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
All analyses will be performed on an intention-to-treat basis. If poor attendance at acupuncture 
treatments is observed, we will perform a per-protocol analysis as a sensitivity analysis.  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Discrete variables will be summarized using frequencies and percentages, while continuous variables will 
be summarized by means and standard deviations. If the continuous variables are found to be skewed, 
we will instead report medians and interquartile ranges. Statistical significance will be determined using 
p-values less than 0.05 and 95% confidence intervals, unless otherwise indicated. All inferential tests will 
be two-sided. For descriptive statistics (means, SDs, proportions) where no inferential statistics were 
conducted, we will refrain from making confirmative statements. All covariates will be pre-specified in the 
sections below. Any additional analyses will be described as post-hoc and exploratory.  
 
Distribution of the outcome variables will be assessed prior to conduct of our analyses to determine if the 
planned tests are appropriate. If variables are found to be non-normally distributed we will explore the 
use of log-transformations or non-parametric tests such as the Wilcoxon-Rank Tests.  
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
The number of headache days per 4 weeks will be captured via a headache diary. The primary outcome, 
change in number of headache days per 4 weeks between the pre-treatment assessment and 4-week post 
treatment assessment, will be compared using a two sample t-test. We will present the mean change by 
group with corresponding standard deviations. If baseline differences are found between study groups, 
they will be adjusted for using a linear regression model. In addition, a mixed-model analysis of variance 
(ANOVA) will be performed with data from all three time points. The outcome will be number of headache 
days per 4 weeks and it will be adjusted for group, time, and a group*time interaction. If significant 
interactions exist, line plots and post hoc tests will be used to define the nature of the interaction. 
 
Prior to analysis, we will plot our outcomes to examine their distribution and decide whether we should 
consider non-parametric analyses. Only subjects with complete data from both pre-treatment assessment 
and 4-week post treatment assessment will be included in the final analysis. Data will be analyzed per an 
intent-to-treat approach regardless of actual treatment received. If a large proportion of missing data is 
noted, we will compare baseline characteristics of subjects who completed the treatment with those who 
were lost to follow-up.  
 
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Secondary analysis are not dependent on results of primary endpoint. All secondary outcomes are 
measured as a single summary measure. 
 
Frequencies and proportions of each study group with at least one AE/SAE will be presented together 
with odds ratios and 95% confidence intervals. To assess compliance with the protocol, the amount of 
acupuncture treatments completed in the two groups will be reported in absolute numbers and 
percentages of target treatments. We will also report the proportion of participants who were unable to 
tolerate a 30-minute session of acupuncture in each treatment group. No inferential statistics will be 
conducted on these secondary outcomes.  
 
9.4.4 SAFETY ANALYSES 
 
AE/SAEs will be reported as described in section 8.3 of this document. They will be classified by severity, 
relationship to study procedures, and expectedness. No other formal safety analyses will be conducted.  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline variables will be compared between groups to ensure randomization achieved balanced 
treatment assignments. This will include demographics (e.g. gender, age, race) and medical history (e.g. 
length of stay in hospital after injury, discharge destination). All such variables are listed in section 8.1 of 
this document. Variables will be summarized using descriptive statistics (e.g. mean and SD, or frequency 
and proportion) and compared inferentially. Continuous variables will be compared using two-sample t-
tests or Wilcoxon rank tests and discrete variables will be compared using chi-square tests for 
independence or Fisher’s exact tests.  
 
9.4.6 PLANNED INTERIM ANALYSES  
 
N/A 
 
9.4.7 SUB-GROUP ANALYSES 
 
Both primary and secondary outcomes will be descriptively summarized based on gender. Our sample size 
is unlikely to allow for other meaningful sub-group analyses.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
N/A 
 
9.4.9 EXPLORATORY ANALYSES 
 
Exploratory outcomes (headache: intensity, duration, type; sleep; and QOL) will be compared between 
groups with Student’s t-test, Chi-square test, and Mann-Whitney-U test and mixed-model ANOVAs, as 
appropriate. As an exploratory analysis, patients who report post-COVID-19 symptoms will be identified 
using the additional COVID-19 set of questions. Types and severity of post-COVID-19 symptoms present 
within the group will be described. The t-test or non-parametric equivalent will be used to determine 
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As some patients’ medication adherence and regimens are expected to change throughout the 
intervention period, a sensitivity analysis will be performed for all primary and secondary endpoints in 
which we exclude patients with medication reginmen ammendments. These results will be compared to 
our main analysis to help contextualize any observed intervention effect. Patients with and without 
changes to their medications during the trial will be described separately and any differences will be 
presented. If necessary, we will conduct a sensitivity analysis in which we exclude participants that had 
protocol deviations (e.g. large delays between treatments) due to illness, for example COVID-19. 
 
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: 
 
• 
Study Volunteer Informed Consent Form 
• 
Study Participant Informed Consent Form 
• 
Recruitment Brochure 
• 
Recruitment Flyer 
• 
Early Withdrawal Phone Call Script 
• 
Lost to Follow-Up Phone Call Script 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
At the end of the Pre-screening phone call, all eligible patients will be provided a copy of the consent and 
HIPAA forms via e-mail. Patients will also be provided an electronic copy of HealthPartners’ statement of 
non-discrimination form.  During the Pre-Treatment phone call, research staff will review the consent and 
HIPAA forms with the patients. Patients will be allowed time to review all documents and ask any 
questions prior to signing electronically. Research staff will confirm that the patients understand the 
information in the forms and answer any questions. To obtain signature, the e-consent framework in 
REDCap will be utilized. This framework allows the patient initials, date, time to be stamped in the footer 
as extra identity as to who is completing the consent and HIPAA documents. Following the consent 
conversation, the staff member will sign and e-mail the consent and HIPAA electronically to the patient. 
The patient will electronically sign, certify, and submit the consent and HIPAA in REDCap.  A fully executed 
PDF copy of the consent and HIPAA will be provided electronically to the patient for their records as well 
as saved via the auto-archiver function in REDCap. Research staff will complete this process during the 
Pre-Treatment phone call, to ensure completion and assist if there are any questions.  
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 

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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, investigators, the funding agency, the IRB 
and regulatory authorities. If the study is prematurely terminated or suspended, the PI will promptly 
inform study participants, the IRB, and the funding 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 the study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
1. Determination of unexpected, significant, or unacceptable risk to participants 
2. Demonstration of efficacy that would warrant stopping    
3. Insufficient compliance of study staff to the protocol   (ie, significant protocol violations) 
4. Data that are not sufficiently complete and/or evaluable 
5. Determination of futility 
 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the funding agency, IRB, or other relevant regulatory or oversight bodies. 
 
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. 
 
All study regulatory binders will be stored in a locked file cabinet within a secure office. The internal study 
monitor, representatives of the IRB, or regulatory agencies, may inspect all documents and records 
required to be maintained by the investigator, 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 the 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 password-protected and stored on REDCap, a secure web-based system. Only research study staff will 
have access to the data. Individual participants and their research data will be assigned a unique study 
identification number. While the study is active, subject identifiers (e.g. name, MRN) will be stored in 
REDCap, however, after the study is closed all subject identifiers will be removed. 
 
The PI will ensure all mechanisms used to share data will include proper plans and safeguards for the 
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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.  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
After the study is completed, the de-identified data will be and stored in REDCap for use in future research. 
Permission to keep the de-identified data will be included in the informed consent.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Amanda Herrmann, PhD, Research Fellow 
HealthPartners Neuroscience Center 
295 Phalen Blvd. St. Paul, MN 55130 
(651) 495-6356 
Amanda.A.Herrmann@HealthPartners.com 
 
10.1.6 SAFETY OVERSIGHT 
 
There is no Data Safety Monitoring Board for this study, as acupuncture has been previously shown to be 
safe and have minimal risks. During team meetings, the PI and study will review a rolling report of adverse 
events and report them appropriately. 
 
10.1.7 CLINICAL MONITORING 
 
N/A, refer to next section. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Study staff will perform internal quality management of study conduct, data collection, documentation 
and completion. 
 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process and 10% 
of the completed consent documents. Feedback will be provided to study staff to ensure proper 
consenting procedures are followed. 
 
Source documents and the electronic data --- The majority of data will be directly entered into eCRFs in 
REDCap. To ensure accuracy for data not directly entered in REDCap, study 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 documented 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 be the responsibility of the research study staff under the supervision of the PI. The PI 
will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All data will be entered directly into eCRFs in REDCap. The data system includes password protection and 
internal quality checks by study staff to identify data that appear inconsistent, incomplete, or inaccurate. 
Treatment logs from the acupuncture treatment sessions will be scanned into and stored in REDCap.  
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Investigator records will be retained in accordance with regulatory, organizational and sponsor or grantor 
requirements, but no less than 6 years following the completion of the research.  All records will be 
maintained securely with limited access. Disposal of investigator records will be done in such a manner 
that no identifying information can be linked to research data. 
 
10.1.10 
PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol. 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.  
 
It will be the responsibility of the PI to use continuous vigilance to identify, document, and report 
deviations as soon as possible, but no later than 10 working days after identification of the protocol 
deviation. Minor deviations, which do not impact participant safety, compromise the integrity of study 
data and/or affect the participant’s willingness to participate in the research are to be reported at the 
time of continuing review. Protocol deviations will be addressed in study source documents and sent to 
the reviewing IRB per their policies. The PI will be responsible for knowing and adhering to the reviewing 
IRB requirements. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 

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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 HealthPartners Institute 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 
ANOVA 
Analysis of Variance 
CPTH 
Chronic Post-traumatic Headache 
CFR 
Code of Federal Regulations 
eCRF 
Electronic Case Report Forms 
GCP 
Good Clinical Practice 
ICH 
International Council on Harmonisation  
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
mTBI 
Mild Traumatic Brain Injury 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PSQI 
Pittsburgh Sleep Quality Index 
QOL 
Quality of Life 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
TBI 
Traumatic Brain Injury 
TBI-QOL Traumatic Brain Injury-Quality of Life 
UP 
Unanticipated Problem 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
12/12/2019 
Response to initial IRB Review 
Response to initial IRB Review 
3.0 
09/17/2020 
Addition of 3 healthy volunteer 
protocol practice participants, in-
person visits changed to phone visits 
(except acupuncture treatment 
visits), consent and assessments to 
be completed electronically, COVID-
19 changes (including PPE) will align 
with NSC clinic policies and 
procedures. 
COVID-19 Pandemic 
4.0 
02/16/2021 
Changes to the inclusion/exclusion 
critieria. (Changed to: No 
acupuncture while enrolled in the 
study and mTBI diagnosis within 2 
years.) 
COVID-19 Pandemic; slow 
recruitment/enrollment 
5.0 
03/30/2021 
Change to inclusion criteria. Change 
upper limit from 65 to 70. 
COVID-19 Pandemic; slow 
recruitment/enrollment 
6.0 
05/04/2021 
Change to acupuncture treatment 
protocol- allow for removal of 
needles or e-stim due to extreme 
pain/discomfort. Also update AE 
reporting. 
Recent minor protocol 
deviation due to removal of e-
stim due to pain/discomfort. 
7.0 
07/29/2021 
Addition of 2 healthy volunteer 
patients to train Twin City 
Acupuncture (TCA) acupuncturists 
on the study protocol. 
We are adding a consulting 
agreement for the study to 
allow 2 TCA acupuncturists to 
assist with the study 
treatments. 
8.0 
09/07/2021 
Remove inclusion criteria: “Stable 
medication regimen for ≥1 months 
and agree to adhere to his or her 
current medication treatment 
regimen through study 
participation.” 
Throughout enrollment, we 
learned that participants 
require more flexibility with 
prescription medication 
changes. We plan to continue 
to record and monitor 
medications for all patients. 
9.0 
05/26/22 
Update PN Address 
Address was incorrect 
10.0 
02/16/23 
Remove PN location and add Como 
Clinic and Healing Response 
Acupuncture 
Change in locations for 
acupuncture treatment 
11.0 
03/03/23 
Add 2 healthy volunteers, increase 
enrollment to 40 (due to 
withdrawals), Add Ayla & Michael. 
Add 2 healthy volunteers, 
increase enrollment to 40 (due 
to withdrawals), Add Ayla & 
Michael. 
 
 

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