Acupuncture Treatment for Individuals With Myasthenia Gravis
Phase: NA
Conditions: Myasthenia Gravis
Sponsor: HealthPartners Institute

 
 
Acupuncture Treatment for Individuals with Myasthenia 
Gravis 
  
Protocol Number: Version 7 
National Clinical Trial (NCT) Identified Number: NCT05230082 
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: A21-197 
Funded by: Park Nicollet Foundation 
Date: September 8th, 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recipient that no unpublished information contained herein will be published or disclosed without prior 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. 
 

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Table of Contents 
STATEMENT OF COMPLIANCE ...................................................................................................................... 1 
INVESTIGATOR’S SIGNATURE ........................................................................................................................ 2 
1 
PROTOCOL SUMMARY ....................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................... 3 
1.2 
Schema..................................................................................................................................... 3 
1.3 
Schedule of activities ............................................................................................................... 5 
2 
INTRODUCTION ................................................................................................................................. 7 
2.1 
Background & Study Rationale ................................................................................................ 7 
2.2 
Risk/Benefit Assessment.......................................................................................................... 8 
2.2.1 
Known Potential Risks ............................................................................................ 8 
2.2.2 
Known Potential Benefits ...................................................................................... 9 
2.2.3 
Assessment of Potential Risks and Benefits .......................................................... 9 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................ 9 
4 
STUDY DESIGN ................................................................................................................................... 9 
4.1 
Overall Design .......................................................................................................................... 9 
4.2 
Scientific Rationale for Study Design ..................................................................................... 10 
4.3 
Justification for Intervention ................................................................................................. 10 
4.4 
End-of-Study Definition ......................................................................................................... 10 
5 
STUDY POPULATION ........................................................................................................................ 11 
5.1 
Inclusion Criteria .................................................................................................................... 11 
5.2 
Exclusion Criteria ................................................................................................................... 11 
5.3 
Lifestyle Considerations ......................................................................................................... 11 
5.4 
Screen Failures ....................................................................................................................... 11 
5.5 
Strategies for Recruitment and Retention............................................................................. 12 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) .................................................. 12 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ............................... 12 
6.1.1 
Study Intervention or Experimental Manipulation Description .......................... 12 
6.1.2 
Administration and/or Dosing ............................................................................. 12 
6.2 
Fidelity ................................................................................................................................... 13 
6.2.1 
Interventionist Training and Tracking .................................................................. 13 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................... 13 
6.4 
Study Intervention/Experimental Manipulation Adherence ................................................. 14 
6.5 
Concomitant Therapy ............................................................................................................ 14 
6.5.1 
Rescue Therapy .................................................................................................... 14 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................................ 14 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ..................................... 14 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................................... 14 
7.3 
Lost to Follow-Up ................................................................................................................... 15 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................... 15 
8.1 
Endpoint and Other Non-Safety Assessments ....................................................................... 15 
8.2 
Safety Assessments ................................................................................................................ 16 

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8.3 
Adverse Events and Serious Adverse Events ......................................................................... 16 
8.3.1 
Definition of Adverse Events ............................................................................... 16 
8.3.2 
Definition of Serious Adverse Events ................................................................... 16 
8.3.3 
Classification of an Adverse Event ....................................................................... 17 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 18 
8.3.5 
Adverse Event Reporting ..................................................................................... 18 
8.3.6 
Serious Adverse Event Reporting......................................................................... 18 
8.3.7 
Reporting Events to Participants ......................................................................... 19 
8.3.8 
Events of Special Interest ..................................................................................... 19 
8.3.9 
Reporting of Pregnancy ....................................................................................... 19 
8.4 
Unanticipated Problems ........................................................................................................ 19 
8.4.1 
Definition of Unanticipated Problems ................................................................. 19 
8.4.2 
Unanticipated Problems Reporting ..................................................................... 20 
8.4.3 
Reporting Unanticipated Problems to Participants ............................................. 20 
9 
STATISTICAL CONSIDERATIONS ............................................................................................... 20 
9.1 
Statistical Hypotheses ............................................................................................................ 20 
9.2 
Sample Size Determination.................................................................................................... 20 
9.3 
Populations for Analyses ....................................................................................................... 21 
9.4 
Statistical Analyses................................................................................................................. 21 
9.4.1 
General Approach ................................................................................................ 21 
9.4.2 
Analysis of the Primary Endpoint(s) ..................................................................... 22 
9.4.3 
Analysis of the Secondary Endpoint(s) ................................................................ 22 
9.4.4 
Safety Analyses .................................................................................................... 22 
9.4.5 
Baseline Descriptive Statistics ............................................................................. 22 
9.4.6 
Planned Interim Analyses .................................................................................... 23 
9.4.7 
Sub-Group Analyses ............................................................................................. 23 
9.4.8 
Tabulation of Individual Participant Data ............................................................ 23 
9.4.9 
Exploratory Analyses ............................................................................................ 23 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..................... 23 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 23 
10.1.1 
Informed Consent Process ................................................................................... 23 
10.1.2 
Study Discontinuation and Closure ...................................................................... 24 
10.1.3 
Confidentiality and Privacy .................................................................................. 24 
10.1.4 
Future Use of Stored Specimens and Data .......................................................... 25 
10.1.5 
Key Roles and Study Governance ........................................................................ 25 
10.1.6 
Safety Oversight ................................................................................................... 25 
10.1.7 
Clinical Monitoring ............................................................................................... 25 
10.1.8 
Quality Assurance and Quality Control ................................................................ 26 
10.1.9 
Data Handling and Record Keeping ..................................................................... 26 
10.1.10 
Protocol Deviations .............................................................................................. 27 
10.1.11 
Publication and Data Sharing Policy .................................................................... 27 
10.1.12 
Conflict of Interest Policy ..................................................................................... 27 

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10.2 
Additional Considerations ..................................................................................................... 27 
10.3 
Abbreviations and Special Terms ........................................................................................... 27 
10.4 
Protocol Amendment History ................................................................................................ 29 
11 
REFERENCES..................................................................................................................................... 30 
 

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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 Associate 
 
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 Individuals with Myasthenia Gravis 
IRB Number: 
A21-197 
Study Description: 
The purpose of the study is to determine the effect acupuncture 
treatment on individuals with a diagnosis of Myasthenia Gravis (MG). A 
total of 25 people with MG will be enrolled in this study to receive 
acupuncture treatment 2 times a week for 12 weeks. Participants will 
be randomized into two groups: 1) Immediate start and 2) Delayed 
start (12 weeks). The delayed start group will act as a control group for 
the first 12 weeks, but then receive acupuncture treatment for 12 
weeks. We hypothesize that patients with MG who receive 
acupuncture treatment will have improved quality of life and activities 
of daily living compared to no treatment.  
Specific Aims: 
 
Specific Aim 1: To determine the effect of acupuncture treatment on 
quality of life in individuals with MG. 
Specific Aim 2: To determine the effect of acupuncture treatment on 
activities of daily living in individuals with MG. 
Endpoints: 
Primary Endpoint: Myasthenia Gravis Quality of Life Scale (MG-QOL15) 
Secondary Endpoint: Myasthenia Gravis Activities of Daily Living Scale 
(MG ADL). 
Study Population: 
25 individuals aged 18-80 with a diagnosis of MG will be recruited for 
this study. 
Description of 
Sites/Facilities Enrolling  
Participants: 
For in-person visits, participants will receive acupuncture treatment at 
HealthPartners 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 12 weeks. Both groups will receive a 
total of 24 treatments. 
Study Duration: 
The duration of this study is 2 years. 
Participant Duration: 
We anticipate that participants will complete all study-related tasks 
within approximately 8 months. 
 
 
 
1.2 
SCHEMA  

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1.3 
SCHEDULE OF ACTIVITIES 
 
 
VISIT SCHEDULE DESCRIPTION 
 
All in-person visits will take place at: HealthPartners Neuroscience Center, 295 Phalen Boulevard, St. 
Paul, MN, 55130, HealthPartners Clinic St. Paul Como, 2500 Como Ave, St. Paul, MN 55108, or Healing 
Response Acupuncture & Functional Neurology, 11550 Stillwater Blvd N. Suite 101, Lake Elmo, MN 
55402. 
 
1. Pre-screening Phone Call (Groups 1 & 2) 
• 
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 
 
o Assist participants with setting up an e-mail account, if they do not have one. 
 
Pre-
screening 
Pre-
treatment 
1 
 
Pre-
treatment 
2 
Study 
Intervention 
Post-
treatment 
1 
Post-
treatment 
2 
2-week 
follow 
up call 
Group 1: 
Immediate 
Start 
Visit 0 
Visit 1 
N/A 
Visit 2-25 
Visit 26 
Visit 27 
N/A 
Group 2: 
Delayed Start 
Visit 1 
Visit 2 
Visit 3-26 
Visit 27 
N/A 
Visit 28 
Review 
Eligibility 
X 
 
 
 
 
 
 
Informed 
Consent 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medication 
Review 
 
X 
X 
X 
X 
X 
 
Symptom 
Severity Scale 
(Treatment Log) 
 
 
 
X 
X 
X 
 
X 
MG-QOL15 
 
X 
X 
 
X 
X 
 
MG-ADL 
 
X 
X 
 
X 
X 
 
Adverse Events 
(AE) Reporting 
 
 
 
X 
X 
X 
X 
Treatment 
Adherence 
 
 
 
X 
 
 
 

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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 (HIPPA), and HealthPartners non-discrimination forms. 
 
2. Pre-treatment Visit 1 (Groups 1 & 2) 
• 
Duration: Approximately 1 hour via phone 
• 
Research staff will:  
o Review the Informed Consent and HIPPA 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 Research Electronic Data Capture (REDCap), a secure web-based 
system, and provide them electronic copies for their records. 
o Complete the Demographics and Medication Review short forms in the relevant 
electronic case report forms (eCRFs) in REDCap. 
o Interview patients using the Myasthenia Gravis Quality of Life Scale (MG-QOL15) 
and Activities of Daily Living (MG ADL) surveys and document in REDCap. 
 
3. Pre-treatment Visit 2 (Group 2 only) 
• 
Duration: Approximately 20 minutes via phone 
• 
Research staff will:  
o Complete the Medication Review short form in the relevant electronic case 
report forms (eCRFs) in Research Electronic Data Capture (REDCap), a secure 
web-based system. 
o Interview patients using the MG-QOL15 and MG ADL surveys and document in 
REDCap. 
 
4. Study Intervention (Groups 1 & 2) 
• 
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. 
 
5. Post-treatment Visit 1 (Groups 1 & 2) 
• 
Duration: Approximately 20 minutes via phone 
• 
Research staff will:  
o Complete the AE Reporting and Medication Review forms in the relevant eCRFs 
in REDCap. 
o Interview patients using the Symptom Severity Scale (from the treatment log), 
MG-QOL15, and MG ADL surveys and document in REDCap. 
o Ask qualitative survey questions about the participant’s experience with 
acupuncture. 
 
6. Post-treatment Visit 2 (Group 1 only) 
• 
Duration: Approximately 20 minutes via phone 
• 
Research staff will:  

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o Complete the AE Reporting and Medication Review forms in the relevant eCRFs 
in REDCap. 
o Interview patients using the Symptom Severity Scale (from the treatment log), 
MG-QOL15, and MG ADL surveys and document in REDCap. 
o Ask qualitative survey questions about the participant’s experience with 
acupuncture. 
 
7. 2-week follow up call (Group 2 only) 
• 
Duration: Approximately 5 minutes via phone 
• 
Research staff will:  
o Complete the AE Reporting in the relevant eCRFs in REDCap. 
 
8. Early Withdrawal Call (for individuals who withdraw from the study early) 
• 
Duration: Approximately 20 minutes via phone 
• 
Research staff will:  
o Complete the AE Reporting and Medication Review forms in the relevant eCRFs 
in REDCap. 
o Interview patients using the Symptom Severity Scale (from the treatment log), 
MG-QOL15, and MG ADL surveys and document in REDCap.Ask qualitative 
survey questions about the participant’s experience with acupuncture. 
 
2 
 
INTRODUCTION 
2.1 
BACKGROUND & STUDY RATIONALE 
Myasthenia gravis (MG) is an autoimmune disease in which antibodies bind to acetylcholine receptors or 
at the neuromuscular junction, causing muscle weakness.1 It is a rare disease affecting approximately 8-
10 people per 1 million people each year.2 Weakness is typically more proximal than distal and can be 
generalized or localized.1 Common symptoms are muscle weakness, fatigue, ptosis, and diplopia. 
Symptoms can also include impaired speaking, swallowing, and chewing. MG can typically be managed 
well through medication therapy, including cholinesterase inhibitors, corticosteroids, and 
immunosuppressants. However, in a recent systematic review, acupuncture was shown to have a 
significant positive effect in treating MG and might enhance the efficacy of medications.3 
Acupuncture is a non-pharmacologic treatment that has been practiced in Chinese medicine for over 
4,000 years.4 It is a technique where fine needles are inserted into specific areas of the body to achieve 
a therapeutic benefit.4 Historically, acupuncture is based on a Chinese/East Asian medical theory that 
acupuncture restores normal function to the body by balancing Qi.4 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. Acupuncture has been shown to be 
safe and effective treatment for treating several chronic conditions, including patients suffering from 
headache,5 migraine,5 and chronic pain.6 Although both minor and serious adverse events (AEs) have 
been reported, serious complications related to acupuncture are rare.7 

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A recent systematic review and meta-analysis done by Zhang and colleagues examined 13 randomized 
controlled trials, which included 775 people with MG that were treated with acupuncture.3 The primary 
outcome measure was the relative clinical score response rate, which is the primary assessment that is 
used to evaluate the severity and treatment effect of MG in China.8 The review concluded that 
integrative long-term therapy, including acupuncture and medication, may be helpful for individuals 
with MG.3 However, the authors also concluded that more rigorous studies and longer follow-up times 
are needed.3 Thus, the primary goal of this study is to examine the effect of acupuncture on quality of 
life and the activities of daily living in patients with MG. 
2.2 
RISK/BENEFIT ASSESSMENT  
2.2.1 KNOWN POTENTIAL RISKS  
 
Acupuncture Treatment 
Reported Side Effects9: 
 
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 
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  

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Tinnitus 
Injury of the 
pericardium 
 
 
Assessments/Questionnaires (MG-QOL15 & MG ADL) 
The Myasthenia Gravis Quality of Life Scale short form self-assessment (MG-QOL15) and Activities of Daily 
Living self-assessment (MG ADL) are standardized questionnaires that will measure personal perception 
of life and activities of daily living. 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 several patient populations. 
Although there is less evidence for individuals with MG, acupuncture treatment may improve quality of 
life and activities of daily living. 
 
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 whether acupuncture treatment improves quality of life and activities of daily living in 
patients with MG outweighs the potential risks. 
 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To determine the effect of acupuncture on quality 
of life in patients with MG. 
MG-QOL15 
Secondary 
 
To determine the effect of acupuncture on 
activities of daily living in patients with MG. 
MG ADL 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 

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Study Design: 
This study is an unblinded, controlled randomized, 2-arm clinical trial. 
 
Hypotheses: 
Primary Hypothesis: We hypothesize that acupuncture will improve the quality of life in MG patients. 
Secondary Hypothesis: We hypothesize that acupuncture will improve activities of daily living in MG 
patients. 
 
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: 10 participants will receive acupuncture treatment immediately 2x per week for 12 
weeks = 24 total. 
Group 2: After a 12-week delay, 10 participants will receive acupuncture treatment 2x per week 
for 12 weeks = 24 total. 
 
Study Intervention: 
Acupuncture treatment will consist of a standardized treatment protocol designed for this study. 
Approximately 23-32 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 
will have a delayed start and who will start immediately, 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: N/A 
 
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 for treating several conditions (e.g. headaches, chronic pain). The purpose of this study is to 
determine whether acupuncture treatment can improve quality of life and activities of daily living in 
patients with MG. 
 
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. The end of the study is defined as completion of the last post-treatment visit for each 
group. 
 

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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 18-80 
• 
Diagnosis of MG 
 
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 any other serious neurological, psychiatric, chronic pain disorders, or seizures 
• 
History of bleeding diathesis, other bleeding disorders, or syncope with needle puncture 
• 
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 activities 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
N/A 
 
5.4 
SCREEN FAILURES 
 
Pre-screening Phone Call: 
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 

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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 MG 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 and Park Nicollet patients and members and invite them to participate. 
 
To reach our target enrollment, we anticipate that we will need to screen 60 people, of those 30 
individuals will sign the informed consent, and of those 25 individuals will be randomized to treatment 
groups. 
 
Remuneration: Participants will be provided gift cards totaling $50 per person for completing certain time 
points of the research study. Group 1: Will receive a $25 gift card after all acupuncture treatments and 
surveys were completed, and another $25 gift card after the last post treatment visit, if all surveys were 
completed. Group 2: Will receive a $25 gift card after half of the acupuncture treatments have been 
completed and surveys were completed, and another $25 after the post-treatment visit, if all surveys were 
completed. 
 
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 
 
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 twice-weekly acupuncture immediately over 12-weeks. After a 12-week delay, Group 
2 will also receive twice-weekly acupuncture over 12-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 0.22 x 30mm; 
Boryeoung, Republic of Korea) will be inserted in the acupuncture point locations (described below), with 
approximately 23-32 needles used for each treatment session. The number of needles used will be based 

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on the patient-reported symptoms. 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, some of the needles will be rotated in order to maintain Deqi 
sensation. Maintaining Deqi sensation has been shown to increase the effectiveness of acupuncture.10,11 
All needles will be left in place for a total of 30 minutes, which is a typical duration in acupuncture practice. 
 
Acupuncture points were selected for their classical Traditional Chinese Medicine indications relevant to 
MG symptom pathology, as well as their modern biomedical muscular, immunological, and neurological 
actions. The anatomical location for each point will be based on the World Health Organization’s 
acupuncture point guideline.12 Traditional Chinese manual acupuncture will be used at up to 32 
acupuncture points. During treatment, acupuncture needles can be removed due to extreme pain or 
discomfort, so as not to exceed the removal of more than 4 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: 
Following IRB approval and prior to recruitment and enrollment, the study acupuncturists will complete 
at least 1 practice session each. For the training, we will seek 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, needle depth, time of first and last needle placement, and total treatment duration.  
 
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.13 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:  

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Study personnel will be unblinded to the randomization, as it will be clear the number of participants who 
have a 12-week delay and those who do not. 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 
 
See section 6.5 (above). 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
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: 
 

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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 7 day 
maximum between visits. 
 
The following actions must be taken if a participant fails to attend any required study visit: 
 
• 
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 MG diagnosis, and e-mail address for 
study contact). 
 
Medication Review: At study enrollment, participants’ prescription medications will be recorded and 
tracked for the study duration. Medication data will be used for exploratory purposes. 
 

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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.  
 
Symptom Severity Scale: This scale will assess the participant’s usual symptoms of MG and the severity 
of their symptoms. This scale was custom designed for this study. 
 
Quality of Life: Participants will be asked to complete the MG-QOL15,14 a brief 15-item disease specific 
questionnaire that is designed to assess aspects of quality of life in Myasthenia Gravis. It includes 
questions regarding quality of life, such as vision, speaking, eating, and activities. 
 
Activities of Daily Living: Participants will be asked to complete the MG-ADL,15 an eight-item patient-
reported scale developed to assess MG symptoms and their effects on daily activities.  It combines 2 items 
on daily life activities (ability to brush teeth or comb hair and ability to arise from a chair) with 6 MG 
symptoms: diplopia, ptosis, chewing, swallowing, voice/speech problems, and respiratory symptoms. 
 
A strong positive correlation between the MG-ADL and the MG-QOL15 (r= 0.76, P < 0.0001) has been 
previously demonstrated.15  
 
Qualitative Feedback Survey: A list of qualitative feedback survey questions will allow for participant’s to 
discuss their experience with acupuncture treatment. 
 
8.2 
SAFETY ASSESSMENTS 
 
Assessment of Adverse and Serious Adverse Events: 
AEs and SAEs will be monitored by acupuncturists during acupuncture treatment sessions, and by study 
staff. 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 

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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.  
 
• 
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). 

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• 
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 MG 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.  
 
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 last post-treatment visit for each group. After the first acupuncture study and until study 
completion, study staff will inquire about the occurrence of AE/SAEs. All reported events will be 
monitored until the last post-treatment visit for each group. We will also conduct a 2-week follow up 
phone call for Group 2 to collect information on any advese events. 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  
 

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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. 
 
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. 
 

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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. 
 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary: 
We hypothesize that quality of life, as assessed by MG-QOL15, will improve with acupuncture 
treatment compared to no acupuncture treatment. 
 
• 
Secondary: 
We hypothesize that quality of life, as assessed by MG ADL, will improve with acupuncture 
treatment compared to no acupuncture treatment.  
 
9.2 
SAMPLE SIZE DETERMINATION 
 
We anticipate enrolling 10 subjects in each study group. The primary analysis is a two-sided two sample 
t-test comparing the mean change in MG-QOL15 over 12-weeks weeks from a delayed start 2-group 
design. We hypothesize that Group 1 who received acupuncture treatment will experience a change in 
QOL over the 12-weeks while Group 2, the untreated control, will not. We will analyze the data such that 
the opposite could be shown. The null hypothesis is that there will be no difference between treatment 

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groups. Our sample size of 10 subjects in each group achieves 80% power at a 5% significance level to 
detect a 1.32 SD difference in mean change in MG-QOL15 between groups (PASS software version 11). No 
interim analyses are planned. The potential effect on our power if for a range of true effect sizes are 
displayed in the table below. If our final analysis shows a smaller effect size than 1.32 SD difference, we 
will include and post-hoc power analysis with the results.  
 
N 
δ/ σ 
Power 
Alpha 
20 
0.9 
0.44 
0.05 
20 
1.0 
0.56 
0.05 
20 
1.3 
0.78 
0.05 
20 
1.6 
0.91 
0.05 
 
N = total sample size, 1:1 Randomization to 2 groups; 
δ = treatment effect (change);  
σ = standard deviation.  
 
Based on preliminary estimates, we do not anticipate difficulty recruiting 20 subjects. HealthPartners 
clinicians see approximately 4 individuals with MG per month at the Neuroscience Center and Park 
Nicollet Clinics, approximately 50 annually. Therefore, we will need a 40% 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 71% to detect a similar effect size. This, and other possible 
changes in power due to attrition, are listed in the table below. *Note: The original sample size estimation 
was for 20 individuals; however, we wrote the protocol so that we could replace anyone who did not start 
the intervention. Thus, we are increasing the enrollment target to 25, which is not reflected in the original 
power analysis. 
 
N 
δ 
σ 
Power 
Alpha 
16 
9.5 
7 
0.71 
0.05 
18 
9.5 
7 
0.77 
0.05 
20 
9.5 
7 
0.82 
0.05 
 
N = total sample size; 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 
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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 MG-QOL15 scores will be collected for each participant at several time points. The primary outcome, 
change in MG-QOL15 scores over the first 12-weeks, will be calculated using the first and second collected 
scores for both groups. Group 1 will have received the full acupuncture intervention between the two 
measurements while Group 2 will act as the untreated control. We will present the mean change by group 
with corresponding standard deviations. Analysis of covariances (ANCOVA) with adjustment for baseline 
MG-QOL15 and covariates identified above will be used to determine if a significant (p<0.05) intervention 
effect is present. If the model identifies a significant difference in change of MG-QOL15 associated with 
acupuncture treatment, next steps will assess if this change is still present 12-weeks after completing the 
full acupuncture treatment. Using data from Group 1, a paired t-test will be used to compare the MG-
QOL15 scores directly after treatment (Post-treatment Assessment 1) and scores 12-weeks post-
treatment (Post-treatment Assessment 2). (Refer to Schema on page 4 for data collection points.) 
 
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 12-week 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. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary analyses are not dependent on results of primary endpoint. Similar ANCOVA models using data 
from both groups will be used to determine whether acupuncture treatments were associated with a 
significant change in MG ADL scores. Before analysis, MG ADL scores will be summarized at each timepoint 
using measures of center and spread as appropriate.  
 
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 
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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 (medications changes, treatment adherence) 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 
whether acupuncture had an effect on post-COVID symptoms. 
 
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 
• 
Study Participant HIPPA Authorziation Form 

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• 
Recruitment Brochure 
• 
Recruitment Flyer 
 
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 
HIPPA 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 HIPPA documents. Following the consent 
conversation, the staff member will sign and e-mail the consent and HIPPA electronically to the patient. 
The patient will electronically sign, certify, and submit the consent and HIPPA in REDCap.  A fully executed 
PDF copy of the consent and HIPPA 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 
 
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.  

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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 
protection of privacy, confidentiality, and security for data dissemination and reuse (e.g., all data will be 
thoroughly de-identified and will not be traceable to a specific study participant). Plans for archiving and 
long-term preservation of the data will be implemented, as appropriate.  
 
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 Associate 
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. 

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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. 
 
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. 
 
We do not anticipate a need for independent monitoring for this study, however, 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. 
 

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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 
 
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 
 
COVID-19: This study will align with the HealthPartners’ and Park Nicollet’s policies regarding COVID-19 
for in-person visits. This will be done to ensure the safety of patients and study staff. Appropriate COVID-
19 screening procedures and personal protective equipment (PPE) will be utilized for all acupuncture 
treatment visits. Participants will be screened for COVID-19 on the day of each 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. 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CFR 
Code of Federal Regulations 
eCRF 
Electronic Case Report Forms 
GCP 
Good Clinical Practice 

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HIPPA 
Health Insurance Portability and Accountability 
ICH 
International Council on Harmonisation  
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
MG 
Myasthenia Gravis 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QOL 
Quality of Life 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
UP 
Unanticipated Problem 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
01/10/22 
Response to RRC & IRB Review 
Addressed reviewer changes 
3.0 
03/02/22 
Removal of electrical stimulation; 
change inclusion criteria age from 70 
to 80; Removal of cardiac/stimulator 
devices for exclusion as this was 
specific to electroacupuncture. 
Pantheon did not support 
settings we planned to use and 
we only planned to stimulate 
one point. This will not change 
our hypothesis. Would like to 
include up to 80 to capture late 
onset MG. 
4.0 
05/26/22 
Update PN address 
Incorrect address 
5.0 
02/16/23 
Add qualitative questions, add letter 
for recruitment, remove Park 
Nicollet, and add Como clinic 
Adding qualitative survey 
questions for additional 
feedback. Sending letter to 
potentially eligible individuals 
for recruitment efforts. 
Removing Park Nicollet clinic 
and adding Como Clinic for 
treatment locations. 
6.0 
04/03/23 
Add Stillwater Clinic 
Change in locations for 
acupuncture treatment 
7.0 
09/08/23 
Increase enrollment target to 25. 
We are requesting to increase 
enrollment to 25, so that we 
can replace any individuals that 
did not begin treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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