Clinical trial NCT04754399
Conditions: Arthralgia Breast Cancer
Keywords: Cannabidiol
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2021-04-16; Completion date: 2023-10-10
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study of Cannabidol to examine the safety and efficacy of 15 weeks of CBD in postmenopausal women with aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). Investigators are looking to see if patients with joint pain see improvement with the use of CBD.

Detailed description:

Arms: arm 1: Oral solution given 2x daily.
Interventions: intervention 1: Cannabidiol (CBD)
Intervention descriptions: intervention 1: week 1: 25 mg twice daily, approximately 12 hours apart, with food

week 2: 50 mg twice daily, approximately 12 hours apart, with food

week 3: 75 mg twice daily, approximately 12 hours apart, with food

week 4+: 100 mg twice daily, approximately 12 hours apart, with food

Protocol documents:
ICF_001.pdf: 
 
 
 
ID: UMCC 
2020.041 
    Cannabidiol (CBD) for Treatment of 
Aromatase Inhibitor-Associated 
Arthralgias 
    NCT04754399 


 
 
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UNIVERSITY OF MICHIGAN 
CONSENT TO BE PART OF A RESEARCH STUDY 
 
 
1.  KEY INFORMATION ABOUT THE RESEARCHERS AND THIS STUDY   
Study title:  
Phase 2 Trial of Cannabidiol (CBD) for Treatment of Aromatase Inhibitor-Associated Arthralgias (UMCC 
2020.041) 
 
Company or agency supporting the study:  
This is an investigator-initiated trial lead by Dr. N. Lynn Henry at the University of Michigan. 
 
Conquer Cancer – Rising Tide Foundation for Clinical Cancer Research is also supporting this study. 
 
Names, degrees, and affiliations of the principal investigator and study coordinator (if applicable): 
Principal Investigator:  
N. Lynn Henry, MD, PhD  
 
Department of Internal Medicine, University of Michigan 
 
1.1 Key Study Information 
You may be eligible to take part in a research study.  This form contains important information that will 
help you decide whether to join the study.  Take the time to carefully review this information.  You 
should talk to the researchers about the study and ask them any questions you have.  You may also wish 
to talk to others such as your family, friends, or other doctors about joining this study.  If you decide to 
join the study, you will be asked to sign this form before you can start study-related activities.  Before 
you do, be sure you understand what the research study is about. 
 
A research study is different from the regular medical care you receive from your doctor.  Research 
studies hope to make discoveries and learn new information about diseases and how to treat them.  You 
should consider the reasons why you might want to join a research study or why it is not the best 
decision for you at this time.   
 
Research studies do not always offer the possibility of treating your disease or condition.  Research 
studies also have different kinds of risks and risk levels, depending on the type of the study.  You may 
also need to think about other requirements for being in the study.  For example, some studies require 
you to travel to scheduled visits at the study site in Ann Arbor or elsewhere. This may require you to 
arrange travel, change work schedules, find child care, or make other plans.  In your decision to 
participate in this study, consider all of these matters carefully.   
 
This is a Phase II study, which means the goal is to test the safety and effectiveness of the investigational 
study intervention, in other words - does it help prevent side effects from your cancer therapy, and do 
the benefits outweigh the risks and side effects. This is usually done by comparing the outcomes of 
subjects in the study to those of people who previously received standard treatment. 
 


 
 
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You are being asked to take part in this study because you are taking an anti-hormone treatment called 
an aromatase inhibitor for treatment of breast cancer, and you are now having bothersome joint pain or 
stiffness.  
 
This research is testing whether treatment with a study intervention called cannabidiol, or CBD, will 
improve joint pain and stiffness.  In the research we will collect health-related information including 
questionnaires and four blood samples to better understand whether this study intervention improves 
symptoms and is safe to take.  
 
There can be risks associated with joining any research study.  The type of risk may impact whether you 
decide to join the study.  For this study, some of these risks may include additional symptoms from 
taking CBD, such as elevated liver enzymes and decreased appetite.  More detailed information will be 
provided later in this document. 
 
This study may offer some benefit to you now or others in the future by decreasing symptoms that you 
experience when taking an aromatase inhibitor medicine.  More information will be provided later in 
this document. 
 
We expect the amount of time you will participate in the study will be 15 weeks. 
 
You can decide not to be in this study.  Alternatives to joining this study include continuing to take the 
aromatase inhibitor medicine while not participating in a clinical trial to treat your joint pain, or 
participating in a different clinical trial to try to improve your joint pain. 
 
Even if you decide to join the study now, you are free to leave at any time if you change your mind. 
 
More information about this study continues in Section 2 of this document. 
 
 
 


 
 
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2. PURPOSE OF THIS STUDY 
2.1 Study purpose:  
Aromatase inhibitor medications have been approved by the U.S Food and Drug Administration (FDA) for 
treatment of hormone receptor positive breast cancer. This treatment has been shown to be very 
effective for treating breast cancer. However, some patients have difficulty tolerating the treatment, and 
some even decide to stop treatment because of the side effects. Research has shown that over half of 
patients who take aromatase inhibitor medications have joint pain and stiffness.  
 
Cannabinoids, which are compounds derived from the cannabis plant, have been shown to reduce pain. 
Cannabidiol, or CBD, is one of these compounds. It does not have the psychoactive properties that 
people usually think of when they think about marijuana. CBD has been shown to improve arthritis pain 
and anxiety in small studies. CBD is now available as an FDA approved medication (Epidiolex) to treat 
children with severe forms of seizures. This study is being conducted to test whether taking CBD will 
improve bothersome joint pain and other symptoms in women with breast cancer who are taking 
aromatase inhibitor medications and who have aggravating joint pain and stiffness.  This research will 
help to answer the following research questions: 
 
1. We know that some women have side effects when they take an aromatase inhibitor medication. 
Does taking CBD in addition to an aromatase inhibitor medication make it easier to tolerate the 
aromatase inhibitor medication? What, if any, side effects might you have when you receive the 
combination study intervention? 
2. What effect does CBD have on the amount of estrogen and inflammation in your body?  
 
3. WHO MAY PARTICIPATE IN THE STUDY 
Taking part in this study is completely voluntary.  You do not have to participate if you don't want to.  
You may also leave the study at any time.  If you leave the study before it is finished, there will be no 
penalty to you, and you will not lose any benefits to which you are otherwise entitled.  
 
3.1 Who can take part in this study?  
Postmenopausal women who are taking an aromatase inhibitor to treat breast cancer that has not 
spread beyond the breast and nearby lymph nodes and who are experiencing bothersome joint pain or 
stiffness may be eligible to participate. If you have taken CBD, tetrahydrocannabinol (THC), or marijuana 
in the past 6 weeks you are not eligible. You are also not eligible to participate if you have chronic liver 
disease or a seizure disorder. 
 
Every study has strict guidelines for determining which people may participate.  These are called 
eligibility criteria.  You will need to meet all of these criteria before you can participate in this study.  If 
you agree to consider participating in this study, you will undergo evaluations to see if you meet the 
eligibility criteria for this study.  Even though you may meet all of the criteria for participation, it is 
possible that you may not be enrolled in this study for other reasons. 
 
3.2 How many people are expected to take part in this study?  
44 subjects are expected to participate in this study, all at the University of Michigan. 
 


 
 
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4.  INFORMATION ABOUT STUDY PARTICIPATION 
4.1 What will happen to me in this study?   
The study team will explain the research study and answer any questions you have about the study.  If 
you still want to participate in the study, the study team will request you sign the consent form prior to 
any activities occurring that pertain to the study.  Once your consent is obtained, the study team will 
look through your medical chart, ask you questions, and begin scheduling tests and procedures to 
determine if you are eligible for the study.  The study team will inform you of the types of tests and 
procedures required before the study begins.   
 
Tests and procedures that you will do in order to determine if you are eligible for the study include: 
• 
You will have measures of your vital signs, including height and weight. If this has been done 
recently it might not need to be repeated. 
• 
You will have blood drawn to check labs to assess the level of blood counts, kidney function, liver 
enzymes, estrogens, and inflammation markers in your blood. About 2.5 tablespoons of blood will 
be collected.  You will be asked to fast for 8 hours prior to having your blood drawn. (Some of this 
is for Research) 
• 
You will complete questionnaires about your symptoms. These questionnaires can either be on 
your smartphone or tablet, an iPad, or on paper, and are expected to take about 5 minutes.  
• 
You will be asked if you have any thoughts about suicide or if you have ever attempted suicide.   
• 
You will also be asked about what medications, vitamins, and other supplements you are currently 
taking. 
• 
The study team will collect information about you from your medical record, including your age, 
information about your cancer, the treatments you have received, and your other medical 
problems. 
 
Once it is determined you are eligible to enter the study, tests and procedures done at your study visits 
as part of your regular cancer care will continue, but some may be done more often because you are 
participating in this research study.  Also, some of the tests or procedures may have to be repeated if, 
for example, they were done too long ago or the results are not normal.  
 
Tests or procedures that are performed only for this research study will be identified below as 
“Research”. 
 
If you decide you will take part in the study and you sign this informed consent form, you will undergo 
baseline assessments and then begin the study intervention.  
 
As a subject participating in this research study, you have certain responsibilities that may apply to this 
study, such as ensuring that you arrive at all of your scheduled appointments, take your study 
medication as directed, and report any adverse reactions you may have during the study.  
 
Study Procedures at the Baseline Visit: 
You will be asked to come to the study clinic and the following tests and procedures will be performed: 
• 
You will be asked about what medications, vitamins, and other supplements you are currently 
taking. 


 
 
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• 
You will complete questionnaires about your symptoms. These questionnaires can either be on 
your smartphone or tablet, an iPad, or on paper, and are expected to take about 30 minutes. It is 
possible to complete the questionnaires online up to 2 days before the clinic visit. 
• 
You will be given a “dosing diary” to track when you take the CBD study intervention. 
 
Study Procedures During the Study Intervention Period (Week 1 through Week 15): 
After the baseline visit you will be given the study intervention to take at home starting either that evening 
or the following Wednesday. You will take the liquid medication twice a day. You should take it 
approximately every 12 hours with food. If you forget to take the medication for more than 8 hours, then 
you should wait until the next scheduled time to take it. You will complete the dosing diary each time you 
take the study intervention, or make a note if you miss a dose. 
 
Once a week for 3 weeks you will be sent a link via email or text message to a short questionnaire about 
your symptoms. You should report all symptoms on the questionnaires, whether or not they are related 
to the cancer or the study intervention.  
 
You will also receive a phone call from the study coordinator to discuss any symptoms you are having from 
the study intervention. Each week they will tell you how much to increase the dose of the study 
medication that you take. 
 
After you have increased the dose of the study intervention to the maximum dose, you will continue to 
take that dose until you have been on the study for 15 weeks.  
 
Study Procedures at Week 4 (or sooner if you stop taking the study intervention early): 
You will not have to be seen in clinic this week, but you will be required to undergo the following tests 
and procedures: 
• 
You will have blood drawn to check labs to assess the level of blood counts, kidney function, and 
liver enzymes in your blood. About 2 tablespoons of blood will be collected.   
• 
You will complete questionnaires about your symptoms. These questionnaires can either be on 
your smartphone or tablet, an iPad or on paper, and are expected to take about 5 minutes. It is 
possible to complete the questionnaires online up to 2 days before the clinic visit. 
 
During Week 6 you will be sent a link via email or text message to a short questionnaire about your 
symptoms. 
 
Study Procedures at the Week 8 visit (or sooner if you stop taking the study intervention early): 
You will be asked to return to the clinic for this visit for the following tests and procedures: 
• 
You will have blood drawn to check labs to assess the level of blood counts, kidney function, liver 
enzymes, estrogens, and inflammation markers in your blood. About 2 tablespoons of blood will 
be collected.  You will be asked to fast for 8 hours prior to having your blood drawn. (Some of 
this is for Research) 
• 
You will complete questionnaires about your symptoms. These questionnaires can either be on 
your smartphone or tablet, an iPad or on paper, and are expected to take about 5 minutes. It is 
possible to complete the questionnaires online up to 2 days before the clinic visit. 


 
 
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• 
You should return your dosing diary. 
• 
You will be given a new bottle of study intervention and a new dosing diary. 
 
During Week 12 you will be sent a link via email or text message to a short questionnaire about your 
symptoms.  
 
Study Procedures at the Week 15 visit (or sooner if you stop taking the study intervention early): 
You will be asked to return to the clinic for this visit for the following tests and procedures: 
• 
You will have blood drawn to check labs to assess the level of blood counts, kidney function, liver 
enzymes, estrogens, and inflammation markers in your blood. About 2 tablespoons of blood will 
be collected. You will be asked to fast for 8 hours prior to having your blood drawn. (Some of 
this is for research) 
• 
You will complete questionnaires about your symptoms. These questionnaires can either be on 
your smartphone or tablet, an iPad or on paper, and are expected to take about 30 minutes. It is 
possible to complete the questionnaires online up to 2 days before the clinic visit. 
• 
You will return your 2 bottles of study medication and the second dosing diary. 
 
You will stop taking the CBD (study intervention) after this visit. If you wish to continue taking it, you 
should discuss the option with your cancer doctor who may be able to provide you with a prescription or 
discuss obtaining CBD from other sources, such as local cannabis dispensaries in Michigan. The cost of the 
prescription medication can be quite high, and there is no support available to provide this medication 
after you finish participating in the clinical trial. 
 
Follow-up 
Once you complete the Week 15 visit, you will continue your usual clinic visits with your cancer team.  
 
OPTIONAL: Unspecified Future Research 
Besides the information about the main study, the following information is specific to unspecified future 
use of identifiable data and/or biospecimens.  We would also like your permission to keep some of your 
blood samples and medical information collected in the main study, so that we may study it in future 
research. The future research may be similar to this study or may be completely different. 
 
You can take part in the main study even if you decide not to let us keep your blood samples and 
medical information for future research. 
 
If you give us your permission, we will use your blood samples and medical information for future 
research.  Even if you give us permission now to keep some of your blood samples and medical 
information, you can change your mind later and ask us to destroy it.  Keep in mind, however, that once 
we have analyzed your blood samples, we may not be able to take the information out of our research.  
 
We may share your blood samples and medical information with other researchers, so that they can use 
it in their research. Their research may be similar to this study or may be completely different. Once we 
have shared your blood samples and medical information with other researchers, we will not be able to 
get it back. 
 


 
 
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As the testing will be performed on samples that were already collected during the main study, there 
are no physical risks associated with this testing.  There are non-physical risks associated with taking 
part in future research, such as the risks associated with the loss of privacy or confidentiality.  See 
Section 5.1 and Section 9.1 of this consent form for more information about these risks. Future use of 
your identifiable data and/or specimens will be conducted in compliance with applicable regulatory 
requirements.  
 
You will not find out the results of the future research on your blood samples.  Allowing us to do future 
research on your blood samples and medical information will not benefit you directly. 
 
With appropriate permissions, your samples and collected information may also be shared with other 
researchers here and around the world and with companies.  
 
Your identifiable private information or identifiable biospecimens may be stripped of identifiers and 
used for future research studies or distributed to another researcher for future research studies without 
additional informed consent. You will not find out the results of future research on your blood.  
 
Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their 
organizations, and other entities, including companies, may potentially benefit from the use of the data 
or discoveries. You will not have rights to these discoveries or any proceeds from them. 
 
You will make your choice in Section 12 of this consent form about whether or not you agree to let the 
study team keep your blood samples for unspecified future research. 
 
4.2 How much of my time will be needed to take part in this study?   
Each subject will receive the study intervention for a total of 15 weeks.  Each subject will have a total of 
3 study visits at baseline, week 8, and week 15, or sooner if she stops taking the study intervention after 
less than 15 weeks. Each visit is expected to last about 30 minutes, plus the time needed to complete 
questionnaires. At these timepoints, questionnaires are expected to take about 30 minutes (except for 
week 8, when the questionnaires are expected to take 5 minutes), and may be completed online before 
the clinic visit. Between visits, each subject will complete a brief set of questionnaires a total of 6 times; 
each is expected to take about 5 minutes. At week 4, each subject will also have a blood draw. 
 
4.3 When will my participation in the study be over?  
Your participation will be over after the Week 15 study visit. The entire study is expected to last about 
2.5 years. 
 
If you wish to continue taking CBD after the 15-week study visit, you should discuss the option with your 
cancer doctor who may be able to provide you with a prescription or discuss obtaining CBD from other 
sources, such as local cannabis dispensaries in Michigan. The cost of the prescription medication can be 
quite high, and there is no support available to provide this medication after you finish participating in 
the clinical trial. 
 


 
 
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4.4 What will happen with my information and/or biospecimens used in this study? 
Your collected information and biospecimens may also be shared with other researchers, both here or 
around the world, or with companies.  Any sharing is subject to contractual obligations with the 
Sponsor.  Additionally: 
• 
With appropriate permissions, your identifiable collected information and biospecimens may be 
shared, and/or, 
• 
Without your additional consent, your identifiable private information and identifiable 
biospecimens may be stripped of identifiers and used for future research studies or distributed 
to another researcher for future research studies. 
 
5.  INFORMATION ABOUT STUDY RISKS AND BENEFITS 
5.1 What risks will I face by taking part in the study?  What will the researchers do to protect me 
against these risks? 
Your study doctor and study staff will monitor you closely for side effects. Even with frequent blood 
tests and other examinations, taking the study intervention involves risks, and some side effects cannot 
be predicted. Many side effects will get better when you stop taking the study intervention, but some 
may be long lasting or may never go away. You should tell your study doctor immediately about any side 
effects that you have or any change in how you feel while on this study. If you have side effects, your 
dose may have to be reduced, or you may have to stop taking the study intervention and wait until you 
feel better before you start again. Your study team may give you medicines or lower your dose of study 
intervention to help lessen side effects.  If any side effect is intolerable, you may have to permanently 
stop taking the study intervention. 
 
The known or expected risks are: 
 
Study Intervention 
The Study Intervention (CBD) may cause one or more of the side effects listed below.  This information is 
based on data from patients in other clinical trials with the Study Intervention. In addition, there may be 
side effects that are not yet known that may occur.  You should tell your doctor or nurse right away about 
any possible side effects that you experience. 
 
MORE COMMON SIDE EFFECTS 
In 100 people receiving CBD, as many as 26 and up to 50 may have: 
• 
Infection 
 
COMMON SIDE EFFECTS 
In 100 people receiving CBD, as many as 11 and up to 25 may have:  
• 
Decreased appetite 
• 
Sleepiness or difficulty sleeping 
• 
Tiredness 
• 
Weakness or lack of energy 
• 
Fever 
• 
Vomiting 


 
 
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LESS COMMON SIDE EFFECTS 
In 100 people receiving CBD, as many as 1 and up to 10 may have:  
• 
Increased liver function tests (AST, ALT) 
• 
Diarrhea 
• 
Decreased weight 
• 
Abdominal pain 
• 
Irritability or aggression 
• 
Rash 
• 
Low oxygen levels  
• 
Increased saliva 
• 
Difficulty walking 
 
Studies have shown that some subjects treated with CBD have low levels of red blood cells (mild anemia). 
Increased creatinine (lowered kidney function) has also been seen in otherwise healthy adults treated 
with CBD, although it generally improved when the drug was stopped. 
  
After you start taking the study medication, if you have any thoughts about suicide you should contact 
the study doctor or your oncologist immediately.   
 
Taking CBD may change how your body reacts to other drugs, which can increase side effects. It is 
important that you check with the study team before making any changes to your medications. 
 
There may be additional unforeseen risks associated with the use of the CBD study intervention in 
combination with aromatase inhibitor treatment. You should tell your study doctor or study staff 
immediately about any side effects that you have or about any change in how you feel while on this study. 
 
Other Risks and Inconveniences  
Blood Draws 
Collection of blood samples may cause pain, bleeding, bruising, or infection. It is also possible that you 
may feel lightheaded or faint. Please tell your study doctor or the study nurse if you do not feel well 
after having your blood drawn at any time during your study participation. 
 
Questionnaires  
As part of the study, you will be asked to complete questionnaires. Some of the questions may seem 
very personal or embarrassing. They may make you uncomfortable. You may refuse to answer any of the 
questions that you do not wish to answer. If the questions make you uncomfortable, we can help you to 
find a counselor. 
 
If you are experiencing bothersome symptoms you should inform the research staff or your health care 
provider. The answers you provide on these questionnaires will not be given to your study doctor, and 
will not be looked at by the researchers until the end of the study. 
 


 
 
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These risks will be minimized by: 
We will minimize the risks by monitoring you carefully.  We will provide the usual supportive care that 
would be routinely given to someone with your condition.  If you have side effects from the 
investigational study intervention, we will make appropriate adjustments as defined by the study 
protocol.  You may need to discontinue the investigational study intervention if the side effects are too 
serious.  If you have signs of infection, you will receive appropriate antibiotics.  If you have signs of 
bleeding, you may need to receive transfusions of platelets, plasma, or red blood cells.  If your 
hemoglobin level is too low, you may receive a red blood cell transfusion.  If you start feeling sick to your 
stomach, you may be given medications to help reduce nausea.  If you have vomiting, you may be given 
fluids through an IV. 
 
Additionally, there may be a risk of loss of confidentiality or privacy.  For example, if your identity as a 
participant in this research or your identifiable health information were disclosed to unauthorized 
persons, there is the possible risk of discrimination by employers or insurance providers.  The 
researchers believe that the risks of such improper disclosure are very small because strict privacy and 
confidentiality procedures for this research have been adopted.  See Section 9 of this document for 
more information on how the study team will protect your confidentiality and privacy. 
 
As with any research study, there may be additional risks that are unknown or unexpected. 
 
5.2 What happens if I get hurt, become sick, or have other problems as a result of this research? 
The researchers have taken steps to minimize the risks of this study.  Even so, you may still have 
problems or side effects, even when the researchers are careful to avoid them. Please tell the 
researchers listed in Section 10 about any injuries, side effects, or other problems that you have during 
this study.  You should also tell your regular doctors. 
 
If you think you have an injury or illness that is related to your participation in this clinical trial, it is 
important that you tell your study doctor immediately.  If you have a clinical trial related injury or 
accident, the study staff will make sure that you get medical treatment.   
You will receive appropriate medical care for any side effects you have while participating in this study.  
Your study doctor may also lower the study intervention dose or stop the study intervention if you 
experience side effects. 
 
You must inform your study doctor immediately if there are any changes in your health/condition, or if 
you have any concerns regarding the study.  If for any reason you are seen by another healthcare 
provider or admitted to another hospital, you should make known your participation in this research 
study.  These healthcare providers may wish to contact your study doctor to discuss your condition.  
Your study doctor may need to contact your other doctors if you develop any potentially significant, 
unexpected diseases or conditions that may have been caused by the study intervention or procedures 
or are discovered during the study. 
 


 
 
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5.3 If I take part in this study, can I also participate in other studies? 
Being in more than one research study at the same time, or even at different times, may increase the 
risks to you.  It may also affect the results of the studies.  You should not take part in more than one 
study without approval from the researchers involved in each study.   
 
5.4 How could I benefit if I take part in this study?  How could others benefit?   
You may not receive any personal benefits from being in this study. It is possible that you may have 
improvement in how well you tolerate aromatase inhibitor therapy because you are taking the study 
intervention.  In addition, others may benefit from the knowledge gained from this study. 
 
5.5 Will the researchers tell me if they learn of new information that could change my willingness to 
stay in this study? 
Yes, the researchers will tell you if they learn of important new information that may change your 
willingness to stay in this study. If new information is provided to you after you have joined the study, it 
is possible that you may be asked to sign a new consent form that includes the new information. 
 
6.  ALTERNATIVES TO PARTICIPATING IN THE STUDY 
6.1 If I decide not to take part in this study, what other options do I have? 
Participating in this trial is voluntary. Alternatives to joining this study include taking the aromatase 
inhibitor medicine while not participating in a clinical trial, or participating in a different clinical trial to 
try to improve your joint pain. 
 
7.  ENDING THE STUDY 
7.1 If I want to stop participating in the study, what should I do? 
You are free to leave the study at any time.  If you leave the study before it is finished, there will be no 
penalty to you. You will not lose any benefits to which you may otherwise be entitled.  If you choose to 
tell the researchers why you are leaving the study, your reasons for leaving may be kept as part of the 
study record. If you decide to leave the study before it is finished, please tell one of the persons listed in 
Section 10 “Contact Information”. 
 
Please note that any information collected before you withdraw will be kept and used to complete the 
research. 
 
Please note that even if you withdraw consent for further follow-up or contacts, if the study doctor 
becomes aware of additional safety information this will be reported to the sponsor in order to comply 
with legal or regulatory requirements. 
 
7.2 Could there be any harm to me if I decide to leave the study before it is finished?  
Tell the study doctor if you are thinking about stopping or decide to stop.  It is important to tell the 
study doctor if you are thinking about stopping so any risks can be evaluated by your study doctor.  The 
study doctor will also tell you how to stop safely and discuss what follow-up care and testing could be 
most helpful for you.  If you decide to leave the study before it is finished, please tell your study doctor 
or one of the researchers listed in Section 10 “Contact Information” (below). 
 


 
 
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7.3 Could the researchers take me out of the study even if I want to continue to participate? 
Yes. There are many reasons why the researchers may need to end your participation in the study.  
Some examples are: 
• 
The researcher believes that it is not in your best interest to stay in the study. 
• 
You become ineligible to participate. 
• 
Your condition changes and you need treatment that is not allowed while you are taking part in 
the study. 
• 
You stop taking the aromatase inhibitor medicine for more than 7 days 
• 
You stop taking the CBD study intervention for more than 14 days 
• 
You have serious side effects 
• 
You do not follow instructions from the researchers. 
• 
The study is suspended or canceled. 
 
8.  FINANCIAL INFORMATION 
8.1 Who will pay for the costs of the study?  Will I or my health plan be billed for any costs of the 
study?   
The study will pay for research-related items or services that are provided only because you are in the 
study.  If you are not sure what these are, see Section 4.1 above or ask the researchers for a list.  If you 
get a bill you think is wrong, call the researcher’s telephone number listed in Section 10.1. 
 
You or your health plan will pay for all the things you would have paid for even if you were not in the 
study, like: 
• 
Health care given during the study as part of your regular care, including the aromatase inhibitor 
medication and standard laboratory tests 
• 
Items or services needed to give you study intervention or devices 
• 
Monitoring for side effects or other problems 
• 
Deductibles or co-pays for these items or services. 
 
If you do not have a health plan, or if you think your health plan may not cover these costs during the 
study, please talk to the researchers listed in Section 10 below or call your health plan’s medical 
reviewer. 
 
The CBD liquid medication (study intervention) will be provided at no cost to you. 
 
What if I am injured while taking part in this study? 
If you are injured or in the event of a medical emergency, dial 911 or visit your nearest Emergency 
Room. If you believe the study has made you sick or caused you injury, contact one of the people listed 
in section 10 of this document (Contact Information). If taking part in the study makes you sick or causes 
you injury, you or your insurance provider will be billed for all costs of treatment as the study does not 
provide compensation for sickness or injury caused by the study. It is possible that your insurance will 
not cover these costs. 
 
By signing this form, you do not give up your right to seek payment if you are harmed as a result of 
being in this study. 


 
 
Page 14 of 19 
Consent Subtitle:  UMCC 2020.041 
         Consent Version:  08/31/2022 
                 Protocol Version 7: 07/20/2022 
 
 
 
 
8.2 Will I be paid or given anything for taking part in this study? 
Yes.  You will be paid $25 dollars per visit after completion of the baseline, week 8, and week 15 visits. If 
you only complete baseline visit you will only receive $25 dollars, but if you complete all three visits you 
will receive $75 dollars. You will receive the payment loaded on a gift card.  
 
8.3 Who could profit or financially benefit from the study results? 
No person or organization has a financial interest in the outcome of this study.  
 
The University of Michigan is receiving payments from Conquer Cancer - Rising Tide Foundation for 
Clinical Cancer Research to support the activities that are required to conduct the study.  No one on the 
research team will receive a direct payment or increase in salary from Conquer Cancer - Rising Tide 
Foundation for Clinical Cancer Research for conducting the study. 
 
Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their 
organizations, and other entities, including companies, may potentially benefit from the use of the data 
or discoveries. You will not have rights to these discoveries or any proceeds from them. 
 
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED 
HEALTH INFORMATION 
The information below describes how the confidentiality of your research records will be protected in 
this study, and any sub-studies described in this document.   
 
9.1 How will the researchers protect my information?  
Your participation will occur at the University of Michigan medical center.  Your data will be kept 
confidential, to the extent permitted by applicable laws, in the following manner: 
• 
Your name will not be used in any reports about the study 
• 
You will be identified only by a study code: a subject ID number, and initials 
• 
Your identifying information will be kept secure 
 
The study team will assign a code number to the study data and may use your initials. Some study data 
may contain information that could be used (perhaps in combination with other information) to identify 
you (e.g., initials, date of birth).  The study team will use the study data for research purposes to support 
the scientific objectives of the study.  Study data (that does not directly identify you) may be published 
in medical journals or shared with others as part of scientific discussions. 
 
We will do everything we can to keep your information private, but we cannot guarantee this. Your 
research information will be stored in a secure computer with password protection and will not be made 
a part of your regular medical record.  However, if the researcher orders any tests, the order and results 
may become part of your regular medical record. We may need to disclose information about you as 
required by law. 
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov/, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. 


 
 
Page 15 of 19 
Consent Subtitle:  UMCC 2020.041 
         Consent Version:  08/31/2022 
                 Protocol Version 7: 07/20/2022 
 
 
 
 
9.2 What protected health information (PHI) about me could be seen by the researchers or by other 
people?  Why?  Who might see it? 
Signing this form gives the researchers your permission to obtain, use, and share information about you 
for this study, and is required in order for you to take part in the study.   
 
Medical information and billing records are protected by the privacy regulations of the federal Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  This type of information is called 
protected health information (PHI).  PHI about you may be obtained from any hospital, doctor, and 
other health care provider involved in your care, including: 
• 
Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.) 
• 
Health plan/health insurance records 
• 
All records relating to your breast cancer, the treatment you have received, and your response 
to the treatment 
• 
Billing information 
• 
Demographic information 
• 
Personal identifiers 
 
There are many reasons why information about you may be used or seen by the researchers or others 
during or after this study.  Examples include: 
• 
The researchers may need the information to make sure you can take part in the study.   
• 
The researchers may need the information to check your test results or look for side effects.   
• 
University, Food and Drug Administration (FDA) and/or other government officials, auditors, 
and/or the IRB may need the information to make sure that the study is done in a safe and 
proper manner.    
• 
Study sponsors or funders, or safety monitors or committees, may need the information to:  
o Make sure the study is done safely and properly 
o Learn more about side effects  
o Analyze the results of the study  
• 
Insurance companies or other organizations may need the information in order to pay your 
medical bills or other costs of your participation in the study. 
• 
The researchers may need to use the information to create a databank of information about 
your condition or its treatment. 
• 
Information about your study participation may be included in your regular UMHS medical 
record. 
• 
If you receive any payments for taking part in this study, the University of Michigan accounting 
department may need your name, address, Social Security number, payment amount, and 
related information for tax reporting purposes. 
• 
Federal or State law may require the study team to give information to government agencies. 
For example, to prevent harm to you or others, or for public health reasons.  
 
The results of this study could be published in an article, but would not include any information that 
would let others know who you are.  
 


 
 
Page 16 of 19 
Consent Subtitle:  UMCC 2020.041 
         Consent Version:  08/31/2022 
                 Protocol Version 7: 07/20/2022 
 
 
 
9.3 What happens to information about me after the study is over or if I cancel my permission to use 
my PHI? 
As a rule, the researchers will not continue to use or disclose information about you, but will keep it 
secure until it is destroyed.  Sometimes, it may be necessary for information about you to continue to be 
used or disclosed, even after you have canceled your permission or the study is over.   
 
Examples of reasons for this include: 
• 
To avoid losing study results that have already included your information  
• 
To provide limited information for research, education, or other activities. (This information 
would not include your name, social security number, or anything else that could let others 
know who you are.)  
• 
To help University and government officials make sure that the study was conducted properly 
As long as your information is kept within the University of Michigan Health System, it is protected by 
the Health System’s privacy policies.  For more information about these policies, ask for a copy of the 
University of Michigan “Notice of Privacy Practices”.  This information is also available on the web at 
http://www.uofmhealth.org/patient+and+visitor+guide/hipaa.  Note that once your information has 
been shared with others as described under Question 9.2, it may no longer be protected by the privacy 
regulations of the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA).   
 
9.4 When does my permission to use my PHI expire?   
Your permission will not expire unless you cancel it. You may cancel your permission at any time by 
writing to the researchers listed in Section 10 "Contact Information" (below).  If you withdraw your 
permission, you may no longer be eligible to participate in this study. 
 
10. CONTACT INFORMATION 
10.1 Who can I contact about this study? 
 
Please contact the researchers listed below to: 
• 
Obtain more information about the study 
• 
Ask a question about the study procedures or treatments 
• 
Talk about study-related costs to you or your health plan  
• 
Report an illness, injury, or other problem (you may also need to tell your regular doctors) 
• 
Leave the study before it is finished 
• 
Express a concern about the study 
 
Principal Investigator: N. Lynn Henry, MD, PhD 
Mailing Address: 
1500 E. Medical Center Drive, Rm 7322 
                                           Ann Arbor, MI 48109 
Telephone: 
(734) 936-6000; (734) 936-4000 (Hospital Operator – 24-hour paging) 
 


 
 
Page 17 of 19 
Consent Subtitle:  UMCC 2020.041 
         Consent Version:  08/31/2022 
                 Protocol Version 7: 07/20/2022 
 
 
 
 
You may also express a question or concern about a study by contacting the Institutional Review 
Board listed below: 
University of Michigan Medical School Institutional Review Board (IRBMED) 
2800 Plymouth Road 
Building 520, Room 3214 
Ann Arbor, MI 48109-2800 
Telephone: 734-763-4768  (For International Studies, include the appropriate calling codes.) 
Fax: 734-763-1234 
e-mail: irbmed@umich.edu  
 
If you are concerned about a possible violation of your privacy or concerned about a study you may 
contact the University of Michigan Health System Compliance Help Line at 1-866-990-0111. 
When you call or write about a concern, please provide as much information as possible, including the 
name of the researcher, the IRBMED number (at the top of this form), and details about the problem.  
This will help University officials to look into your concern.  When reporting a concern, you do not have to 
give your name unless you want to. 
 
11.  RECORD OF INFORMATION PROVIDED 
11.1 What documents will be given to me? 
Your signature in the next section means that you have received copies of all of the following 
documents: 
• 
This "Consent to be Part of a Research Study" document.  (Note: In addition to the copy you 
receive, copies of this document will be stored in a separate confidential research file and may be 
entered into your regular University of Michigan medical record.) 
 
 
 
 
 
 


 
 
Page 18 of 19 
Consent Subtitle:  UMCC 2020.041 
         Consent Version:  08/31/2022 
                 Protocol Version 7: 07/20/2022 
 
 
 
12.  SIGNATURES 
 
 
 
 
 
 
  
 
 
 
 
Consent/Assent to Participate in the Research Study 
 
I understand the information printed on this form.  I have discussed this study, its risks and potential benefits, 
and my other choices with _________________________________________.  My questions so far have been 
answered.  I understand that if I have more questions or concerns about the study or my participation as a 
research subject, I may contact one of the people listed in Section 10 (above).  I understand that I will receive a 
copy of this form at the time I sign it and later upon request.  I understand that if my ability to consent or assent 
for myself changes, either I or my legal representative may be asked to re-consent prior to my continued 
participation in this study. 
 
Print Legal Name: ___________________________________________________________________ 
 
Signature: _________________________________________________________________________ 
 
Date of Signature (mm/dd/yy): ________________________ 
 
Consent/Assent to Collect for Optional Unspecified Future Research 
This project involves the option to allow the study team to keep your identifiable specimens/data for use in 
future research.  I understand that it is my choice whether or not to allow future use of my specimens.  I 
understand that if my ability to consent or assent for myself changes, either I or my legal representative may be 
asked to re-consent prior to my continued participation in this study. 
 
_____ Yes, I agree to let the study team keep my blood specimens for future research. 
 
_____ No, I do not agree to let the study team keep my blood specimens for future research. 
 
Print Legal Name: ___________________________________________________________________ 
 
Signature: _________________________________________________________________________ 
 
Date of Signature (mm/dd/yy): ______________________________ 
 


 
 
Page 19 of 19 
Consent Subtitle:  UMCC 2020.041 
         Consent Version:  08/31/2022 
                 Protocol Version 7: 07/20/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator or Designee 
 
I have provided this participant and/or his/her legally authorized representative(s) with information about this 
study that I believe to be accurate and complete.  The participant and/or his/her legally authorized 
representative(s) indicated that he or she understands the nature of the study, including risks and benefits of 
participating. 
 
Printed Legal Name: __________________________________________________________________ 
 
Title: ______________________________________________________________________________ 
 
Signature: _________________________________________________________________________ 
 
Date of Signature (mm/dd/yy): ________________________ 


 
 
 
UMCC 2020.041 
 
PERSONAL CENSUS FORM 
 
 
Name _______________________________________________ 
Date ____________________ 
 
The National Cancer Institute requires that The University of Michigan Comprehensive Cancer 
Center report race and ethnicity information about people who participate in clinical research to 
ensure that all populations are offered the opportunity to participate.  
 
 Check here if you do not wish to provide some or all of the information below. 
 
 
1. What race do you consider yourself to be?  
American Indian/Alaska Nativea 
(Please select one or more) 
 
 
 
Asianb 
 
 
Black or African Americanc 
 
 
 
 
 
 
 
Native Hawaiian or Other 
Pacific Islanderd 
 
Whitee 
 
More than one racef 
 
 
2. Do you consider yourself to be Hispanicg?           Yes                 No 
________________________________________________________________________ 
 
a American Indian or Alaska Native- A person having origins in any of the original peoples of North, Central, or 
South America, and who maintains tribal affiliation or community attachment. 
 
b Asian- A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian 
subcontinent, including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine 
Islands, Thailand and Vietnam. 
 
c Black or African American- A person having origins in any of the black racial groups of Africa.  (Terms such as 
“Haitian” or “Negro” are sometimes used in addition to “Black” or “African American.”) 
 
d Native Hawaiian or Other Pacific Islander- A person having origins in any of the original peoples of Hawaii, Guam, 
Samoa, or other Pacific Islands. 
 
e White- A person having origins in any of the original peoples of Europe, the Middle East, or North Africa. 
 
f More than one race- (It is preferred that this be selected in addition to the selection of the specific races listed 
above, but this may also be solely selected.) 
 
g Hispanic or Latino- A person of Mexican, Puerto Rican, Cuban, Central or South American, or other Spanish 
culture or origin, regardless of race.  The term “Spanish origin” is sometimes used in addition to “Hispanic” or 
“Latino.” 
 
 

Prot_SAP_002.pdf: 
ID: UMCC 
2020.041 
Cannabidiol (CBD) for Treatment of Aromatase Inhibitor-
Associated Arthralgias 
NCT04754399 


Phase 2 Trial of Cannabidiol (CBD) for Treatment of Aromatase Inhibitor-Associated 
Arthralgias
Protocol Number: UMCC 2020.041 
Principal Investigator 
N. Lynn Henry, MD, PhD
Co-Investigators 
Monika Burness, MD 
Erin Cobain, MD 
Daniel F. Hayes, MD 
Kathleen Kemmer, MD 
Aki Morikawa, MD, PhD 
Nicole Grogan, MD 
Anne Schott, MD 
Jeffrey Smerage, MD 
Catherine Van Poznak, MD 
Statistician(s) 
Kelley Kidwell, PhD 
University of Michigan School of Public Health 
kidwell@umich.edu 
NCT Number (CT.gov) 
NCT04754399 
Protocol Version Dates 
Version 1: 5/13/2020 
Version 2: 7/8/2020 
Version 3: 10/13/2020 
Version 4: 11/30/2020 
Version 5: 12/21/2020 
Version 6: 05/24/2021 
Version 7: 07/20/2022 


 
 
Page 2 of 38 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 2 
ABBREVIATIONS ........................................................................................................................ 4 
STUDY SUMMARY...................................................................................................................... 5 
SCHEMA ........................................................................................................................................ 7 
1 
OBJECTIVES ......................................................................................................................... 8 
1.1 
Primary Objective ............................................................................................................ 8 
1.2 
Secondary Objectives ....................................................................................................... 8 
1.3 
Exploratory Objectives ..................................................................................................... 8 
2 
BACKGROUND .................................................................................................................... 8 
2.1 
Hypothesis ........................................................................................................................ 8 
2.2 
Rationale and Background: .............................................................................................. 8 
3 
DRUG INFORMATION ...................................................................................................... 11 
3.1 
Cannabidiol .................................................................................................................... 11 
4 
STUDY DESIGN.................................................................................................................. 13 
4.1 
Description ..................................................................................................................... 13 
4.2 
Number of Patients ......................................................................................................... 14 
4.3 
Number of Study Centers ............................................................................................... 14 
4.4 
Study Duration ............................................................................................................... 14 
5 
ELIGIBILITY CRITERIA.................................................................................................... 15 
5.1 
Inclusion Criteria ............................................................................................................ 15 
5.2 
Exclusion Criteria ........................................................................................................... 15 
6 
STRATIFICATION FACTORS ........................................................................................... 16 
7 
TREATMENT PLAN ........................................................................................................... 16 
7.1 
Cannabidiol .................................................................................................................... 16 
7.2 
Concomitant Medications and Therapies ....................................................................... 17 
7.3 
Duration of Therapy ....................................................................................................... 18 
8 
TOXICITIES AND DOSAGE MODIFICATION ............................................................... 18 
8.1 
Dose Modifications and Guidelines for Adverse Event Management  .......................... 18 
8.2 
Supportive Care .............................................................................................................. 20 
8.3 
Contraception ................................................................................................................. 20 
9 
STUDY CALENDAR .......................................................................................................... 21 
10 STUDY PROCEDURES ...................................................................................................... 23 
10.1 
Screening Evaluations ................................................................................................ 23 
10.2 
Patient-Reported Outcomes ........................................................................................ 23 
11 CRITERIA FOR EVALUATION AND ENDPOINT .......................................................... 25 
11.1 
Safety .......................................................................................................................... 25 
11.2 
Stopping Rules ............................................................................................................ 25 
N/A ................................................................................................................................................ 25 
12 STATISTICAL CONSIDERATIONS.................................................................................. 25 
12.1 
Statistical hypothesis .................................................................................................. 25 
12.2 
Sample size determination .......................................................................................... 25 
12.3 
Statistical Analyses ..................................................................................................... 26 
13 REGISTRATION GUIDELINES ......................................................................................... 27 
14 DATA SUBMISSION SCHEDULE .................................................................................... 27 
15 SPECIAL INSTRUCTIONS ................................................................................................ 27 


 
 
Page 3 of 38 
15.1 
Patient-reported questionnaires .................................................................................. 27 
15.2 
Correlative Studies ..................................................................................................... 28 
16 ETHICAL AND REGULATORY CONSIDERATIONS .................................................... 29 
16.1 
Informed consent ........................................................................................................ 29 
16.2 
Human Subjects Protections ....................................................................................... 29 
16.3 
Institutional Review .................................................................................................... 29 
16.4 
Data and Safety Monitoring Plan ............................................................................... 29 
16.5 
ADVERSE EVENTS ................................................................................................. 30 
16.5.1 
Experimental Therapy ................................................................................................ 30 
16.5.3 
Definitions .................................................................................................................. 31 
16.5.4 
Adverse Event Characteristics .................................................................................... 33 
16.5.7 
Reporting of Unanticipated Problems ........................................................................ 34 
16.6 
Reporting of Pregnancy .............................................................................................. 34 
16.7 
Protocol Amendments ................................................................................................ 35 
16.8 
Protocol Deviations .................................................................................................... 35 
16.9 
Food and Drug Administration (FDA) ....................................................................... 35 
16.10 
Clinical Trials Data Bank ........................................................................................... 35 
17 REFERENCES ..................................................................................................................... 35 
 
 


 
 
Page 4 of 38 
ABBREVIATIONS 
AI 
Aromatase inhibitor 
AIMSS 
Aromatase inhibitor-associated musculoskeletal symptoms  
BPI 
Brief Pain Inventory 
CBD 
Cannabidiol 
CNS 
Central nervous system 
DSMC 
Data and Safety Monitoring Committee 
ER 
Estrogen receptor 
GRC 
Global Ratings of Change 
HR 
Hormone receptor 
IRB 
Institutional Review Board 
LHRH 
Luteinizing Hormone Receptor Hormone 
METE 
Mao Expectation of Treatment Efficacy 
NSAID 
Non-steroidal anti-inflammatory drugs 
O-CTSU 
Oncology Clinical Trial Support Unit 
PANAS 
Positive and Negative Affect Scale 
PARP 
Poly adenosine diphosphate-ribose polymerase 
PR 
Progesterone receptor 
SAE 
Serious adverse event 
THC 
∆9-tetrahydrocannabinol  
 


 
 
Page 5 of 38 
STUDY SUMMARY 
Title 
Phase 2 Trial of Cannabidiol (CBD) for 
Treatment of Aromatase Inhibitor-Associated 
Arthralgias 
Short Title 
CBD for AIMSS (CBD-AIM) 
Protocol Identifiers (IRB – internal) 
HUM00182109 
IND number 
TBD 
Phase 
Phase 2 
Design 
Single arm phase II interventional trial 
Study Duration 
2.5 years 
Study Center(s) 
Single-center  
Objectives 
Primary Objective: 
 
To determine the effect of 15 weeks of CBD on 
AI-associated worst joint pain, as assessed with 
the Brief Pain Inventory (BPI) 
Secondary Objectives: 
 
To determine the effect of 15 weeks of CBD on 
other AI-associated pain symptoms, including 
average pain and pain interference, as assessed 
with the BPI 
 
To determine the effect of 15 weeks of CBD on 
other AI-associated symptoms, including 
anxiety, depression, insomnia, and cognitive 
function, as assessed with the PROMIS-29+2 
Profile  
 
To examine the safety and tolerability of 15 
weeks of CBD in patients with breast cancer 
taking aromatase inhibitor therapy 
 
To examine the effect of 15 weeks of CBD on 
circulating estradiol concentrations 
 
Exploratory objectives: 
 
To examine the impact of 15 weeks of CBD 
therapy on inflammatory biomarkers in patients 
with breast cancer taking aromatase inhibitor 
therapy 


 
 
Page 6 of 38 
 
To examine demographic, clinical, psychosocial, 
and inflammatory predictors of response to CBD 
therapy 
 
Number of Subjects 
44 (goal 40 evaluable patients) 
Study drug 
Cannabidiol 25 mg – 100 mg BID orally  
Duration of administration 
15 weeks 
Reference therapy 
N/A 
Statistical Methodology 
The primary endpoint of this study is the 
absolute difference in worst pain from baseline 
to 15 weeks with CBD. Differences from 
baseline at each time point for all patient 
reported outcomes (worst and average pain 
severity, pain interference, sleep disturbance, 
fatigue, physical function, anxiety, depression, 
and cognitive function over time) will be 
summarized via mean, standard deviation, and 
the change in the pattern over time will be 
explored with linear mixed models including a 
subject-specific random effect to account for the 
natural heterogeneity across patients. 
Normalizing transformations will be used if 
necessary to ensure accurate model fit. 
Secondarily, the proportion of patients who have 
at least a 2-point reduction in worst and average 
pain from baseline to 15 weeks will be reported 
with the corresponding exact binomial 
confidence intervals.   
 
 
 


 
 
Page 7 of 38 
SCHEMA 
 
 


 
 
Page 8 of 38 
1 OBJECTIVES 
1.1 
Primary Objective 
 
To determine the effect of 15 weeks of CBD on AI-associated worst joint pain, as assessed 
with the Brief Pain Inventory (BPI) 
 
1.2 
Secondary Objectives 
 
1. To determine the effect of 15 weeks of CBD on other AI-associated pain symptoms, 
including average pain and pain interference, as assessed with the BPI 
 
2. To determine the effect of 15 weeks of CBD on other AI-associated symptoms, including 
anxiety, depression, insomnia, and cognitive function, as assessed with the PROMIS-
29+2 Profile 
 
3. To examine the safety and tolerability of 15 weeks of CBD in patients with breast cancer 
taking aromatase inhibitor therapy 
 
4. To examine the effect of 15 weeks of CBD on circulating estrogen concentrations 
 
1.3 
Exploratory Objectives 
 
1. To examine the impact of 15 weeks of CBD therapy on inflammatory biomarkers in 
patients with breast cancer taking aromatase inhibitor therapy 
 
2. To examine demographic, clinical, psychosocial, and inflammatory predictors of 
response to CBD therapy 
 
2 BACKGROUND 
2.1 
Hypothesis 
2.2 
Rationale and Background:  
 
Aromatase inhibitor (AI) therapy for breast cancer  
Breast cancer is the most common cancer diagnosis among women in the United States, 
affecting one in eight women in her lifetime. With advancements in screening and 
treatment, nearly 90% of women diagnosed with breast cancer in the United States (US) 
survive beyond five years and comprise an estimated 25% of cancer survivors. About 
80% of breast cancers diagnosed in postmenopausal women are hormone receptor 


 
 
Page 9 of 38 
positive (HR+). For these women, daily oral adjuvant endocrine therapy for five to ten 
years following primary treatment (surgery, radiation, chemotherapy) is indicated.1 
Third generation AIs are the preferred endocrine treatment for postmenopausal women 
with early stage HR+ breast cancer. Aromatase is the key enzyme that converts 
androgens to estrogens. In postmenopausal women, aromatase is only expressed in non-
glandular tissues including fat, liver, brain, and breast tissues.2 AIs prevent the 
biosynthesis of estrogen in these tissues, thus preventing the proliferation of HR+ 
breast cancer cells. Large-scale comparative effectiveness trials demonstrated the 
superiority of AIs over other endocrine treatment (i.e., tamoxifen), in terms of 
prolonged disease-free survival, rates of distant metastasis, and contralateral breast 
cancer, as well as a preferable toxicity profile.3  
 
AI-Associated Musculoskeletal Symptoms (AIMSS) 
Despite their clinical utility, AIMSS affect ~50% of the 200,000 patients who start AI 
therapy per year in the US.4 Musculoskeletal symptoms, including arthralgias, 
myalgias, and joint stiffness, are the primary symptoms reported by AI-treated patients. 
These symptoms typically emerge within about 3 months of AI initiation, and peak at 
6 months.4, 5 Despite considerable research, the etiology of AIMSS remains poorly 
understood.4, 6-9 Postulated mechanisms include inflammation and reductions in 
naturally anti-nociceptive properties of estrogen.10, 11 While multiple randomized 
clinical trials of AIMSS treatments have been conducted, only a few interventions 
including acupuncture and duloxetine have demonstrated improvement in 
musculoskeletal pain and stiffness,12, 13 and are currently unavailable to most patients 
due to access issues (acupuncture) and perceived stigma and toxicity (duloxetine). 
 
AIMSS can lead to early treatment discontinuation in one-fifth of patients, which can 
increase risk of breast cancer recurrence by 45-50%.4, 14-16 Despite well-established 
clinical benefits of long-term AI treatment, more than 20% of patients discontinue AI 
therapy prematurely, primarily because of toxicity of therapy. While the primary 
toxicity of therapy is AIMSS, AI-treated women also report bothersome vasomotor and 
gynecologic symptoms, as well as insomnia, fatigue, anxiety, and depression. In 
addition, studies have shown an increase in inflammatory markers in patients with co-
existing 
symptoms, 
supporting 
an 
underlying 
inflammatory 
mechanism.11 
Discontinuation of AI therapy before the recommended 5-10 years has been shown to 
increase risk of cancer recurrence and mortality.14-16 Therefore, well-tolerated and 
effective interventions to improve AI-associated symptoms, primarily AIMSS, are 
urgently needed. 
 
Cannabinoids  
Cannabinoids produce analgesia in patients with pain.17 These compounds, such as 
cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC), act on cannabinoid receptors 
1 and 2 (CB1 and CB2) and other receptors in the endocannabinoid system, which are 
involved in complex behaviors and responses such as pain, sleep, and mood.18-20 THC’s 
activation of CB1 receptors is primarily responsible for the psychoactive effects that 
characterize cannabis intoxication.21, 22 In contrast to THC, CBD is non-intoxicating 


 
 
Page 10 of 38 
and well tolerated in numerous medical conditions. CBD-related adverse events are 
minor, even in the context of long-term, high-dose paradigms.23-28 CBD is a 
promiscuous compound that acts on numerous systems (e.g., the serotonergic 5HT1a 
receptor, transient receptor potential cation channel subfamily V member 1) and exerts 
anti-inflammatory and analgesic effects.28 In a recent clinical trial among individuals 
with chronic pain due to knee osteoarthritis, transdermally-administered CBD 
significantly reduced pain and improved function.29 Murine models of induced arthritis 
provide mechanistic support for this finding, as CBD slowed arthritis progression, 
prevented and/or reduced joint damage, and reduced spontaneous tumor necrosis factor 
release following lipopolysaccharide injection.26, 27 Further, CBD administration 
during days 0-3 of monoiodoacetate-induced arthritis in a rat model dramatically 
reduced tactile allodynia and inhibited nerve demyelination, suggesting that early CBD 
administration could protect against nerve damage from inflammatory flares.28  
CBD also exerts anxiolytic effects, which is of special import given that anxiety is 
common among individuals with breast cancer and is associated with worsened pain 
symptoms.30-32 A recent clinical trial among individuals with social anxiety disorders 
showed that 300mg of CBD/day for 4 weeks resulted in decreased anxiety.  Acute CBD 
administration (300-600 mg) has been shown to decrease anxiety compared to placebo 
during public speaking tasks.33-36 In a retrospective chart review among 47 psychiatric 
outpatients, CBD (25-175 mg/day) reduced anxiety scores by 31% after 3 months.37 
Taken together, these anti-inflammatory, analgesic, and anxiolytic effects suggest that 
CBD may have value as an analgesic in AIMSS. Although CBD is widely used by the 
general public for pain, arthritis, and anxiety, clinical research on CBD is limited and 
no clinical trials have examined CBD alone for cancer pain. Thus, the proposed study 
will shed light on precisely how CBD is exerting its analgesic effects in patients with 
AIMSS, as well as rigorously investigate the safety profile in this condition. 
Cannabidiol 
Until recently, the only options for conducting clinical trials of CBD was to use over-
the-counter products, which are highly variable in potency, there is poor quality control 
and testing for contaminants (e.g., heavy metals), and products are typically not 
consistent from lot to lot due to inherent variability in the hemp crop. However, a 
prescription version of CBD (Epidiolex) was recently FDA approved for treatment of 
refractory seizures in children. This formulation is ideal for testing in patients with 
AIMSS because it is non-intoxicating, is produced using Good Manufacturing 
Practices, which guarantee consistent product quality, and is not illegal under federal 
law.  
Cannabidiol is relatively well tolerated at higher doses than planned in this trial; 
doses for treatment of refractory seizures are typically 5-20 mg/kg/day. Doses 
planned in this trial are 25 mg BID to 100 mg BID. For a 50 kg person, this is 
equivalent to a range of 1-4 mg/kg/day. For an 80 kg person, this is equivalent to a 
range of 0.625-2.5 mg/kg/day. 
 
 
Assessment of AIMSS 


 
 
Page 11 of 38 
No published scales have been established or validated to specifically measure the 
effects of treatments for AI-induced joint pain and stiffness. Therefore, we have chosen 
to use a combination of scales to assess the effect of CBD for improving tolerance of 
AI therapy. As has been used in multiple prior trials of treatments for AIMSS, patients 
will complete self-reported questionnaires including the Brief Pain Inventory-Short 
Form (BPI-SF)38 to assess severity of joint pain/stiffness and the Global Ratings of 
Change (GRC) scale to identify overall change in pain/stiffness since starting AI 
therapy. To assess other symptoms related to endocrine therapy, patients will complete 
the PROMIS-29+2.39 To assess expectation of benefit from CBD, patients will 
complete the Mao Expectation of Treatment Efficacy (METE).40 Finally, patients will 
complete multiple questionnaires to further characterize pain and associated 
psychosocial symptoms, including the 2011 Fibromyalgia Survey to assess symptoms, 
the PANAS to assess affect, and a coping questionnaire to assess catastrophizing. All 
of these questionnaires are described in greater detail in section 10. 
3 DRUG INFORMATION 
3.1 
Cannabidiol 
3.1.1 Pharmacology 
The mechanism of action of CBD for treatment of pain is not entirely clear. CBD has weak 
affinity for CB1 and CB2, but binds to other receptors, including serotonin 5-HT1A.41, 42 CBD 
is well tolerated in humans at doses up to 700 mg/day43, 44 and is non-intoxicating.45 In 
animal studies, CBD exerts anti-inflammatory and anti-nociceptive effects, and slows 
arthritis progression.26-28 However, no systematic mechanistic studies of CBD have been 
conducted in individuals with chronic pain. 
3.1.2 Physical and Chemical Properties  
 
Cannabidiol is a cannabinoid designated chemically as 2-[(1R,6R)-3-Methyl-6-(1-
methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (IUPAC/CAS). Its empirical 
formula is C21H30O2 and its molecular weight is 314.46. Cannabidiol, the active ingredient in 
EPIDIOLEX, is a cannabinoid that naturally occurs in the Cannabis sativa L. plant. 
Cannabidiol is a white to pale yellow crystalline solid. It is insoluble in water and is soluble 
in organic solvents. 
3.1.3 Pharmaceutical Properties and Formulation  
EPIDIOLEX (cannabidiol) oral solution is a clear, colorless to yellow liquid containing 
cannabidiol at a concentration of 100 mg/mL. Inactive ingredients include dehydrated 
alcohol, sesame seed oil, strawberry flavor, and sucralose. EPIDIOLEX contains no 
ingredient made from a gluten-containing grain (wheat, barley, or rye). 
 
3.1.4. Pharmacokinetics  
Cannabidiol demonstrated an increase in exposure that was less than dose-proportional over 
the range of 5 to 20 mg/kg/day in patients.  
 


 
 
Page 12 of 38 
Absorption  
 
Cannabidiol has a time to maximum plasma concentration (Tmax) of 2.5 to 5 hours at steady 
state (Css).  
 
Effect of Food  
Co-administration of EPIDIOLEX with a high-fat/high-calorie meal increased Cmax by 5-
fold, AUC by 4-fold, and reduced the total variability, compared with the fasted state in 
healthy volunteers.  
 
Effect on P-glycoprotein (P-gp) substrates 
Coadministration of EPIDIOLEX with orally administered everolimus, a P-gp and CYP3A4 
substrate, results in an approximately 2.5-fold increase in mean Cmax and AUC of 
everolimus [see Clinical Pharmacology (12.3) in the drug prescribing information]. When 
initiating EPIDIOLEX in patients taking everolimus, monitor therapeutic drug levels of 
everolimus and adjust the dosage accordingly. When initiating everolimus in patients taking 
a stable dosage of EPIDIOLEX, a lower starting dose of everolimus is recommended, with 
therapeutic drug monitoring. Increases in exposure of other orally administered P-gp 
substrates (e.g., sirolimus, tacrolimus, digoxin) may be observed on coadministration with 
EPIDIOLEX. Therapeutic drug monitoring and dose reduction of other P-gp substrates 
should be considered when given orally and concurrently with EPIDIOLEX. 
 
Distribution  
 
The apparent volume of distribution in healthy volunteers was 20963 L to 42849 L. Protein 
binding of the cannabidiol and its metabolites was >94% in vitro.  
 
Elimination  
 
The half-life of cannabidiol in plasma was 56 to 61 hours after twice-daily dosing for 7 days 
in healthy volunteers. The plasma clearance of cannabidiol following a single EPIDIOLEX 
1500 mg dose (1.1 times the maximum recommended daily dosage) is 1111 L/h.  
 
Metabolism  
 
Cannabidiol is metabolized in the liver and the gut (primarily in the liver) by CYP2C19 and 
CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms. After repeat dosing, the 
active metabolite of cannabidiol, 7-OH-CBD, has a 38% lower AUC than the parent drug. 
The 7-OH-CBD metabolite is converted to 7-COOH-CBD, which has an approximately 40 
fold higher AUC than the parent drug. Based on preclinical models of seizure, the 7-OH-
CBD metabolite is active; however, the 7-COOH-CBD metabolite is not active.  
 
Excretion  
 
EPIDIOLEX is excreted in feces, with minor renal clearance. 


 
 
Page 13 of 38 
3.1.4 Clinical Safety 
 
Cannabidiol had the following adverse reactions in clinical trials of EPIDIOLEX (%): 
 
Adverse reaction 
CBD 10 
mg/kg/day 
CBD 20 
mg/kg/day 
Placebo 
Elevated transaminases 
8 
16 
3 
Decreased appetite 
16 
22 
5 
Diarrhea 
9 
20 
9 
Decreased weight 
3 
5 
1 
Gastroenteritis 
0 
4 
1 
Abdominal pain 
3 
3 
1 
Somnolence 
23 
25 
8 
Sedation 
3 
6 
1 
Lethargy 
4 
8 
2 
Fatigue 
11 
12 
4 
Insomnia 
11 
5 
4 
Irritability 
9 
5 
2 
Aggression 
3 
5 
<1 
Salivary hypersecretion 
1 
4 
<1 
Gait disturbance 
3 
2 
<1 
Infection 
41 
40 
31 
Rash 
7 
13 
3 
Hypoxia 
3 
3 
1 
 
Adverse reactions were similar across pediatric and adult patients.  
 
Epidiolex can cause decreases in hemoglobin. The mean decrease in clinical trials was 0.42 
g/dL, compared to a decrease of 0.03 g/dL on placebo. 
 
Epidiolex can cause increases in serum creatinine; the mechanism is unknown. An increase 
of approximately 10% was observed within 2 weeks of starting Epidiolex. The increase was 
reversible in healthy adults. 
 
 
4 STUDY DESIGN 
4.1 
Description 
This will be a single arm phase 2 trial of CBD to examine the safety and efficacy of  15 weeks 
of CBD in postmenopausal women with AIMSS. In addition, change in inflammatory 
biomarkers with treatment will be examined to obtain preliminary information about the 
mechanism of action of CBD in this condition, and to identify predictors of response to therapy. 


 
 
Page 14 of 38 
4.2 
Number of Patients 
A total of 44 patients will be enrolled, assuming a 10% dropout rate, for a total of 40 
evaluable patients. Patients who discontinue trial participation prior to initiating CBD therapy 
will be replaced. 
4.3 
Number of Study Centers 
This will be a single center trial run at the Rogel Cancer Center at the University of Michigan. 
4.4 
Study Duration 
The study is anticipated to be open for 2.5 years. 
 
 
 


 
 
Page 15 of 38 
5 ELIGIBILITY CRITERIA 
5.1 
Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
5.1.1 _____ Female subject aged ≥ 18 years who is postmenopausal according to standard 
clinical criteria (see section 8.3) or who has been receiving concomitant LHRH agonist 
therapy. 
5.1.2 _____ Taking the currently prescribed aromatase inhibitor therapy (anastrozole, 
exemestane, or letrozole) for adjuvant treatment of breast cancer or for 
chemoprevention for at least 3 weeks and no more than 2 years at the time of 
enrollment.  
5.1.3 _____ Planning to take the same AI therapy for at least 15 weeks. 
5.1.4 _____ New or worsening joint pain and/or myalgias since starting the AI therapy, with 
worst pain score of at least 4 out of 10 on the BPI over the 7 days prior to enrollment. 
5.1.5 _____ Completion of surgery (mastectomy or lumpectomy/partial mastectomy) for 
treatment of breast cancer at least 3 months prior to enrollment. Completion of axillary 
surgery as indicated (not required). 
5.1.6 _____ Completion of chemotherapy, if given. Concurrent use of LHRHa therapy, anti-
HER2 therapy, bisphosphonate therapy, PARP inhibitor therapy, and CDK4/6 inhibitor 
therapy is permitted.  
5.1.7 _____ Patients receiving treatment with NSAIDs, acetaminophen, opioids, duloxetine, 
gabapentin, and/or pregabalin must have been taking a stable dose for at least 30 days 
prior to enrollment if they plan to continue the drug during study participation. If they 
do not plan to take the medication during study participation, they should stop the 
medication at least 7 days before initiation of study treatment. 
5.1.8 _____ ECOG Performance Status 0-2. 
5.1.9 _____ Able to self-complete questionnaires in English. 
5.1.10 _____ Able to provide informed consent and willing to sign an approved consent form 
that conforms to federal and institutional guidelines. 
 
5.2 
Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
5.2.1 _____ Metastatic breast cancer. 
5.2.2 _____ Planned surgery during the 15-week study period. 


 
 
Page 16 of 38 
5.2.3 _____ ALT/AST > 3x ULN or bilirubin > 1.5x ULN. If known Gilbert’s syndrome, 
bilirubin may not be > 2x ULN (obtained ≤28 days of registration).  
5.2.4 _____ Clinically significant laboratory abnormalities, including: Creatinine >1.5 x 
ULN or Hemoglobin <9 g/dL (obtained ≤28 days of registration).  
5.2.5 _____ History of or currently has suicidal ideation or attempted suicide  
5.2.6 _____ History of seizure other than febrile seizures in childhood. 
5.2.7 _____ Current use of valproate or clobazam. If patient takes valproate or clobazam, 
should discontinue 7 days prior to enrollment. 
5.2.8 _____ Use of cannabidiol, THC, or marijuana (oral, inhaled, or topical) within the 6 
weeks prior to enrollment.  
5.2.9 _____ Known allergy or hypersensitivity to CBD or any of the excipients in the 
medication, including sesame. 
5.2.10 _____ Unable to take oral medications. 
5.2.11 _____ Pregnant or breast feeding. 
5.2.12 _____ Any medical condition that would interfere with the absorption of study 
medication. Prior gastric bypass is permitted. 
5.2.13 _____ Concurrent medical or arthritis disease such as active rheumatoid arthritis or 
inflammatory arthritis that could confound or interfere with evaluation of pain or 
efficacy. Patients with osteoarthritis are eligible. 
5.2.14 _____ Patients with a prior or concurrent malignancy whose natural history or 
treatment, in the opinion of the treating investigator, has the potential to interfere with 
the safety or efficacy assessment of the investigational regimen. 
6 STRATIFICATION FACTORS 
N/A 
7 TREATMENT PLAN 
7.1 
Cannabidiol 
7.1.1 How Supplied, Stored, Packaged and Labeled 
Cannabidiol (EPIDIOLEX, Greenwich Biosciences) will be purchased from commercial 
supply and stored in the University of Michigan Research Pharmacy. The Research 
Pharmacy will dispense one bottle per patient at the baseline study visit; if the patient is 
unable to come to clinic for the baseline visit then the medication will be mailed to the 
patient and the study medication log will be mailed or emailed to the patient.  A second bottle 


 
 
Page 17 of 38 
will be provided at the week 8 study visit; if the patient is unable to come to clinic for the 8 
week visit then the medication will be mailed to the patient and the study medication log will 
be mailed or emailed to the patient.  
EPIDIOLEX is a strawberry flavored clear, colorless to yellow solution supplied in a 105 mL 
amber glass bottle with a child-resistant closure containing 100 mL of oral solution (NDC 
70127-100-01). Each mL contains 100 mg of cannabidiol. EPIDIOLEX is packaged in a 
carton with two 5 mL calibrated oral dosing syringes and a bottle adapter (NDC 70127-100-
10). The pharmacy will provide 1 mL calibrated oral dosing syringes when doses less than 
1mL are required.  
Store EPIDIOLEX in its original bottle in an upright position at 20°C to 25°C (68°F to 
77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). Do not refrigerate or 
freeze. Keep the cap tightly closed. The bottle with any unused drug will be returned to the 
study coordinator/Research Pharmacy at the completion of the trial.  
7.1.2 Preparation and Administration 
Patients should be instructed to take 25 mg (0.25 ml) twice a day approximately 12 hours 
apart for the first week, with food. Each week the patient should increase the dose by 25 mg 
twice a day until she reaches a maximum of 100 mg (1 ml) twice a day, unless she has 
difficulty tolerating the medication. If a dose is missed the patient should take it as soon as 
she remembers, although if it has been more than 8 hours she should not double up on 
dosing. If a dose is vomited it should not be made up. 
The drug should be drawn up into a dry syringe. If the syringe is wet, it can make the drug 
appear cloudy; this does not affect its safety or efficacy. 
Patients will be advised not to drive or operate machinery until they have gained sufficient 
experience on the study drug to gauge whether it adversely affects their ability to drive or 
operate machinery. Participants will be advised that concomitant use of alcohol or other CNS 
depressants may increase sedation and somnolence. 
7.1.3 Accountability and Compliance 
Study drug compliance during any period will be monitored by having the patient 
complete an IRBMED approved study drug diary.   
7.2 
Concomitant Medications and Therapies 
7.2.1 Allowed Therapy 
Patients are permitted to take concomitant aromatase inhibitor therapy, LHRH agonist 
therapy, anti-HER2 directed therapy, CDK4/6 inhibitor therapy, and/or anti-osteoclast 
therapy. Patients are permitted to use vaginal estrogen preparations. 
Because of the potential for drug-drug interactions, consider a reduction in dosage of 
sensitive CYP1A2, CYP2B6, CYP2C8, CPY2C9, CYP2C19, and P-gp substrates, as 
clinically appropriate (see https://drug-interactions.medicine.iu.edu/MainTable.aspx and the 
drug prescribing information). 


 
 
Page 18 of 38 
Patients who are taking opioids, NSAIDs, acetaminophen, duloxetine, gabapentin, and/or 
pregabalin at the time of study drug initiation should continue to take the same dose of 
medication for the 15 week study duration. 
7.2.2 Prohibited Therapy 
Patients with a history of hormone receptor positive breast cancer should avoid taking 
systemic or transdermal estrogen products (vaginal estrogen preparations are permitted). 
Patients should not take valproate or clobazam while participating on this clinical trial.  
7.3 
Duration of Therapy 
Patients will be treated with the study drug for 15 weeks (+/- 7 days). 
7.3.1 Criteria for discontinuation of treatment (“off study”) 
The following will result in study treatment discontinuation: 
• Discontinuation of AI therapy, defined as:  
o Discontinuation of the currently prescribed AI therapy for more than 7 days 
• Evidence of new cancer or cancer recurrence 
• Unacceptable toxicity (see section 8.1) 
• Delay of 14 consecutive days of study treatment (CBD) due to any reason 
• The participant may discontinue study treatment (CBD) at any time for any reason 
including participant request to be withdrawn from study 
• Death 
8 TOXICITIES AND DOSAGE MODIFICATION 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf) for adverse event and serious adverse event reporting. 
8.1 
Dose Modifications and Guidelines for Adverse Event Management  
8.1.1 Dose Modifications 
Dose levels: 
Dose level 1  
25 mg BID 
Dose level 2 
50 mg BID 
Dose level 3 
75 mg BID 
Dose level 4 
100 mg BID 


 
 
Page 19 of 38 
If the dose is reduced because of toxicity, that dose should be maintained for the remainder 
of the trial and not re-escalated. 
 
Toxicity Grade 
What to do 
Grade 1 – possibly, probably, or 
definitely related to study drug 
For ALT/AST > 3x ULN, discontinue study 
medication. 
 
For all other grade 1 toxicities, monitor as needed 
until the problem has resolved (i.e., grade 0), 
stabilized (i.e., remains as grade 1), or is otherwise 
explained.  
If Grade 1 symptoms persist, the PI or Co-I will 
assess whether the dose should be reduced by 1 dose 
level or, if the patient is receiving dose level 1, 
whether the patient should discontinue study 
medication. 
Grade 2 – possibly, probably, or 
definitely related to study drug 
For total bilirubin > 2x ULN, discontinue study 
medication. 
For all other grade 2 toxicities, monitor as needed 
until the problem has resolved (i.e., grade 0), 
stabilized (i.e., remains as grade 1 or grade 2), or is 
otherwise explained.  
If Grade 2 symptoms persist, the PI or Co-I will 
assess whether the dose should be reduced by 1 dose 
level or, if the patient is receiving dose level 1, 
whether the patient should discontinue study 
medication. 
Grade 3 – possibly, probably, or 
definitely related to study drug 
If the patient was receiving dose level 1 at the time of 
toxicity development, the patient should discontinue 
study drug. 
For patients receiving dose level 2 or higher, if the 
symptoms resolve or improve to grade 1 or 2 within 7 
days, the dose should be reduced by 1 dose level and 
the drug restarted at the time of symptom 
improvement. This dose is to be maintained if no 
further Grade 3 toxicity is noted.  
If the symptoms do not resolve or improve to grade 1 
or 2 within 7 days, the patient can continue to hold 
study drug for another 7 days. If the symptoms 
resolve or improve to grade 1 or 2, the dose should be 
reduced by 1 dose level and the drug restarted at the 
time of symptom improvement. This dose is to be 
maintained if no further Grade 3 toxicity is noted. If 


 
 
Page 20 of 38 
the symptoms remain Grade 3 possibly, probably, or 
definitely related to the study drug, the patient should 
be permanently removed from protocol treatment.  
If upon restarting the medication at the lower dose 
the patient again experiences Grade 3 toxicity, the 
patient can again be given a 7-day drug holiday. 
Subsequently the patient may be rechallenged one 
dose level lower. If symptoms do not recur (i.e., if 
symptoms resolve to grade 0), the dose should be 
maintained. Alternatively, if Grade 1 or Grade 2 
symptoms occur, the PI or Co-I will assess whether 
the patient should be removed from protocol 
treatment.  
Grade 4 – possibly, probably, or 
definitely related to study drug 
Study drug should be permanently discontinued. 
Patients who experience hypersensitivity reactions to the study medication should 
discontinue the study medication. 
  
8.2 
Supportive Care 
All supportive measures consistent with optimal patient care may be given throughout the 
study. 
8.3 
Contraception 
Only post-menopausal women (including those rendered postmenopausal with LHRH 
agonist therapy) are eligible for enrollment on this clinical trial. Postmenopausal is defined as 
one or more of the following: 
- 
Absence of menses for at least 12 months 
- 
Concurrent use of LHRH agonist therapy 
- 
Prior bilateral salpingo-oophorectomy 
- 
Serum or plasma concentrations of estradiol within postmenopausal range according to 
local lab values 
 


 
 
Page 21 of 38 
9 STUDY CALENDAR 
 
Required Studies 
Screening 
a 
Baseline b 
Weeks 1, 2, 
3 (+/- 2 
days) c 
Weeks 4, 6 
(+/- 2 days) c 
Week 8 (-2, 
+7 days) c 
Week 12 
(+/- 2 
days) c 
Week 15 
(-2, +7 
days) c, j 
Off Study (if 
prior to 
week 15) d 
Informed consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Performance statusm 
X 
 
 
 
 
 
 
 
Study visitsi 
Xq 
X 
 
 
X 
 
X 
X 
Study coordinator phone callsk, n 
 
 
X 
X 
X 
X 
Xl 
Xl 
Vital signs e 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X  
 
 
 
 
 
 
Adverse event assessment 
 
 
X 
 
X 
 
X 
X 
Patient reported questionnaires f 
 
 
 
 
 
 
 
 
- 
BPI 
X 
X 
X 
X 
X 
X 
X 
X 
- 
PROMIS 
 
X 
 
X (wk 4 only) 
X 
 
X 
X 
- 
GRC 
 
 
Xo 
X (wk 4 only) 
X 
X 
X 
X 
- 
METE 
 
X 
 
 
 
 
 
 
- 
FM Survey 
 
X 
 
 
 
 
X 
X 
- 
CSQ 
 
X 
 
 
 
 
X 
X 
- 
PANAS 
 
X 
 
 
 
 
X 
X 
- 
PHQ9 p 
X 
X 
 
 
 
 
 
 
Phlebotomy g 
 
 
 
 
 
 
 
 
- 
Research 
Xr 
 
 
 
X 
 
X 
X 
- 
Clinical labs (aspartate 
aminotransferase, alanine 
aminotransferase, total 
bilirubin, serum 
creatinine, complete 
blood count) 
X 
 
 
X (wk 4 only) 
X 
 
X 
X 
AI therapy (standard of care) 
 
 
 
 
 
 
 
 
Dispense study medicine 
 
X 
 
 
X 
 
 
 
CBD treatment h 
 
 
 
 
 
 
 
 
Medication log  
 
X 
 
 
X 
 
Xi 
Xi 
 
a. Screening and baseline visits can take place on the same day. The informed consent can be completed either in person or remotely using SignNow. The BPI 
and PHQ9 will be completed after signing the ICF and can be completed by phone or electronically. Screening clinical lab studies must be completed within 28 
days of registration; if they have already been completed for another reason (other than participating in this clinical trial) they do not need to be repeated.  
b. Baseline visit can take place up to 4 weeks after the screening visit. Patient does not need to be seen by physician or advanced practice provider. 
c. Timed based on initiation of CBD therapy. 
d. This is the visit conducted at the time of AI discontinuation and/or study drug discontinuation as per section 7.3.1. These questionnaires should be completed 
within 3 business days of medication discontinuation. Patients will return remaining study drug and medication log at that study visit or at their next routine clinic 


 
 
Page 22 of 38 
visit. Also if a patient discontinues study drug early, she should continue to complete questionnaires according to the study calendar through the 15 week 
timepoint.  
e. Height and weight at screening visit. If these values have been documented in the medical record within 90 days they do not need to be repeated. 
f. Questionnaires will be completed electronically within 2 days before the scheduled visit, at the time of the visit, or within 2 days after the visit. It is preferable to 
have patients complete the questionnaires before or at each visit. Emailed reminders will be sent to patients from REDCap, and telephone reminders may also be 
used. If a scheduled visit is rescheduled after the questionnaires have been completed by the patient, they will not be considered out of window. If a patient 
declines to complete questionnaires electronically they may be completed on paper (baseline and week 8 and 15) or by phone (all timepoints). 
g. It is preferred, but not required, that subjects fast for at least 8 hours prior to all blood collections (except for week 4). Time of blood draw and fasting status 
should be recorded. Details about research labs are in section 15.2.1.  
h. Study medication should begin the first Wednesday morning after the baseline visit whenever possible. If the baseline visit is on a Wednesday, the participant 
can start the study medication the evening of the baseline visit. The medication should be taken with food twice a day approximately 12 hours apart.  
i. At weeks 8 and 15 or off study, patient will meet with research study coordinator or otherwise return the medication log and/or remaining medication to the study 
team, depending on the timepoint. Patient does not need to be seen by physician or advanced practice provider. Patients will return medication log #1 at the 8 
week study visit and return all remaining study drug and medication log #2 at the 15 week study visit, or at the off study visit if it occurs at a different time. If they 
forget to bring the medication and log to the visit, they should return the items at their next routine clinic visit. 
j. For patients who wish to continue on therapy beyond the 15 week study visit, clinicians can provide a written prescription for off-label Epidiolex and/or provide 
recommendations for patients to go to local cannabis dispensaries in Michigan (since recreational cannabis is legal in this state), but drug will not be provided by 
the clinical trial following the week 15 study visit. 
k. Study coordinator calls are to assess adverse events including suicidality and (if applicable) determine if there is a reason that the patient should not increase 
the dose by one dose level (as per section 8.1.1). If there is a question about whether the patient should or should not increase the dose, the study coordinator will 
contact the PI or Co-I. Also if patients have not completed questionnaires or if they decline to complete questionnaires electronically, the study coordinator should 
ask the questions by phone. 
l. The study coordinator should follow-up with the patient by phone 30 days following the off-study visit to assess resolution of any AEs as per section 16.5. 
m. Performance status assessment at screening will be performed by a licensed physician (or physician’s assistant or nurse practitioner) or registered nurse. Can 
have been performed up to 28 days before the screening visit, and can be performed during a virtual visit. 
n. The study coordinator will ask about suicidal ideation on the phone calls using question 9 from the PHQ9: “How often have you been bothered by the following in 
the past week: Thoughts that you would be better off dead, or thoughts of hurting yourself in some way? Not at all, several days, more than half the days, nearly 
every day”. If a patient reports anything other than “Not at all” to the question, the patient’s oncology treatment team will be notified and the patient will be managed 
according to usual clinical protocols. If the treatment team is not available, the PI or another of the co-Is will be notified. 
o. GRC should be completed at week 2. 
p. The study coordinator should review the response to PHQ9 question 9 prior to dispensing the study medication to the patient. If the answer to the question is 
anything other than “Not at all”, the study medication should not be dispensed and the patient’s clinical team or covering provider should be notified immediately. 
q. The screening study visit can be conducted virtually if the necessary patient information (other than lab results) can be found in the medical chart. Patient will 
need to undergo phlebotomy prior to enrollment in the study if screening lab studies have not otherwise been performed within the past 28 days.  
r. If clinical lab studies do not need to be performed at screening because they have been performed within the 28 day window, the research blood specimens at 
screening can instead be collected at baseline. 
 
 
 
 


 
 
Page 23 of 38 
10 STUDY PROCEDURES 
10.1 
Screening Evaluations 
A review of inclusion/exclusion criteria will be conducted to determine the patient’s 
eligibility for enrollment. Study procedures will be reviewed with the patient, and 
documentation of informed consent will be obtained. After signing the informed consent 
form (ICF) either in person or electronically using SignNow or other process approved by the 
UM IRBMED, patients will be assigned a unique study ID number in sequential order. 
Patients will complete the BPI and PHQ9 questionnaires after signing the ICF in order to 
confirm eligibility. Those who are found to be ineligible will be replaced. 
 
The following medical history elements will be abstracted from the medical record: date of 
breast cancer diagnosis, tumor information (e.g., tumor histology, receptor status), treatment 
information (e.g., surgery type and dates, chemotherapy doses and dates, radiation therapy 
doses and dates), information about other relevant medical co-morbidities and concomitant 
medications (as outlined on the case report form). The patient’s email address and phone 
number will also be recorded. 
 
10.2 
Patient-Reported Outcomes 
 
The validated instruments used in this study are as follows: 
 
Brief Pain Inventory (BPI): The BPI is a 17-item patient self-rating scale that assesses 
sensory and reactive components of pain.38 For sensory components, it addresses severity, 
location, chronicity, and degree of relief due to therapy. For reactive components, it assesses 
depression, suffering, and perceived availability of relief. Reliability has been demonstrated 
over short intervals using test retest item correlation; worst pain, r=0.93, usual pain, r=0.78, 
pain now r=0.59. It has been validated in patients with both cancer and non-cancer pain.46, 47 
Ratings of pain interference with various activities increased as ratings of pain severity were 
higher. The proportion of patients receiving opioid analgesics also increased with increased 
severity rating.  
The BPI uses 0 to 10 numeric rating scales for item rating because of its simplicity and lack 
of ambiguity. Since pain can be variable over a day, the BPI asks patients to rate their pain at 
the time of completing the questionnaire, and also at its worst, least, and average over the 
previous 7 days. The primary endpoint for this clinical trial will be based on the 7-day worst 
joint pain and/or myalgias as reported on the BPI. The ratings can be combined to give a 
composite index of pain severity. Also, using numeric 0 to 10 scales, with 0 being “no 
interference” and 10 being “interferes completely”, the BPI asks for ratings of the degree to 
which pain interferes with mood, walking and other physical activity, works, social activity, 
relations with others, and sleep. The mean of these scores can be used as a pain interference 
score. This will be completed at each timepoint. 
 


 
 
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PROMIS-29+2 Profile v2.1: A validated questionnaire that assesses patient-reported 
symptoms over the past 7 days in 9 PROMIS domains (fatigue, sleep disturbance, physical 
functioning, depression, anxiety, ability to participate in social roles and activities, cognitive 
function-abilities, and pain intensity and interference). Raw scores for each domain are 
calculated and then converted to a T-score, with a mean of 50 and a standard deviation of 10. 
Higher T scores represent more of the concept being measured.39 Pain severity and 
interference will be excluded since overlaps with BPI. This 26-item questionnaire will be 
completed at baseline, 4, 8, and 15 weeks (and off study if patient discontinues before week 
15).  
 
Global Ratings of Change (GRC) Scale: This is a single-item measure to assess the overall 
change in pain and stiffness since stopping AI therapy. It is a 7-point Likert scale from -3 to 
+3. This will be completed at 2, 4 8, 12, and 15 weeks (and off study if patient discontinues 
before week 15). 
 
Mao Expectancy of Treatment Effect (METE): The METE is a validated 4-item self-report 
questionnaire rated on a scale of 1-5 (from total disagreement to total agreement), which 
assesses a patient’s expectation that CBD will relieve her AIMSS symptoms.40 The 
instrument had good internal consistency (Cronbach’s α 0.95) in a prior study of acupuncture 
in patients with cancer.48 Will be completed at baseline. 
 
Fibromyalgia (FM) Survey: The FM survey is a combined measure of widespread pain (body 
map of painful sites) and symptom severity (e.g., fatigue, cognitive problems, headache, poor 
mood, scores range 0-12), as a self-reported proxy of centralized pain, assessed at baseline. 
This is a continuous measure with scores ranging from 0-31.49, 50 Will be completed at 
baseline and week 15 (or off study if patient discontinues before week 15). 
 
Coping Strategies Questionnaire catastrophizing scale: The CSQ catastrophizing subscale is 
a validated 6 item subscale that assesses pain catastrophizing, a thinking style has been 
associated with the progression of acute pain to chronic states, and with poorer outcomes 
generally.51 Will be completed at baseline and week 15 (or off study if patient discontinues 
before week 15). 
 
Positive and Negative Affect Scale (PANAS): The PANAS is a validated 20-item instrument 
that measures positive and negative affect.52 It can be scored to include a metric of affect 
balance (e.g., greater negativity over positivity).53-55 Will be completed at baseline and week 
15 (or off study if patient discontinues before week 15). 
 
Patient Health Questionnaire-9 (PHQ-9): The PHQ-9 is a validated 9-item instrument to 
assess depression that is used in both research and clinical practice.56 Question 9 specifically 
addresses suicidal ideation. 


 
 
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11 CRITERIA FOR EVALUATION AND ENDPOINT 
11.1 
Safety 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms and the laboratory studies (LFTs, creatinine, hemoglobin). More frequent safety 
evaluations may be performed if clinically indicated or at the discretion of the investigator.  
11.2 
Stopping Rules 
N/A 
12 STATISTICAL CONSIDERATIONS 
12.1 
Statistical hypothesis 
Use of CBD in postmenopausal women with breast cancer who are experiencing 
AIMSS will result in improvement in joint pain and stiffness. As a secondary 
hypothesis, use of CBD will result in improvement in anxiety. 
12.2 
Sample size determination  
The primary endpoint of this study is the absolute change in worst pain from baseline 
to 15 weeks with CBD. Analysis will be based on intention-to-treat, and all patients 
who complete the 15 week assessment with BPI will be evaluable for the primary 
endpoint. There are no available prior data on symptom response in patients with 
AIMSS treated with CBD. Therefore, the statistical plan for this study was based on 
data from other studies of patients with AIMSS. Based on prior data from 
acupuncture therapy for treatment of AIMSS, we expect a baseline worst pain score 
of 6.5 and standard deviation of 3. Therefore, with a sample size of 40 evaluable 
patients, a two-sided type I error of 5%, we can detect a standardized effect size of 
0.45 or a change in worst pain of 1.4 points with 80% power. Based on IMMPACT 
guidelines, a 2-point reduction in pain is considered to be clinically meaningful for an 
individual patient.57 We power to find a slightly smaller effect size based on 
potentially more heterogeneity in our sample (i.e. higher variability). To account for 
anticipated treatment discontinuation rates of 10%, we will need an additional 4 
patients (for 40 completing patients). 
 
An increased sample size of 44 patients and a longer duration of therapy (15 weeks) 
were chosen to allow for precise evaluation of the efficacy of CBD and to expand our 
ability to perform and interpret the correlative studies. Further, the funder of this 
study voiced concern that a smaller sample size (of 20 patients) and a shorter 
treatment duration (8 weeks) were insufficient to evaluate the primary endpoints of 
this study.  


 
 
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12.3 
Statistical Analyses 
12.3.1 Primary endpoint   
The primary endpoint is defined as the absolute change in BPI worst pain from 
baseline to 15 weeks. This change will be reported with the corresponding 95% 
confidence interval. Differences from baseline at each time point for worst pain will 
be summarized via mean and standard deviation. Patient reported outcomes will be 
analyzed using linear mixed effects models and include a subject-specific random 
effect to account for the natural heterogeneity across patients. Normalizing 
transformations will be used if necessary to ensure accurate model fit. 
      12.3.2  Secondary endpoints 
1. The proportion of patients who have at least a 2 point reduction in worst pain 
from baseline to 15 weeks will be reported with the corresponding exact binomial 
confidence interval.  
2. The proportion of patients who have at least a 2 point reduction in average pain 
from baseline to 15 weeks will be reported with the corresponding exact binomial 
confidence interval. Differences from baseline at each time point for average pain 
and pain interference will be summarized via mean and standard deviation. 
Patient reported outcomes will be analyzed using linear mixed effects models and 
include a subject-specific random effect to account for the natural heterogeneity 
across patients. Normalizing transformations will be used if necessary to ensure 
accurate model fit. 
3. Differences from baseline at each time point for all other patient reported 
outcomes (sleep disturbance, fatigue, physical function, anxiety, depression, and 
cognitive function over time) will be summarized via mean and standard 
deviation. Patient reported outcomes will be analyzed using linear mixed effects 
models and include a subject-specific random effect to account for the natural 
heterogeneity across patients. Normalizing transformations will be used if 
necessary to ensure accurate model fit. 
4. Safety will be assessed throughout the trial and adverse events will be reported 
using descriptive statistics and stratified by dose.   
5. We will report the proportion of individuals with undetectable levels of estradiol 
at baseline and 15 weeks with corresponding exact binomial 95% confidence 
intervals. The exact levels of estradiol at baseline and  15 weeks will be 
summarized using descriptive statistics. 
12.3.2 Exploratory endpoints  
 
1. In this exploratory aim, all inflammatory markers and cytokine levels will be 
summarized using descriptive statistics at baseline and 15 weeks. The changes in 
inflammatory biomarkers will be assessed using one sample t-test of the difference 
(or sign test). Linear models will examine the association between the 8 and 15-week 
worst pain score (controlling for baseline worst pain score and change in pain worst 


 
 
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pain) and baseline and 8 and 15-week inflammatory markers and cytokines. 
Normalizing transformations will be used if required.58, 59 We are limited in the 
number of covariates in each model based on sample size, so we will be careful of 
overfitting recognizing that patient and disease characteristics may be confounders in 
analysis.  No correction for multiple comparisons will be applied based on the 
hypothesis generating nature of the aim. 
2. In this exploratory aim, all questionnaire scores will be summarized using 
descriptive statistics at baseline and 15 weeks. The changes in survey responses will 
be assessed using one sample t-test of the difference (or sign test). We will use a 
linear model to examine the association between the 15-week worst pain severity (as 
measured by the BPI) and the baseline worst pain severity, and baseline and 15-week 
FM score. Similarly, separate models of the 15-week worst pain score will control for 
baseline worst pain severity and assess associations with baseline and  15-week 
PANAS scores and catastrophizing scores. We are limited in the number of covariates 
in each model based on sample size, so we will be careful of overfitting recognizing 
that patient and disease characteristics may be confounders in analysis.  No correction 
for multiple comparisons will be applied based on the hypothesis generating nature of 
the aim.  
3. We will report the proportion of individuals with undetectable levels of estrone 
and estrone sulfate at baseline and 15 weeks with corresponding exact binomial 95% 
confidence intervals. The exact levels of estrone and estrone sulfate at baseline and  
15 weeks will be summarized using descriptive statistics. 
 
13 REGISTRATION GUIDELINES 
Study related screening procedures can only begin once the patient has signed a consent form.  
Patients must meet all of the eligibility requirements listed in Section 5 prior to registration. All 
eligibility will be reviewed and confirmed by PI or co-I prior to enrollment. 
Patients must be registered before receiving any study treatment and must begin study treatment 
within 4 weeks of registration. See study calendar (section 9) for details. 
14 DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each patient that 
provides a record of the data generated according to the protocol. These forms will be completed 
on an on-going basis during the study. The medical records will be source of verification of the 
data. The CRFs will be completed by the Investigator or a member of the study team as listed on 
the Delegation of Duties Log.  
15 SPECIAL INSTRUCTIONS  
15.1 
Patient-reported questionnaires 
 


 
 
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Prior to the first time the patient completes the questionnaires: Patients should be directed to 
report all symptoms and limitations whether or not they are related to the cancer or its 
treatment. They should also be told that their treating provider will not be told about 
symptoms that they report on the questionnaires, and they should mention them during their 
visit.  
When patients are completing them at the time of the clinic visit, it is permissible to assist 
patients with completing the questionnaires being careful not to influence the patient’s 
response. Discourage family members from influencing patient responses to the questions. 
The study coordinator will review the questionnaires after completion on paper to ensure that 
no questions were accidentally skipped or that more than one answer was provided. 
Whenever possible, questionnaires will be completed online, although if a patient states that 
she is unable or unwilling to complete the questionnaire online then a paper form will be 
provided.  
If a patient is unwilling to complete the questionnaires at the time of the study visits 
(baseline, week 8, and week 15) and has not yet done so within 2 working days following the 
visit, the study coordinator will follow-up with the patient by phone to remind her to 
complete the questionnaires. The questionnaires should be completed electronically, or the 
study coordinator can have the patient answer the questions by phone. They should be 
completed within 2 days after the baseline visit and within 7 days after week 8 and 15 visits. 
For the assessment times that are not linked with a study visit, patients will be sent an email 
link via REDCap to questionnaires 2 days before each assessment time weeks 1-6 and 12. If 
they have not completed the questionnaire by the scheduled assessment time (based on date 
of CBD initiation) they will be sent a reminder by email and/or phone. If they do not answer 
the questions by 2 days after the assessment they will be contacted by the study coordinator 
to complete them by phone. 
 
15.2 
Correlative Studies 
15.2.1 Blood correlative studies 
The following samples will be collected: 
A. 10 cc blood will be collected for isolation of plasma at screening (or baseline as per study 
calendar), 8, and 15 weeks and stored in 500 ul aliquots at -80C. 
B. Blood will be collected in TruCulture system 1 ml tubes containing either LPS or media 
at screening, 8, and 15 weeks. Within 15 minutes of the blood draw the samples should 
be incubated at 37C for 24-48 hours, then the supernatant will be isolated and stored in 
250 ul aliquots. (instructions for blood processing: https://myriadrbm.com/products-
services/truculture/truculture-video/) 
Samples will be collected at the time of standard of care phlebotomy whenever possible. 
Patients will fast for at least 8 hours prior to phlebotomy whenever possible. The study 
coordinator will record time of blood draw and whether or not patient was fasting. 


 
 
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15.2.2 Correlative analyses 
Thawed samples will be batch-analyzed for estrogens, high sensitivity C reactive protein, and 
a panel of pro-inflammatory (e.g., IL-6, IL-1, TNF-α, IL-17) and regulatory cytokines (e.g., 
IL-10) using high sensitivity tandem mass spectroscopy-based, immunoturbidimetric, and 
multiplex assays, respectively.60 Stimulated cytokine and chemokine analysis will be 
performed using the TruCulture system. 
16 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 
Informed consent  
Informed consent will be obtained from all research participants prior to performing any study 
procedures using the most recent IRB-approved version.  
16.2 
Human Subjects Protections 
16.2.1 Rationale for Subject Selection 
This clinical trial is open to all patients with AIMSS with minimal restrictions in order to 
permit inclusion of as broad a population as possible. Only patients who read English will be 
enrolled because not all of the patient reported questionnaires have been linguistically 
validated in other languages. 
16.2.2 Participation of Children 
Patients must be at least 18 years of age to participate. 
16.3 
Institutional Review 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to be provided to subjects, must be reviewed and approved by a properly 
constituted IRB. Any amendments to the protocol must be reviewed and approved by the 
IRB.  
16.4 
 Data and Safety Monitoring Plan 
 
This study will be monitored in accordance with the NCI approved University of Michigan 
Rogel Cancer Center Data and Safety Monitoring Plan. 
 
The study team will meet quarterly or more frequently depending on the activity of the 
protocol. The discussion will include matters related to the safety of study participants 
(SAE/UaP reporting), validity and integrity of the data, enrollment rate relative to 
expectations, characteristics of participants, retention of participants, adherence to the 
protocol (potential or real protocol deviations) and data completeness. At these regular 
meetings, the protocol specific Data and Safety Monitoring Report form will be completed 
and signed by the Principal Investigator or by one of the co-investigators. 
 


 
 
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Data and Safety Monitoring Reports will be submitted to the University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Committee (DSMC) on a quarterly basis for 
independent review. 
 
16.5 
ADVERSE EVENTS 
16.5.1 Experimental Therapy 
For the most recent safety update, please refer to the current Study Agent 
Prescribing Information. 
 
16.5.2 Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical 
trial and is done to ensure the safety of subjects enrolled in the studies as well as 
those who will enroll in future studies using similar agents. Data on adverse 
events will be collected from the time of the initial study treatment through 30 
days after the last dose of study treatment. Any serious adverse event that occurs 
more than 30 days after the last study treatment and is considered related to the 
study treatment must also be reported. Serious Adverse Events (SAEs) will 
continue to be followed until: 
• Resolution or the symptoms or signs that constitute the serious adverse 
event return to baseline; 
• There is satisfactory explanation other than the study treatment for the 
changes observed; or  
• Death. 
The investigator is responsible for the detection, documentation, grading and 
assignment of attribution of events meeting the criteria and definition of an AE or 
SAE. The definitions of AEs and SAEs are given below. It is the responsibility of 
the principal investigator to ensure that all staff involved in the trial is familiar 
with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial 
study treatment administration is considered to be pre-existing in nature. Any 
known pre-existing conditions that are ongoing at time of study entry should be 
considered medical history. 
All events meeting the criteria and definition of an AE or SAE, as defined in 
Section 8.3, occurring from the initial study treatment administration through 30 
days following the last dose of the study treatment must be recorded as an adverse 
event in the patient’s source documents and on the CRF regardless of frequency, 
severity (grade) or assessed relationship to the study treatment.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity 
grade) of a pre-existing condition that occurs after the patient begins study 
treatment is also considered an adverse event. 


 
 
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16.5.3 Definitions 
 
1. 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment and which does not necessarily have a causal 
relationship with this treatment. An AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an experimental intervention, 
whether or not related to the intervention.  
 
• 
Diagnostic and therapeutic non-invasive and invasive (i.e., 
surgical) procedures will not be reported as adverse events. However, the 
medical condition for which the procedure was performed must be 
reported if it meets the definition of an adverse event unless it is a pre-
existing (prior to protocol treatment) condition. 
 
• 
Symptoms of the original or targeted disease are not to be 
considered adverse events for this study. The following symptoms are 
indicative of underlying disease (breast cancer) or its treatment and will 
not be reported as adverse events (unless the event is considered serious): 
• 
AI-associated arthralgias (will be collected on patient-reported 
questionnaires) 
• 
Symptoms and signs due to prior treatments (chemotherapy, 
radiation therapy, surgery) 
• 
Adverse events related to disease progression 
• 
Hospitalization or treatment related to breast surgery or breast 
reconstruction procedures 
 
• 
Abnormal laboratory values or test results constitute adverse 
events if they induce clinical signs or symptoms or require therapy. They 
are to be captured under the signs, symptoms or diagnoses associated with 
them. 
1. 
Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the investigator, 
it results in any of the following outcomes: 
 
o Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
o A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of 
either the investigator, its occurrence places the patient or subject at 


 
 
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immediate risk of death. It does not include an adverse event that, had 
it occurred in a more severe form, might have caused death.  
 
o Inpatient hospitalization or prolongation of existing hospitalization for 
> 24 hours. 
 
o A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
 
o A congenital anomaly/birth defect 
 
o Important medical event 
Any event 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 and 
may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition of “Serious Adverse Event”. 
Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; 
convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries 
should not be reported as SAEs unless the underlying medical condition 
has worsened during the course of the study. Preplanned hospitalizations 
or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be 
considered SAEs. Hospitalization or prolongation of hospitalization 
without a precipitating clinical AE (for example, for the administration of 
study therapy or other protocol-required procedure) should not be 
considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
 
2. 
Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
• For approved and marketed drugs, those adverse events are 
described in the approved Package Insert (Label).  
• For investigational new drugs, those adverse events are described 
in the FDA Investigator’s Brochure.  
• In clinical research studies, information on expected adverse 
events is also summarized in the protocol and in the consent 
document.  See section 9.1 for the list of expected adverse events 
related to the drug under study. 


 
 
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3. 
Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in 
the Package Insert, Investigator’s Brochure, in published medical 
literature, in the protocol, or in the informed consent document.  
16.5.4 Adverse Event Characteristics 
1. CTCAE Term 
AE description and grade: The descriptions and grading scales found in 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of 
the CTCAE version 5.0 can be downloaded from the CTEP web site. 
(http://ctep.cancer.gov) 
2. Attribution of the AE 
The investigator or co-investigator is responsible for assignment of 
attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
16.5.5 Serious Adverse Event Reporting Guidelines 
1. The Principal Investigator must be notified within 2 business days of study 
team’s knowledge of any event meeting the criteria and definition of a 
serious adverse event, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study related treatment.  
2. The investigator must report all events meeting the criteria and definition 
of a serious adverse event that are unexpected and possibly related 
(definite, probable or possible) to study treatment administration as per the 
local IRB reporting requirements.  
3. All Serious Adverse Events that are unexpected and possibly related 
(definite, probable or possible) to study treatment administration will be 
reported to the IRB using the CTSU Serious Adverse Event form. 
 
• The Clinical Trial Support Unit Staff will coordinate with the Michigan 
Institute for Clinical and Health Research (MICHR) IND/IDE Investigator 
Assistance Program (MIAP) office for the reporting of any and all IND 
safety reports to the FDA as per the requirements outlined in 21 CFR 
312.32. This includes reporting of all Serious Adverse Events (SAEs) that 
are both unexpected and related to the drug as soon as possible, but in no 
case later than 15 calendar days after the sponsor determines that the 
information qualifies for reporting. If the unexpected and related SAE is 


 
 
Page 34 of 38 
either fatal or life-threatening, then the SAE must be reported as soon as 
possible but in no case later than 7 calendars days after the sponsor’s 
initial receipt of the information. 
A summary of all non-expedited safety reports will be submitted in the 
annual report. 
 
16.5.6 Routine Reporting 
All other adverse events will be reported per current institutional guidelines. 
16.5.7 Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the 
conduct of human subjects research that represent unanticipated problems but are 
not considered adverse events. For example, some unanticipated problems 
involve social or economic harm instead of the physical or psychological harm 
associated with adverse events. In other cases, unanticipated problems place 
subjects or others at increased risk of harm, but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an 
adverse event) that may represent an unanticipated problem, the investigator 
should assess whether the incident, experience, or outcome represents an 
unanticipated problem. The incident, experience or outcomes is considered 
unanticipated if it meets all of the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of 
harm than was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents 
an unanticipated problem, the investigator must report it to the IRB according to 
the local IRB policies. 
 
16.6 
Reporting of Pregnancy  
Although pregnancy is not considered an adverse event, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject as an SAE. 
Pregnancies or lactation that occurs during the course of the trial or with 30 days of 
completing the trial or starting another new anticancer therapy, whichever is earlier, must be 
reported to the DSMC and IRB as applicable. All subjects who become pregnant must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious events. Since only postmenopausal women are eligible 
to enroll on this trial, it is unlikely that participants will become pregnant during study 
participation. 


 
 
Page 35 of 38 
16.7 
Protocol Amendments 
Any amendments or administrative changes in the research protocol during the period, for 
which the IRB approval has already been given, will not be initiated without submission of 
an amendment for IRB review and approval.   
These requirements for approval will in no way prevent any immediate action from 
being taken by the investigator in the interests of preserving the safety of all subjects 
included in the trial.  
16.8 
Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and 
treatment plans as outlined in the approved protocol version. Protocol deviations have the 
potential to place participants at risk and can also undermine the scientific integrity of the 
study thus jeopardizing the justification for the research. Protocol deviations are unplanned 
and unintentional events. All deviations will be reported to the IRB per current institutional 
guidelines.  
16.9 
Food and Drug Administration (FDA) 
Prior to study commencement, an Investigator Initiated New Drug (IND) application, if 
needed, will be submitted to the FDA for review and approval. 
16.10 Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical Trials 
Reporting Program) by the Oncology Clinical Trials Support Unit (O-CTSU). 
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