Clinical trial NCT02186015
Conditions: Adult Women Metastatic Breast Cancer Estrogen Receptor Positive
Keywords: Metastatic Breast Cancer MBC Vitamin D Supplementation Symptom Management
Sponsor: Loyola University
Start date: 2015-02-01; Completion date: 2017-11-09
Enrollment: 43 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Background: Several clinical trials are underway to investigate if variable forms of vitamin D (D2 vs. D3) prescribed at different doses (10,000-50,000 IUs/week) can improve the side-effects associated with treatment for estrogen receptor positive (ER+) breast cancer, specifically aromatase inhibitors (AIs.) Presumably for generalizability and potential safety purposes, these trials predominantly exclude women with metastatic breast cancer (MBC); a rapidly expanding sector of the cancer survivor population who experience significant treatment-related side-effects. Evaluation of the safety of vitamin D3 supplementation is crucial since supplementation can lead to high calcium and importantly, in lab studies have shown that vitamin D3 affects a gene that increases estrogen production. To assure that vitamin D3 does not affect the clinical effects of anti-estrogen therapies, the effect of vitamin D3 supplements on estrogen production requires an evaluation that further explores and defines its potential role in symptom management for this population.

Objectives: This pilot study will evaluate the feasibility of vitamin D3 supplementation in women with MBC, providing much needed data on the preliminary safety and efficacy of this treatment in this patient population. This study will determine: 1) if weekly supplementation of high dose vitamin D3 increases serum vitamin D levels without adverse effects related to such therapy (primary aim); 2) the effects of vitamin D3 supplementation on symptom management (secondary aim); and 3) if vitamin D3 supplementation is associated with improved inflammation (exploratory aim.)

Methods: This is an 8 week "proof of concept" study to monitor laboratory parameters and to assess potential effects on short-term outcomes. Adult, female patients (\>=18 years) with ER+ MBC (Stage IV) of any race/ethnicity and a history of vitamin D \< 30 mg/dl will be recruited from within and around LUMC. Following current clinical practice guidelines, eligible participants will receive 50,000 IUs of vitamin D3 weekly for 8 weeks. Laboratory values, muscle function and inflammation will be examined pre- and post-supplementation, while symptoms will be assessed at baseline, 4 and 8 weeks post-supplementation. We will assess if increases in vitamin D are associated with clinically significant improvements in symptoms and QOL, and decreased inflammation.

Detailed description:
Study Aims

Several clinical trials are underway to investigate if vitamin D2 or D3 provided at various doses (10,000-50,000 IUs/week) can improve the side-effects associated with anti-estrogen therapies, specifically aromatase inhibitors (AIs). However, these current trials use variable forms of vitamin D and predominantly include women with Stage I-III disease, excluding women with metastatic breast cancer. Evaluation of the safety of vitamin D3 supplementation is crucial since supplementation can lead to hypercalcemia and importantly, in vitro studies have shown that vitamin D3 influences the transcription of a gene that increases estrogen production.27,28 To assure that vitamin D3 does not abrogate the clinical effects of anti-estrogen therapies, the effect of vitamin D3 supplementation on estrogen production requires evaluation. Therefore, the overarching goal of this pilot study is to evaluate the safety, feasibility and efficacy of vitamin D3 supplementation in women with MBC. We will address and test the following aims and hypotheses, respectively:

Aim 1: To determine if weekly supplementation of 50,000 IUs of vitamin D3 raises serum levels of 25(OH)D to \>30 mg/dl without adverse effects.

Hypothesis 1: Women who are compliant with vitamin D3 supplementation, as evidenced by normalization (\>30 mg/dl) or increases in their serum 25(OH)D levels, will not experience significant changes in serum calcium, parathyroid hormone or serum estradiol levels.

Aim 2: To determine the effect of vitamin D3 supplementation on symptom management.

Hypothesis 2: Women who achieve serum concentrations of 25 (OH)D ≥30 mg/dl or experience significant increases in 25(OH)D will exhibit improvements in pain, fatigue, sleep, mood, muscle function and overall quality of life.

Exploratory Aim: To explore the mechanistic effects of vitamin D3 supplementation on inflammatory markers and its potential association with symptom management.

Summary: Evidence from studies involving early stage breast cancer participants confirms that musculoskeletal pain, endocrine related symptoms and mood disturbances are commonly associated with breast cancer treatment, particularly hormone deprivation therapies. The high prevalence of vitamin D deficiency/insufficiency among breast cancer survivors is well accepted and further hypothesized to aggravate treatment-related side effects, particularly arthralgias. Women with MBC are excluded from the majority of on-going vitamin D supplementation trials for safety and generalizability purposes. However, novel therapies are continuing to improve and prolong the lives of these women, resulting in a rapidly expansive group of breast cancer survivors. While vitamin D supplementation is prescribed to correct an underlying nutrient deficiency in the clinical context of preserving bone health, emerging evidence suggests it may have more systemic effects. Thus, vitamin D repletion/supplementation has profound potential implications for women with MBC, whose primary goal of treatment is to minimize the side-effects of treatment in support of optimal quality of life. This study reflects a highly innovative, yet simple therapy that could ultimately provide these survivors with a much needed evidence-based supportive care strategies.

Arms: arm 1: All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks. arm 2: All participants were ineligible for the intervention due to sufficient serum 25(OH)D levels at screening/baseline.
Interventions: intervention 1: Cholecalciferol
Intervention descriptions: intervention 1: Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.

Protocol documents:
ICF_002.pdf: 
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Document ID#:206519am3.120514 
Version Date: 12/05/2014 
IRB NUMBER:   206519061814 
 
LOYOLA UNIVERSITY CHICAGO 
HEALTH SCIENCES DIVISION 
MAYWOOD, ILLINOIS 
MARCELLA NEIHOFF SCHOOL OF NURSING       
 
INFORMED CONSENT 
 
Participant’s Name: _________________________________________________________ 
 
Medical Record Number: _____________________________________________________ 
 
PROJECT TITLE:  Safety, feasibility and efficacy of vitamin D supplementation in women 
with metastatic breast cancer (SAFE-D) 
 
THE APPROVAL FOR THIS PROJECT EXPIRES ON 06/18/2015. 
 
Participant Information 
 
PRINCIPLES CONCERNING RESEARCH:  You are being asked to take part in a research 
project.  It is important that you read and understand the principles that apply to all individuals 
who agree to participate in the research project described below: 
 
1. Taking part in the research is entirely voluntary. 
 
2. We do not know if you will benefit from taking part in the research but the knowledge 
obtained may help others. 
 
3. You may withdraw from the study at any time without anyone objecting and without 
penalty or loss of any benefits to which you are otherwise entitled. 
 
4. If during your participation in the research project new information becomes available 
which would affect your being in the research project (such as better treatments or the 
side effects of the treatments), your doctor will discuss this new information with you and 
will help you make a decision about your continuing in the research. 
 
The purpose of the research, how it is to be done, and what your part in the research will be is 
described below.  Also described are the risks, inconveniences, discomforts and other important 
information which you need to make a decision about whether or not you wish to participate.  
You are urged to discuss any questions you have about this research with the staff members. 
 
PURPOSE OF RESEARCH:  You are being asked to participate in this study because you are a 
women undergoing treatment for metastatic breast cancer. Many women who have received 
breast cancer treatments have low levels of vitamin D.  


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The purpose of this study is two-fold. First, we will determine the safety and effectiveness of 
treating low blood vitamin D levels in women who have advanced breast cancer.  Several studies 
have shown that increasing serum levels of vitamin D may alleviate some of the joint and muscle 
pains resulting from breast cancer therapy, but these have been done mainly in women with 
earlier stage disease and they primarily focus on pain. There is also evidence in patients without 
breast cancer to suggest that raising levels of serum vitamin D may improve mood and decrease 
inflammation. Therefore, we are specifically interested in assessing the effects of 8 weeks of high 
dose vitamin D supplementation on raising vitamin D levels in your blood and measuring 
whether or not supplementation can improve your symptoms and not interfere with your current 
breast cancer treatments. This dose you will receive is what is currently recommended for 
treating low levels of serum vitamin D. You will be asked to provide blood samples before 
starting on vitamin D to make sure you are eligible to participate in the intervention. If you are 
eligible and do participate, we will ask you to complete the questionnaires at baseline, half way 
through the study and then again after you have completed 8 weeks of supplementation. At the 
end of the study, you will also be asked to provide blood samples and to complete a body scan to 
assess your body composition.  
 
The second purpose of this study is to examine the occurrence of symptoms and to gauge quality 
of life in a broader group of women with advanced breast cancer. Therefore, if your serum levels 
of vitamin D are normal, you will not need the vitamin D supplementation; however, you can 
still participate in this research project by completing questionnaires and study measures. 
 
Approximately 50 people will participate in this research.   
 
WHAT IS INVOLVED IN THE STUDY? 
 
Vitamin D screening:  
You will be initially screened for study eligibility at a routine visit with your medical oncologist 
or with the study staff. You will have your blood drawn in the Cardinal Bernadin Cancer Center 
Phlebotomy Laboratory to determine serum levels of vitamin D and other relevant laboratory 
values (e.g., complete metabolic profile).  
 
By agreeing to be in this study, you will also allow the phlebotomist to draw extra blood (~2 
tubes or ~2 tablespoons) so the research team can analyze study specific hormones and 
inflammatory markers in your blood. Based on the results of your vitamin D blood test, you will 
be able to participate in one of two study groups.  
 
DESCRIPTION AND EXPLANATION OF PROCEDURES:   
 
Group 1: If your serum levels of vitamin D are low and you agree to participate in this study, 
you will be given 50,000 IUs (one capsule to swallow) of vitamin D each week for 8 weeks to 
treat your low level of vitamin D. This is the same amount and time that is recommended by The 
Endocrine Society to treat low serum levels of vitamin D.  Bio-Tech Pharmacal, Inc. will be 


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providing the study supplements. You will be asked to come to Loyola University Medical 
Center for 2 visits to collect information needed for the study.  
 
At the first visit, you will complete baseline data collection and provided the vitamin D 
supplement.  
 
Following 8 weeks of vitamin D supplementation, you will be asked to return for your follow up 
visit. Each visit will last 1 to 2 hours.  
 
At the baseline and follow up visit, you will be asked to: 
 
1)  Complete questionnaires that ask you about your symptoms, sleep, mood, overall   health, 
quality of life and factors that potentially impact your vitamin D level (e.g., sun exposure, diet, 
etc.).  
 
2) Perform non-invasive tests to assess your muscle function and to obtain other body measures 
like height, weight and body composition  
 
3) At the follow up visit, you will have another blood draw (about 2 tablespoons) for tests that 
will tell us about your serum levels of vitamin D, other relevant laboratory tests (e.g.,serum 
calcium), as well as study related hormones and inflammation levels. We will also perform a 
body composition scan (e.g., DXA) to get information about your bones, muscle mass and 
percent body fat.     
 
Midway through the study (i.e., approximately 4 weeks after supplementation), you will be asked 
to complete some symptom questionnaires. This information will be gathered at a time that is 
convenient for you and should take less than an hour to complete.  
 
To help you remember to take your vitamin D each week, we will contact you by your preferred 
method (phone, text or email) to remind you to take your vitamin D. You will be instructed to 
call us at any time with any questions or concerns at 708-216-0344. 
 
A description of this clinical trial will be available on www.clinicaltrials.gov as required by U.S. 
law.  The web site will include a summary of the results.  You can search this web site at any 
time. 
 
Group 2: If your serum levels of vitamin D are normal (i.e., you do not require high dose 
vitamin D supplementation), you will be invited to complete the study questionnaires and study 
measures. We will use this information, in conjunction with markers in your blood sample, to 
characterize symptoms in women with advanced breast cancer and to identify potential areas for 
future intervention. You will be offered the option to complete the questionnaires over the 
telephone, via mail or in person at Loyola University Medical Center. 
  
Optional bio-banking: You may optionally agree to allow us to collect and store approximately 
two tablespoons of blood collected from you during your study visit. This blood will be coded 


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and paired with coded clinical data for future research purposes. We will ask you to sign a 
second, separate informed consent document if you agree to bank samples for future research. 
You do not need to agree to the collection and storage of your blood in order to participate in this 
study. 
 
RISKS/DISCOMFORTS: There are several risks/discomforts associated with your 
participation in this study. 
 
Group 1 only: First, it is possible that vitamin D supplementation could interfere with your 
breast cancer treatments.  There is a risk that vitamin D supplementation could lead to increased 
estrogen production, and higher estrogen levels are associated with increased breast cancer 
activity. 
 
Second, it will be important that you do not take other vitamin D supplements while in this study 
other than your 50,000 IUs per week. Published reports suggest that 50,000 IUs per day of 
vitamin D (note this study is approximately 7,000 IUs per day) can increase vitamin D and cause 
high calcium levels; a condition known as hypercalcemia. We will be checking your calcium 
level in your blood before and after you start taking your supplement. 
 
Third, there are potential side-effects of taking vitamin D. The most common side-effects 
reported include: bone pain, constipation, dry mouth, headache, nausea and vomiting. Since 
vitamin D can increase serum calcium, there is the potential to develop kidney stones. While you 
are involved in this study, you will be instructed to get your calcium from dietary sources and 
limit calcium supplementation to no more than 1,000 mg per day to help minimize the risks of 
developing a kidney stone. We will be monitoring for side-effects during your study visits and 
via the phone. If you are unsure if you should participate in this study, you should speak with 
your healthcare provider first. 
 
Fourth, a DXA scan will be used to measure your body composition. There is radiation 
associated with a DXA scan, which is about 12 microSieverts. However, this amount is less than 
the radiation absorbed by a passenger on a transcontinental flight (about 60 microSieverts.) 
 
Groups 1 & 2: You may experience a slight discomfort when the blood is drawn for the 
laboratory tests. 
 
You may also experience some mild discomfort or anxiety in answering questions of a personal 
nature about your health and behavior. If you feel uncomfortable at any point answering these 
questions, you may skip a given question. 
 
While every effort will be made to protect your identity and health information, there is a small 
risk of loss of confidentiality that information about your health might become known to 
individuals outside the study. To minimize this risk, we will keep identifying information 
separate from your data, use identification code numbers on data forms, use locked filing 
cabinets and storage areas, and use password-protected computer files. 
 


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In addition to the risks mentioned above, there may be unknown or unanticipated risks associated 
with participating in this study. 
 
REPRODUCTIVE AND SEXUAL ACTIVITY INFORMATION: The vitamin D 
intervention in this study could affect a developing baby. Therefore, you cannot participate in this 
research project if you are currently pregnant, trying to get pregnant or breast feeding.  
 
If you are a woman of childbearing potential, a pregnancy test will be done to make certain that 
you are not pregnant before beginning the study and prior to the body composition scan. 
 
Women who are able to have children must use an effective method of preventing pregnancy 
while participating in this study.  
 
In addition, as study medications may remain in the body for a period beyond their 
administration, you will be asked to continue to employ an effective method of preventing 
pregnancy for 6 months after you have finished taking the study medication.    
 
BENEFITS: We do not know if you will directly benefit from participating in this study. 
Through your participation you will provide valuable information on how often low levels of 
vitamin D occur and what treatment side effects exist for women with advanced breast cancer. If 
you are eligible and do participate, you could receive an effective treatment to raise your vitamin 
D level and this may help with treatment-related symptoms, like pain, fatigue and mood. The 
information we learn may also help others in the future.  
 
ALTERNATIVE TREATMENTS:  You do not have to participate in this research project.  
You can choose to start vitamin D treatment without participating in the research project.  You 
should consult with your health care provider.  
 
FINANCIAL INFORMATION:  You will be financially responsible for the cost of all routine 
laboratory tests, procedures, hospitalizations (if necessary), non-study medications and 
physicians fees. However, neither you nor your insurance provider will be billed for any 
procedures that are performed exclusively for this research study. Those procedures that are 
being performed for research purposes only include study related laboratory testing and a study 
related DXA. The vitamin D supplementation will be provided for free. 
 
If you choose to participate in this study, beyond the vitamin D screening, you will be 
compensated for your time. Participants who receive the high dose vitamin D supplementation 
will receive a maximum of $50 for participation, including $20 for completion of the baseline 
visit and $30 for completing the follow-up visit. Participants in group 2, will receive $20 for the 
completion of the baseline study visit activities. Parking will be paid for those who return to 
LUMC for study-related visits. 
 
RESEARCH RELATED INJURY: In the event that you are injured or have side effects as a 
result of participating in this research project, your doctor will take the necessary steps to treat 
the problem.  There are no funds available from Loyola University Medical Center, Loyola 


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University Health System or Loyola University Chicago to pay for the cost of care of the 
problem. You will be financially responsible for the cost of care of any problems.  By signing 
this form, you are not giving up any legal rights to seek to obtain compensation of injury. 
 
IN THE EVENT OF AN EMERGENCY: In the case of a life-threatening emergency, 
regardless of whether or not it is related to your participation in this study, please call 911 or 
proceed to the nearest Emergency Room. 
 
INFORMATION COLLECTED AND WHAT WILL HAPPEN TO IT:  In order to meet the 
goals of the research study (see Purpose of Research section of this consent), we will collect 
information on you, your test results, and any medical conditions from you, your Loyola 
University Medical Center (LUMC) medical records or your medical oncologist. The information 
will be collected by Dr. Patricia Sheean and her research team, the study physician(s), the 
research nurses, data administrators and secretaries.   
 
Information about you will be provided to Loyola University Chicago; Loyola University 
Medical Center, data collection and study verification agencies; and/or government regulatory 
agencies such as the Food and Drug Administration. 
 
In this way, we will learn more about vitamin D and its relationship to symptom management.   
 
The information we will collect and send includes:  
 
X____ DEMOGRAPHIC INFORMATION (e.g., name, address, phone number, Social Security 
Number) 
X____ BLOOD SAMPLES 
X_____SURVEYS 
X_____BODY COMPOSITION AND PHYSICAL MEASURES 
X_____INFORMATION FROM YOUR MEDICAL RECORD ABOUT YOUR BREAST 
CANCER, YOUR TREATMENTS AND YOUR SYMPTOMS. 
 
We will collect and provide this information about you for as long as you are in the study.     .  
 
Once the information is disclosed outside of LUMC, it may no longer be protected by federal 
privacy laws. 
 
It is possible that the research nurses, data collection and/or study verification agencies, data 
administrators or staff, or the Food and Drug Administration will come to LUMC and view the 
medical record (see above for description of content) and the research records.  They may take 
notes or copy pages of the medical record.  This is done to verify the accuracy of the information 
LUMC is sending to them. 
 


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The results of this research study may be published in a journal for the purpose of advancing 
medical knowledge.  You will not be identified by name or by any other identifying information 
in any publication or report about this research. 
 
Consent for LUMC to use and disclose your medical information is required in order for you to 
participate in the study.   
 
WITHDRAWAL OF CONSENT: Your consent to use and disclose your medical information 
for the purpose of this research study is completely voluntary.  You can withdraw your consent 
for LUMC to use and disclose your information and your consent to participate in this study at 
any time without affecting your ability to receive care and treatment at LUMC unrelated to the 
research study.  Withdrawal means that all study procedures and follow-up will stop.  However, 
information already used and disclosed prior to the time of your withdrawal from this study may 
continue to be used and disclosed by LUC and/or LUMC. 
 
For your safety, we may ask that you return to clinic one more time for laboratory tests if the 
supplement is discontinued by the study physician.  We will also ask that you return any unused 
study medication.  If you withdraw from the study, you will need to contact your physician(s) to 
discuss what other options may be available. 
 
If you withdraw from the study, we will ask that you sign the form attached to this consent and 
send it to Patricia Sheean, PhD, RD or give it to the study staff. Your withdrawal from the study 
will not have any effect on any actions by LUMC taken before the attached form is received by 
LUMC. 
 
Your study doctor, the Institutional Review Board, the regulatory authorities, may terminate the 
study at any time with or without your consent. 
 
Your study doctor may choose to take you out of the study because of unexpected or serious side 
effects, treatment non-compliance, or because you are not taking the medication as you were 
instructed. You may also be removed from the study if your study doctor feels that you are not 
benefiting from the study treatment.   
 
CONSENT 
 
I have fully explained to ____________________________ the nature and purpose of the above- 
described procedure and the risks that are involved in its performance.  I have answered and will 
answer all questions to the best of my ability.  I may be reached at 708-216-0344     .  
 
________________________________________________Date:____/_____/____ 
Signature 
 
Patricia Sheean, the principal investigator for this study, or her associate will be available to 
answer any questions you may have.  Dr. Sheean can be reached at:  708-216-0344. 
 


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If you ever feel that you have been injured by participating in this study or if you have any 
questions concerning your rights as a research participant, you may contact either Kenneth 
Micetich, MD, Chair of the Institutional Review Board for the Protection of Human Subjects-
Loyola University Chicago Health Sciences Division, at 708-216-2633 or Elaine Fluder, MSN, 
Director of the Human Research Subjects Protection Program at 708-216-4608.   
 
Although you have the right to revoke this authorization, you accept that such revocation will not 
apply to any uses and disclosures of your information that are described in the Loyola University 
Health System Notice of Privacy Practices or otherwise allowable under any Federal or State 
laws.   
 
You will receive a signed copy of this informed consent document. 
 
You have been fully informed of the above-described research program with its possible benefits 
and risks.  Your signature below indicates that you are willing to participate in this research study 
and agree to the use and disclosure of information about you as described above.  You do not 
give up any of your legal rights by signing this consent document.   
 
________________________________________________Date:____/_____/____ 
Signature:   Participant 
 
________________________________________________Date:____/_____/____ 
Signature:   Witness 
 
 
 
 
 
 
 
 
 
 
 
 


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PROJECT TITLE:  Safety, feasibility and efficacy of vitamin D supplementation in women 
with metastatic breast cancer 
 
 
REVOCATION OF AUTHORIZATION TO 
RELEASE PROTECTED HEALTH INFORMATION (PHI) 
 
 
I, _____________________________________, hereby revoke my consent to participate 
in the study titled, “Safety, feasibility and efficacy of vitamin D supplementation in women with 
metastatic breast cancer”, at Loyola University Medical Center (“LUMC”).  I also revoke my 
consent to release information I provided to LUMC that allowed LUMC to use and disclose my 
medical information  as outlined on the consent form, which I signed on ____/_____/____ 
(INSERT DATE CONSENT WAS SIGNED ORIGINALLY).  I understand that this revocation 
does not apply to any action LUMC has taken in reliance on the consent I signed earlier.   
 
 
________________________________________________Date:____/_____/____ 
Signature:  Participant 
 
 
 
 
Please return this form to: 
 
Patricia Sheean, PhD, RD 
Loyola University Medical Center 
2160 South First Avenue 
Maywood, Il 

Prot_000.pdf: 
1 
 
Protocol title: Safety, feasibility and efficacy of vitamin D supplementation in women with metastatic 
breast cancer (SAFE-D) 
Protocol version: 1.2 
Protocol date: 11/01/2014 
Principal Investigator: Patricia Sheean, PhD, RD 
Research Team: William Adams, MS; Stephanie Kliethermes, PhD, Sue Penckofer, PhD, RN; Ruta Rao, 
MD; Patricia Robinson, MD;  
 
I. Abstract:  
 
Background: Several clinical trials are underway to investigate if variable forms of vitamin D (D2 vs. D3) 
prescribed at different doses (10,000-50,000 IUs/week) can improve the side-effects associated with 
treatment for estrogen receptor positive (ER+) breast cancer, specifically aromatase inhibitors (AIs.) 
Presumably for generalizability and potential safety purposes, these trials predominantly exclude women 
with metastatic breast cancer (MBC); a rapidly expanding sector of the cancer survivor population who 
experience significant treatment-related side-effects. Evaluation of the safety of vitamin D3 
supplementation is crucial since supplementation can lead to hypercalcemia and importantly, in vitro 
studies have shown that vitamin D3 influences the transcription of a gene that increases estrogen 
production. To assure that vitamin D3 does not abrogate the clinical effects of anti-estrogen therapies, the 
effect of vitamin D3 supplements on estrogen production requires an evaluation that further explores and 
defines its potential role in symptom management for this population. 
 
Objectives: This pilot study will evaluate the feasibility of vitamin D3 supplementation (n=25) in women 
with MBC, providing much needed data on the preliminary safety and efficacy of this treatment in this 
patient population. This study will determine: 1) if weekly supplementation of high dose vitamin D3 
increases serum levels of 25(OH)D without adverse effects related to such therapy (primary aim); 2) the 
effects of vitamin D3 supplementation on symptom management (secondary aim); and 3) if vitamin D3 
supplementation is associated with improved biomarkers of inflammation (exploratory aim.) Additionally, 
we will examine the prevalence of symptoms and quality of life in (n=25) women with advanced breast 
cancer who have normal serum levels to investigate associations with biomarkers of inflammation.  
 
Methods: . Adult, female patients (>18 years) with ER+ MBC (Stage IV) of any race/ethnicity will be 
recruited from within and around LUMC. Women with a serum 25(OH)D <30 mg/dl will be invited to 
participate in an 8 week “proof of concept” study. Following current clinical practice guidelines, eligible 
participants will receive 50,000 IUs of vitamin D3 weekly for 8 weeks. Laboratory values (e.g., serum 
25(OH)D, calcium, , serum estradiol), muscle function and inflammatory biomarkers (e.g.,CRP) will be 
examined pre- and post-supplementation, while symptoms (pain, sleep, fatigue, mood, and overall quality 
of life) will be assessed at baseline, 4 and 8 weeks post-supplementation. We will assess if increases in 
serum 25(OH)D are associated with clinically significant changes in serum estradiol, improvements in 
symptoms and QOL, and decreased inflammation, controlling for sunlight exposure, diet, physical activity 
and body composition. Women with a serum 25(OH)D ≥ 30 mg/dl who do not require supplementation will 
be invited to complete the study questionnaires at baseline.  
 
Significance/Impact: Vitamin D3 may be a cost-effective, adjuvant therapy to combat the side-effects of 
treatment, to increase medication adherence and to enhance supportive care in this unique population in 
need of evidence-based strategies. These findings will help to characterize symptom burden in this 
growing population and to demonstrate the feasibility of this clinical trial. Ultimately, these data will 
provide novel, preliminary data to justify a larger randomized trial. 
 
 
 


2 
 
II. Background  
Breast cancer accounts for more than one-fourth of all new cancer diagnoses among women in the 
United States, with more than 232,000 new cases estimated for the year 2013.1 Despite the advances in 
the management of this disease, a significant number of women will go on to develop metastatic breast 
cancer (MBC), typically reflecting spread to the bone, lungs or viscera. Johnson et al recently showed that 
the incidence of MBC at diagnosis is increasing, showing greater disparities among younger women 
(aged 25-39) and minority populations.2 However, the introduction of novel targeted therapies, in 
particular treatments for HER-2 positive disease, has altered the natural history of advanced breast 
cancer, with an unprecedented impact on survival from such treatments. As such, the number of women 
living with MBC will continue to grow, reflecting a unique, rapidly expanding sector of the cancer survivor 
population with considerable supportive care needs that are largely unknown.  
 
a. MBC and QOL: Cancer-related QOL is a complex entity, taking into account physical, psychological, 
social and sexual factors.3 It is an important outcome measure in all patients with breast cancer, but it is 
critical in the metastatic population since the disease is no longer considered curative and treatments are 
dictated by QOL. Although QOL has been examined extensively in women with early stage breast cancer, 
fewer studies have focused on women with MBC. Using a cross-sectional study design, Reed et al 
examined the QOL and supportive needs of women (n=235) with MBC. QOL was significantly lower in 
women with MBC compared to women with earlier stage disease (89.0 ± 21.8 vs. 112.8 ± 20.9, 
respectively). Thirty-four percent reported high levels of pain and 38% complained of significant fatigue, 
suggesting that symptom control was inadequate.4 In a smaller study, Meisel et al reported good QOL 
among long-term (>5 years) survivors of MBC (n=18), yet these women reported significant anxiety and 
depression. Additional work is needed to more comprehensively identify symptoms and to implement and 
test appropriately tailored therapies. 
 
b. MBC and vitamin D: Low levels of serum 25(OH)D at the time of diagnosis have been shown to 
predict recurrence and death,5,6 underscoring the clinical significance of widespread vitamin D 
deficiency/insufficiency reported among breast cancer survivors.7-9 Purportedly 1,25 (OH)2D has been 
show to induce cell-cycle arrest, increase expression of receptor activator of nuclear factor ĸB ligand, and 
down regulate the expression of cyclooxygenase-2.10 Hence, sufficient levels of vitamin D are needed to 
favorably impact breast cancer biology. In women previously diagnosed and treated for breast cancer, the 
prevalence of vitamin D deficiency/insufficiency is ~75%, yet these studies predominantly focused on 
women with early disease (Stage I-III).8,9 Vitamin D studies conducted in women with MBC are limited, but 
report similar prevalence estimates with lower overall levels of serum vitamin D.11,12  
 
c. Breast cancer treatment and symptom management: For women with estrogen receptor positive 
(ER+) disease, aromatase inhibitors are considered a frontline therapy, since they efficiently and 
effectively decrease circulating estrogen by halting the conversion of androgens to estrogen. 
Unfortunately, arthlagias and myalgias are highly prevalent within weeks of initiation and may result in 
discontinuation.13 The etiology of these musculoskeletal disturbances is not well understood; however, it 
has been postulated that estrogen itself has analgesic properties14 and that cytokines, such as Il-1, TNF-
α, are suppressed with higher levels of estrogen.15 It has been further suggested that cartilage turnover 
increases as estrogen decreases,16 and that the combination of efficient estrogen deprivation combined 
with low serum 25(OH)D accentuates muscle and joint pain.7 Thus, low levels of estrogen are associated 
with reduced pain tolerance and increased inflammation. Additionally, breast cancer treatment is 
accompanied by a myriad of endocrine symptoms, including weight gain, fatigue and mood swings. In 
non-breast cancer populations, vitamin D supplementation has been shown to regulate weight,17 mood18 
and to decrease inflammation.19  
 
d. Significance: A diagnosis of MBC is accompanied by a multitude of physiologic and psychological 
sequela.20 Managing symptoms to maintain an optimum quality of life (QOL) is the major goal of care in 
the metastatic setting because all therapy is considered palliative. For women with ER+ breast cancer 


3 
 
(~75% of cases), therapies primarily target decreasing the production and absorption of estrogen. These 
reductions in circulating estrogen are associated with significant bone loss, arthralgia and myalgia,21-23 
limiting adherence and compromising QOL. The pathophysiology of these side-effects may involve sub-
optimal vitamin D status, which may be more pronounced in a hypoestrogenic environment.7  Therefore, 
supplementation with vitamin D3 (cholecalciferol) shows promise as a cost-effective, adjuvant therapy to 
combat the side-effects of treatment, to increase medication adherence and to enhance supportive care. 
However, preliminary data are critical to demonstrating the safety of high dose vitamin D3 
supplementation in this unique patient population and to evaluate if this therapy has a favorable impact on 
symptom management and possibly inflammation. Ultimately, this study could provide insights into 
improving QOL and offer novel, preliminary data to justify a larger randomized trial. 
 
e. Conceptualization 
For this study, we hypothesize that low levels of vitamin D are highly prevalent among women with MBC 
and that repletion to achieve serum 25(OH)D levels ≥ 30 mg/dl will be safe. We are also postulating that 
the therapeutic effects of serum vitamin 
D normalization will be associated with 
improvements in symptom management 
and biomarkers of inflammation. 
(Depicted in Figure 1) The association 
between vitamin D deficiency and 
inflammation has been recognized from 
observational studies24 and 
administration of vitamin D has been 
shown to improve inflammatory markers 
in non-cancer patient populations.19,25 
Mechanistically, 1,25-dihydroxyvitamin 
D3 (the active form of vitamin D) inhibits 
the production of pro-inflammatory 
cytokines (ex,  IL-6, IL-1β, TNFα) 
leading to reduced T cell activation and 
reduced secretion of these cytokines.26  
 
f. Preliminary work: 
Prior work in women with MBC: To explore the diet and physical activity habits of women with MBC, we 
recruited 25 women with advanced disease from two university hospitals over a 4 month period. Eligible 
women were identified by their medical oncologist (Drs. Kent Hoskins and Ruta Rao) and referred to Dr. 
Sheean (PI). Demographic and medical information was collected, and questionnaires were completed to 
quantify nutritional symptoms, physical activity, quality of life, functional performance and dietary intake. 
Participants were 58.8 (±12.7) years of age, predominantly minority (n=15) and had been living with MBC 
for 37 (± 29) months. Dietary supplements were used by 68% (n=17) of women. The majority had an 
Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (n=20) and most (n=13) had only 
received one or two different drug therapies to treat their disease, signifying a relatively healthy subset of 
MBC patients.  
Overall QOL was lower when compared to other women with breast cancer (107 ± 20 vs. 119 ± 
18) but higher compared to other women with MBC (107 ± 20 vs. 89 ± 22),4 respectively. These 
participants displayed lower physical well-being compared to other breast cancer survivors (22 ± 5 vs. 24 
± 5, p=0.05), with 92% (n=23) of women reporting pain symptoms and 60% (n=15) reporting fatigue. We 
acknowledge that patients with greater disease acuity were not approached for study inclusion, reflecting 
an inherent selection bias. As such, we believe our findings overestimate QOL and underestimate 
symptom reports in the broader MBC population. Despite these limitations, we believe these findings 
highlight that interventions targeting the supportive care needs of these women are greatly needed and 
desired. 


4 
 
 
III. Study Aims 
Several clinical trials are underway to investigate if vitamin D2 or D3 provided at various doses (10,000-
50,000 IUs/week) can improve the side-effects associated with anti-estrogen therapies, specifically 
aromatase inhibitors (AIs).  However, these current trials use variable forms of vitamin D and 
predominantly include women with Stage I-III disease, excluding women with metastatic breast cancer. 
Evaluation of the safety of vitamin D3 supplementation is crucial since supplementation can lead to 
hypercalcemia and importantly, in vitro studies have shown that vitamin D3 influences the transcription of 
a gene that increases estrogen production.27,28 To assure that vitamin D3 does not abrogate the clinical 
effects of anti-estrogen therapies, the effect of vitamin D3 supplementation on estrogen production 
requires evaluation. Therefore, the overarching goal of this pilot study is to evaluate the safety, feasibility 
and efficacy of vitamin D3 supplementation in women with MBC. We will address and test the following 
aims and hypotheses, respectively: 
 
Aim 1: To determine if weekly supplementation of 50,000 IUs of vitamin D3 raises serum levels of 
25(OH)D to >30 mg/dl without adverse effects.   
 
Hypothesis 1: Women who are compliant with vitamin D3 supplementation, as evidenced by 
normalization (>30 mg/dl) or increases in their serum 25(OH)D levels, will not experience significant 
changes in serum calcium or serum estradiol levels. 
 
Aim 2: To determine the effect of vitamin D3 supplementation on symptom management. 
 
Hypothesis 2: Women who achieve serum concentrations of 25 (OH)D ≥30 mg/dl or experience 
significant increases in 25(OH)D will exhibit improvements in pain, fatigue, sleep, mood, muscle function 
and overall quality of life.  
 
Exploratory Aim: To explore the mechanistic effects of serum vitamin D levels and vitamin D3 
supplementation on inflammatory markers and potential associations with symptom management. 
 
Summary: Evidence from studies involving early stage breast cancer participants confirms that 
musculoskeletal pain, endocrine related symptoms and mood disturbances are commonly associated with 
breast cancer treatment, particularly hormone deprivation therapies. The high prevalence of vitamin D 
deficiency/insufficiency among breast cancer survivors is well accepted and further hypothesized to 
aggravate treatment-related side effects, particularly arthralgias. Women with MBC are excluded from the 
majority of on-going vitamin D supplementation trials for safety and generalizability purposes. However, 
novel therapies are continuing to improve and prolong the lives of these women, resulting in a rapidly 
expansive group of breast cancer survivors.  While vitamin D supplementation is prescribed to correct an 
underlying nutrient deficiency in the clinical context of preserving bone health, emerging evidence 
suggests it may have more systemic effects. Thus, vitamin D repletion/supplementation has profound 
potential implications for women with MBC, whose primary goal of treatment is to minimize the side-
effects of treatment in support of optimal quality of life. This study reflects a highly innovative, yet simple 
therapy that could ultimately provide these survivors with a much needed evidence-based supportive care 
strategies.  
 
IV. 
Administrative Organization 
This study involves collaboration among investigators and support staff from the School of Nursing, the 
Department of Medicine, Hematology/Oncology and Public Health Sciences divisions, the Cardinal 
Bernadin Cancer Center, the Loyola University Medical Center (LUMC) Pharmacy and the Clinical 
Research Office (CRO). This investigation will be conducted on the Loyola University Health Sciences 
Campus. Participants will be evaluated in the Bernadin Cancer Center and in a devoted research space 
within the Maguire Building utilizing the nursing expertise offered by the School of Nursing research staff. 


5 
 
Laboratory analyses will be completed in the Core Laboratory of LUHS, within a Basic Science 
Laboratory at LUHS and/or outsourced to Quest Diagnostics Biospecimens will be stored in the 
biorepository supported by the CRO (LU# 204853). Additionally, the CRO will offer biostatistical support, 
data management oversight and regulatory services required for this trial. The LUMC Pharmacy will 
provide and dispense the study medication and the Public Health Science division will provide the 
machinery and technical expertise for body composition assessment. Because participants may be 
referred from surrounding oncologists, this study will leverage existing relationships among investigators 
to promote collaborations across institutions. The investigators on this study reflect a multidisciplinary 
team with expertise in medicine, nutrition, nursing, oncology, biostatistics, and public health.   
 
V. 
Study Design 
a. Research design: This study is comprised of an intervention arm (Group 1) and non-intervention arm 
(Group 2). For eligible women with low serum levels of vitamin D, we propose an 8 week open label, 
single arm “proof of concept” study to address concerns regarding vitamin D3 dosing, to monitor important 
laboratory parameters and to assess potential effects on short-term outcomes. While a randomized 
controlled trial (RCT) has been the traditional model to evaluate the efficacy of vitamin D 
supplementation, this design may be considered premature until the safety of this therapy has been 
evaluated in a patient population with the potential for high clinical acuity. For the women who meet all 
eligibility criteria except they have normal serum levels of vitamin D (Group 2), we will assess their 
symptomology and test associations with the biomarkers of inflammation.  
 
b. Study population: Adult females with ER+ MBC can participate in the present study provided they are 
under the care of medical oncologist and meet all eligibility criteria.  Women with early stage disease 
(Stages 0-3) or women with MBC who are ER- are unable to participate in this study. 
 
c. Sample size and power considerations: Because this is a pilot project that will assess the feasibility, 
preliminary safety and short-term efficacy of a vitamin D3 interventionin this population, typical sample 
size calculations will not be employed. We will assess symptoms at baseline for all participants to 
establish prevalence estimates and at three time points in the intervention group to help increase our 
abilities to detect changes over time. Because of the high prevalence of vitamin D deficiency among 
breast cancer survivors (~75%) and the high volume of patients seen at LUMCand by Dr. Rao 
(collaborator), we anticipate that we can successfully recruit and enroll 50 women who meet  the eligibility 
criteria. Our goal is to recruit 25 women for the intervention arm. Factoring in an attrition rate of ~20%, we 
should have complete data on 20 women who complete the intervention. This sample size is sufficient to 
demonstrate feasibility and will allow for the generation of effect size and variance estimates, as well as 
confidence interval widths around these estimates for future applications. 
 
d. Study endpoints: The primary endpoint in this study is serum 25(OH)D. We will use this serum 
biomarker to assess if repletion levels are obtained (≥30 ng/dl), to test associations with symptoms and/or 
to assess the degree of change from baseline to follow up. Serum calcium and serum estradiol levels will 
be monitored to be sure these levels normalize or to assess clinically significant changes following 
supplementation, respectively.  
 
To address our secondary endpoints, we will be assessing symptoms, including pain (Brief Pain 
Inventory; Cleeland,1994; FACT-Bone pain, Broom, 2009), fatigue (Piper Fatigue Scale; Piper, 1998), 
mood (Hospital Anxiety and Depression Scale; Herrmann, 1997; Patient Health Questionnaire-8; 
Kroenke, 2001), muscle function (handgrip strength), sleep (Pittsburg Quality Sleep Index; Carpenter, 
1998), overall health and QOL (FACT-B; Brady, 1997; FACT-ES; Fallowfield, 1999.) These specific tools 
were selected because they have been utilized in breast cancer populations and/or other cancer 
populations and will provide the ability to compare our findings to others. In addition, to address important 
confounders, we will gather data on diet (Block Calcium/Vitamin D screener; Cummings, 1987), physical 
activity (Godin Leisure Time Activity, 1985), body composition (bioelectrical impedance, dual energy x-ray 


6 
 
absorptiometry), sunlight exposure (Glanz sunlight exposure, 2008), social support (Multiple Outcomes 
Social Support; Sherbourne, 1991) and previous/current breast cancer treatments.  
 
VI. 
Study Procedures 
a. Study subject procedures: Subjects must meet all of the inclusion and none of the exclusion criteria 
to be enrolled into the intervention arm of the study. In addition, women meeting all of the inclusion and 
exclusion criteria except the serum 25(OH) cut point will be offered the opportunity to participate in the 
cross-sectional arm of the study. 
i. The following criteria will be used to assess eligibility and participation. 
 
Inclusion Criteria:  
 
 
1. Metastatic breast cancer (Stage IV) 
2. Histologically confirmed estrogen receptor positive disease 
3. Female 
4. Serum 25(OH) <30 ng/ml 
5. Age ≥ 18 years 
6. Pre or post-menopausal  
7. ECOG Performance status 0-2 
8. Adequate organ function as defined as GFR> 30 mls/min and serum 
calcium ≤ 10.4 mg/dl  
9. Any race/ethnicity 
10. English speaking 
11. No changes to MBC treatments within 30 days of enrollment and/or 
deemed clinically stable by their treating physician 
12. Willingness to sign a written informed consent and complete 
questionnaires 
13. Cease ingestion of vitamin D supplementation not study related 
 
Exclusion Criteria: 
 
 
1. Women with Stage I-III breast cancer 
2. Serum 25(OH)D levels ≥ 30 ng/ml 
3. Untreated CNS involvement 
4. History of kidney stones 
5. History of renal failure 
6. History of hyperparathyroidism 
7. History of hypersensitivity to vitamin D 
8. Non-English speaking 
9. Currently pregnant or lactating, or anticipating pregnancy  
10. Unwilling to cease ingestion of calcium supplements (>1000 mg/d) 
11. Unwilling or unable to complete informed consent or study 
questionnaires 
12. Psychiatric or other clinical conditions that preclude study compliance 
13. Other important medical or safety considerations at the discretion of the 
investigator and/or study physician, including non-compliance with the 
study therapy or other activities 
 
 
ii. Recruitment sites and recruitment: Women with MBC will be recruited from Cardinal Bernadin 
Cancer Center at LUMC with the direct assistance of the research nurses in the Breast Oncology Clinic 


7 
 
and support from the medical oncologists who treat these women. Participants will be informed of the 
study verbally and provided with a study brochure during their clinic appointment. Interested participants 
will be contacted by the study staff to explain the study in more detail and answer questions. In order to 
inform a broader sample of patients from LUMC about the study, we will send letters describing the 
investigation to the appropriate patients under the care of LUMC medical oncologists. An IRB approved 
waiver of HIPPA authorization will be used to identify patients from these physicians who meet the study 
criteria using CPT codes. We will provide flyers in the breast oncology clinic and surrounding clinics for 
potential participants to contact us. In addition, Dr. Ruta Rao, a medical oncologist at Rush University 
Medical Center (RUMC), will verbally inform her patients about the study, provide handouts to those who 
express interest, and refer them to Dr. Sheean for further evaluation. (Drs. Rao and Sheean successfully 
collaborated on a previous pilot described in Preliminary work.) Women with confirmed interest will be 
screened via telephone to see if they can be scheduled to return to the research office for consent and 
baseline study assessment. 
 
iii. Initial screening: Referred participants will be phoned or seen in clinic to describe the study. If 
interested, age, health information and questions regarding vitamin D supplementation will be asked. If 
any of the exclusion criteria are reported, they will not be able to continue their participation. If initially 
eligible, they will be scheduled for a blood draw. 
iv. Baseline screening and enrollment: Interested participants will be consented by the PI or study 
nurse in a private room, assigned a unique study identification number and undergo phlebotomy. 
Participants will have their blood drawn in the Cardinal Bernadin Cancer Center Phlebotomy Laboratory 
to determine serum levels of vitamin D and other relevant laboratory values (Refer to Measurements.) 
Participants will in the non-intervention arm (Group 2) will be asked to complete the questionnaires, either 
in person, over the phone or via mail.) The research study staff with review the results of the serum 
vitamin D blood tests and confer with the medical oncologist regarding further participation in the study. 
Participants who are vitamin D deficient (<30 mg/dl) will return to LUMC to participate in the intervention 
arm (Group 1), to complete questionnaires and to receive the study medication.  
 
Optional Biobanking.  At the study completion visit, participants may optionally agree to reposit up to 
two tablespoons of blood into CRO-BIOREP (LU# 204853) for future research purposes.  Participants will 
sign a second informed consent document should they agree to reposit their blood.  The research team 
members and Biorepository staff will each retain a copy of the signed repository informed consent 
document.  It is important to point out that participants do not need to agree to reposit blood in order to 
participate in the trial. 
All patients who agree to reposit blood specimens into CRO-BIOREP (LU# 204853) will be assigned a 
unique code using our SMART-ID system. This number will be used to connect coded specimens and 
coded data to other studies conducted by the Clinical Research Office in which they may participate.  To 
receive this number, we will ask participants for sex at birth, month of birth, day of birth, year of birth, and 
social security number.  This information is entered into a secure website where it is hashed into a unique 
ID using a java script.  The participant and research team will receive the unique ID number.  Once the 
number is created, the information that was entered is immediately deleted.  This means the website will 
not retain any of the information that is entered to create the SMART-ID.  However, should anyone need 
to retrieve a SMART-ID number, you will be able to get it again at a later date by going to the website and 
entering the same information (i.e., sex, date of birth, and social security number) that was entered 
before. 
Freezerworks, the biospecimen tracking software used in the repository, will also automatically assign 
specimen numbers to incoming specimens. These numbers will identify all donated specimens.  The list 


8 
 
that links these codes with patients’ identifying information will be kept separate from all research 
specimens and clinical data. 
 
Information that may readily identify patients will never be shared with anyone. 
 
v. Study intervention: Following the clinical practice guidelines of the Endocrine Society, participants in 
Group 1 will receive 50,000 IU of vitamin D3 once a week for 8 weeks.29 This dose of vitamin D3 is similar 
to those used in other breast cancer trials involving women with Stage 0-III disease, and should be 
sufficient to increase levels in normal weight, overweight and obese women within an 8 week time frame. 
In addition, weekly dosing will also help to increase study compliance and participants will receive a 
weekly reminder (phone call, email or text) to take their supplement. Because this is a single arm, open 
label trial, all participants will be aware that they are taking the study medication and that no placebo is 
being offered in this trial. Participants will be encouraged to take less than 1000 mg/d of calcium 
supplementation and to emphasize food sources of calcium (see calcium handout in the appendices). 
Participants in the non-intervention arm (Group 2) will complete all of the baseline (Week 0) study 
questionnaires and physical measures.  
 
vi. Study assessments and activities: Guided by the Wilson and Clearly health-related QOL model,30 
we will examine seven levels of patient outcomes, including: a) biological and physiological, b) symptom 
status, c) functional status, d) health perceptions, e) overall QOL, and f) characteristics of the individual 
and the environment. Variables, measures and times are delineated below (Table 1). Brief details about 
each of the measurement tools are described below. 
 
Table 1. SAFE-D study variable, measures, constructs and timing 
 
Variables 
Measures 
Wilson & Cleary 
construct 
Week 
Aim 1 
Low vitamin D (Primary) 
25(OH)D, calcium, , serum 
estradiol, CMP 
Biological 
0,8 
Aim 2 
General well-being 
(Secondary) 
Pain 
Fatigue 
Mood 
Muscle function 
Performance status 
Sleep 
Overall health 
QOL 
 
 
Brief Pain Inventory, FACT-Bone 
pain 
Piper Fatigue Scale 
HADS, PHQ8 
Hand grip strength 
ECOG 
PSQI 
Single item question 
FACT-B, FACT-ES 
 
 
Symptom status 
 
Symptom status 
Symptom status 
Functional status 
Functional status 
Symptom status 
Health perceptions 
Overall QOL 
 
 
0,4,8 
 
0,4,8 
0,4,8 
0,8 
0 
0,4,8 
0,4,8 
0,8 
 
Serum vitamin d and 
Inflammation (Exploratory) 
 
CRP, interleukins, TNF-α 
 
Biological 
 
0,8 
Other 
Factors 
Demographics and cancer 
history 
Age, race, employment, home 
life, treatments 
Individual, 
Physiological 
0 
 
Diet 
Calcium/Vit D & Fruit, vegetable, 
fiber screeners 
Biological 
0 
 
Obesity 
Body composition, 
Anthropometrics 
Physiological 
0,8 
 
Physical activity 
Godin  
Physiological 
0,8 
 
Support 
MOS Social Support 
Environmental 
0,8 
 
Sunlight  
Sun exposure tool 
Physiological 
0,8 
 
 
vii. Laboratory Outcomes: Laboratory analyses will be conducted by the Core Laboratory of LUHS, 
within a Basic Science Laboratory at LUHS and/or by Quest Diagnositics. Serum vitamin D and serum 


9 
 
estradiol will be measured using liquid chromatography/tandem mass spectrometry (LC-MS/MS). This 
technique is considered the ‘gold standard,’ providing total 25(OH)D which includes vitamin D2 and 
vitamin D3, as well as total serum estradiol levels Calcium will be quantified by spectrophotometry 
Biomarkers of inflammation (e.g., C-reactive protein (high sensitivity), interleukins, TNF-α) will be 
measured at baseline and follow up with the laboratory analyses conducted in batch to decrease intra-
assay variability. The comprehensive metabolic panel (CMP) will be completed to assess baseline organ 
function, and includes albumin, alkaline phosphatase, ALT, AST, calcium, CO2, BUN/Creatinine, chloride, 
creatinine with estimated GFR, globulin (calculated), glucose, urea nitrogen, potassium, sodium, total 
bilirubin, and total protein.  
 
viii. General well-being outcomes: To increase comparability across studies, the selected tools have 
been used previously in breast cancer and/or other cancer populations. (Copies of the tools can be found 
in the Appendices.)  
 
Demographics and treatment: Similar to our previous study, we will obtain information on age, 
race/ethnicity, employment status, living situation, diagnosis, treatments (medical, surgical and radiation) 
and metastatic sites. 
 
Brief Pain Inventory-Short Form: This validated instrument was designed to assess pain in cancer 
patients.31 It includes four items measuring the severity of pain in the last 24 hours on a scale of 0–10, 
plus seven additional items measuring the extent to which pain interferes with life activities.  
 
Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP): This 16-item questionnaire was 
developed to assess bone pain. It was validated in women with metastatic breast cancer involving the 
bone.32 It is scored similarly to other FACT instruments (range 0-4), takes ~5 minutes to complete and 
has been used in a previous vitamin D supplementation trial for cross-comparison.11 
Piper Fatigue Scale (PFS): The PFS is composed of 22 numerically scaled, "0" to "10" items that 
measure four dimensions of subjective fatigue: behavioral/severity (6 items); affective meaning (5 items); 
sensory (5 items); and cognitive/mood (6 items.) Four sub-scale/dimensional scores and total fatigue 
scores can be calculated to provide reliable, valid assessments of fatigue in breast cancer patients.33 
 
Hospital Anxiety and Depression Scale (HADS): The HADS is a validated, fourteen item scale with 7 
items to categorize anxiety and 7 items to measure depression.34 Each item on the questionnaire is 
scored from 0-3, meaning a person can score between 0 and 21 for either anxiety or depression. 
 
Patient Health Questionnaire 8 (PHQ8): The PHQ8 is a reliable and valid measure of depression 
severity.35 It has 8 questions, each scored 0-3. The sum of all 8 items is used to determine depression, 
with scores of 10-20 considered major depression and >20 is severe major depression.  
 
Handgrip strength: Handgrip strength is measured with a handgrip dynamometer (Jamar) which tests grip 
strength up to 90 kg. It is often used as a test of skeletal muscle function and correlates with total body 
muscle strength36 and mortality.37 
 
Eastern Cooperative Oncology Group Performance Status (ECOG): This scale is used by clinicians and 
researchers to assess globally assess disease progress, the impact of the disease on daily living abilities 
and helps guide appropriate treatment and prognosis.38 Grades range from 0-5 with scores of 0-2 
reflecting full activity to compromises in self-care. 
 
Pittsburg Sleep Quality Index (PSQI): This tool contains 19 self-rated questions (7 component scores, 
ranging from 0-3) and has been validated in a subset of breast cancer patients (Cronbach’s alpha 0.8).39 


10 
 
In all cases a score of “0” indicates no difficulty, while a score of “3” indicates severe difficulty. The 7 
component scores are added to yield a “global” score (range 0-21).  
 
Overall health: Using a single item, participants will be asked, “How would you rate your overall health at 
this time?” This global question format is based on national survey data and scored 1-5 (1=excellent, 
2=very good, 3= good, 4=fair and 5=poor.)  
 
Functional Assessment of Cancer Therapy-Breast and Endocrine Symptoms: The FACT-B and FACT-ES 
are widely-used tools that measures multidimensional QOL in patients with breast cancer. They have 
good reliability, validity and are sensitive to change.3  There are four QOL subscales: Physical Well-
Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being with additional breast 
cancer and endocrine subscales. Higher scores indicate better QOL and total and subscale scores can 
be compared to normative scores in breast cancer patients with early and advanced disease.4,40 
 
Body composition: This will be assessed using three methods. First, weight, height, waist and hip 
circumference measures will be taken to calculate body mass index and estimate android and gluteal 
adiposity.  Bioelectrical impedance will be used to assess adiposity at baseline for all participants due to 
its ease and low costs. Finally, participants will undergo dual energy x-ray absorptiometry (DXA) imaging 
using the Discovery W by Hologic, located down the hall from the study exam room. This noninvasive, 
imaging technique provides precise whole-body measurements of fat (total and visceral) and lean tissue, 
only takes 10 minutes to complete and will be completed on Group 1 participants at their final study visit.  
 
Dietary intake: Because dietary sources of vitamin D are restricted to a limited number of foods, precise 
intakes are easily obtained and quantified with a short measurement tool. The Block Calcium/Vitamin D 
screener is a brief dietary assessment tool validated and developed from the National Health and 
Nutrition Examination Survey 1999-2001 dietary recall data.41 This screener takes 5-7 minutes to 
complete and includes 19 food items, 3 supplement questions, and adjusts for food fortification practices. 
To help further characterize dietary intake, participants will also complete the fruit, vegetable and fiber 
screener. This screener contains 7 questions and takes 3-5 minutes to complete. 
 
Sun exposure: Because sunlight constitutes the major source of vitamin D, the adult sun habits 
questionnaire by Glanz et al will be used.42 Two questions inquiring about summer sun exposure will be 
used quantify time spent in the sun, which directly correlates with serum vitamin D levels. 
 
Godin Exercise Leisure-time Questionnaire: This 4-item tool allows for the quick quantification of time 
spent engaged in strenuous, moderate or light activities over a typical 7-day period showing reliability 
coefficients of 0.8 with V02 measures.43 A weekly leisure activity score is generated, as well as the 
frequency of leisurely activities. This tool is recommended and made available by the NCI. 
 
Medical Outcomes Study Social Support Survey: The self-administered survey is a 19-item multi-
dimensional scale assessing four aspects of social support: tangible support, affectionate, positive social 
interaction and emotional/informational support (Cronbach’s alphas >0.9 for all subscales.)44 Total and 
subscale scores are obtained and compared, with higher scores indicating more support. 
 
ix. Study completion: Participants in the intervention will return to LUMC after 8 weeks of 
supplementation for their final blood analyses (serum 25(OH)D, calcium, , serum estradiol, inflammatory 
markers), anthropometric and body composition evaluations, pill counts and questionnaire completion. An 
8 week intervention was selected because: 1) this timeframe is consistent with the clinical practice 
guidelines of the Endocrine Society for vitamin D repletion, and 2) it is an efficient and opportune time to 
assess the effects of vitamin D on biological and symptom outcomes. Participants in the non-intervention 
arm will not be followed after their baseline visit. They will be considered “complete” after their baseline 
visit. 


11 
 
 
x. Patient participation and compensation: We anticipate that we can screen, recruit, and ultimately 
enroll 50 women over a 12 month time period (n=25 in Group 1, n=25 in Group 2) using patients at LUMC 
and those referred from RUMC. To enhance retention, participants will be scheduled on a day that is 
convenient for them and parking tokens will be provided to offset any costs of parking. Honorarium for 
data collection will be given in a graduated manner [$20 baseline, $30 follow up (Group1 only)]. To 
enhance medication compliance in the intervention arm, participants will be contacted weekly (phone call, 
text or email) and reminded to take their vitamin D supplements. For persons who drop out, we will 
assess the reason for study discontinuation and notify their medical oncologists regarding any recent 
laboratory findings, as appropriate.  
 
VII. 
Safety Monitoring Plan 
a. 
Published reports suggest that 50,000 IUs of vitamin D taken daily can increase vitamin D levels to 
more than 150 ng/dl and cause hypercalcemia.45 The proposed dosing for this study is 50,000 IUs 
per week, which equates to ~7,000 IUs/day. This dose has minimal side-effects in healthy 
populations, but may include bone pain, constipation, dry mouth, headache, stomach upset and loss 
of appetite. We will be monitoring laboratory values at baseline and 8 weeks, and patient symptoms 
at baseline, 4 and 8 weeks. 
  
i. Any patient who receives treatment on this protocol will be evaluable for toxicity. This 
study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 available at (http://ctep.cancer.gov). Participants will be called after 4 
weeks of supplementation to ascertain pill counts, gauge their general tolerance and 
capture symptom management data related to pain, fatigue, mood, sleep and overall 
health. Although toxicity and adverse side-effects from vitamin D3 supplement are rare, 
participants will be queried their general tolerance to the study medication during the 4 
week phone call. The following criteria will be utilized to determine supplement 
suspension or supplement discontinuation: .If the participant develops Grade 1 toxicity 
that is felt to be possibly, probably, or definitely related to study supplement, the 
participant will continue to be monitored.  
ii. If the participant develops Grade 2 toxicity that is felt to be possibly, probably, or 
definitely related to study supplement, the participant may go on study supplement 
holiday until toxicities are Grade 1 or lower (for no longer than 4 consecutive weeks).  
iii. If a participant develops any Grade 3 or Grade 4 or has persistent Grade 2 toxicity 
beyond four consecutive weeks possibly, probably, or definitely related to the study 
supplement, the study supplement will be discontinued. A blood draw at the nearest 
Quest Diagnostics facility or the Cardinal Bernadin Cancer Center Phlebotomy 
Laboratory will be procured to obtain 25(OH)D and a comprehensive metabolic profile. 
iv. If a participant’s serum calcium and corrected calcium* exceeds 10.5 mg/dL, then 
study supplement will be suspended. The participant will be encouraged to lower any 
calcium intake and provided a handout on calcium sources. The serum calcium will be 
rechecked in two weeks and the participant may continue on study supplement if the 
serum calcium is below 10.5 mg/dL. Otherwise, the participant will be removed from 
study intervention. The participant may also be removed from study intervention for any 
Grade 2 or higher hypercalcemia (serum calcium > 11.5 mg/dl). 
*Corrected calcium = serum calcium + [(4.0 – serum albumin) x 0.8]  
v. In each of these cases, the follow up questionnaires and follow-up blood analyses will 
still be collected as per protocol eight weeks after the initial start of the intervention. 
 
b. 
Participants may be re-challenged following a suspension.  Specifically, participants who have had a 
study physician-ordered dose suspension may be re-challenged by returning to the full dosage, or 


12 
 
the study physician may decide to have the participant continue her participation on a reduced dose 
(e.g., 25,000 IUs/week) until study completion.  
 
c. 
A participant will be taken off study if she experiences any of the following adverse events: 1) 
hypercalemia (>11.5 mg/dL), 2) a serum 25(OH)D level >100 mg/dL with normal calcium or 
symptoms of vitamin D indicating possible toxicity, 3) clinically significant increases in serum 
estradiol indicating a potential drug-nutrient interaction, or 4) has intolerable side-effects believed to 
be associated with vitamin D3 supplementation. Serious and/or unanticipated adverse events will be 
reported to the Loyola IRB within 24 hours of occurrence. 
 
d. 
To ensure the safety of participants, we will complete an exhaustive review of all safety 
measurements employed in this study after 7, 19, and 25 patients are enrolled.  This includes 
examining their laboratory values, adverse event logs, and notifications in order to make a 
determination about whether the study should continue for all participants or whether the study 
should terminate. 
 
VIII. 
Data Management and Analyses 
All hard copies of the data will be kept in a folder, in a locked file cabinet in a locked office in a secure 
building. Data will be double-entered into appropriate data management software, correcting all data entry 
errors prior to import into SAS (v 9.2) for statistical analyses.  
Standardized descriptive statistics including means, median, standard deviations, frequency and 
ranges for continuous variables will be calculated to describe the participants and the overall and subscale 
means for the respective instruments. For specific aim 1, the number of participants who achieve sufficient 
levels of serum 25(OH)D will be calculated, and paired t tests will be used to assess differences between 
mean laboratory values from baseline and follow up. Using logistic regression, we will also explore the 
clinical characteristics of those who achieve sufficient levels vs. those who remain insufficient after the 
intervention. For specific aim 2, repeated measures analyses will be conducted to examine changes in 
symptom scales from baseline to interim and follow up.  
 
IX. 
Other considerations 
 
a. Potential benefits of the proposed research and future directions: Seeking to live as normal a life 
as possible, including the ability to fulfill roles and maintain relationships, is a goal for many that are 
negatively affected by MBC. Many patients with MBC have serious concerns, including the fear of dying, 
declining quality of life, side effects of treatment, the ability to care for family, decreasing physical 
functioning and care at the end of life. Managing symptoms to maintain an optimum quality of life is the 
major goal of care in the metastatic setting. Many women with MBC who consume vitamin D take it to 
‘protect their bones.’ This study has the potential to provide preliminary evidence to support that vitamin D 
levels can improve QOL and enhance survivorship care. Additionally, we will be asking participants to 
biobank their blood for future studies related to vitamin D. Findings from this study will be used for to 
design and justify a larger trial. 
 
b. Timeline: This study is designed and intended to be completed within 18 months. We anticipate that 
we can screen, recruit and enroll 25 women in the intervention in months 1-12. We will enroll women in 
the cross-sectional arm of this study until the intervention is complete. Data entry will be on-going 
throughout the study with final data collection will conclude in month 14. In month 15, we will complete 
data entry, conduct data cleaning and begin initial statistical analyses. In months 15-18, we will complete 
our statistical analyses and prepare these data for grant, manuscript and oral presentation.  
 
c. This study completed an IND application and has been issued  a “study may proceed” decision by the 
FDA. 
 


13 
 
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15 
 
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16 
 
 
VII. Appendices 
 
A. Study Instruments 
1. Demographics and treatments 
2. Brief Pain Inventory- Short form 
3. Piper Fatigue Scale 
4. Hospital Anxiety and Depression Scale 
5. Patient Health Questionnaire 8  
6. Eastern Cooperative Oncology Group Performance Status 
7. Pittsburg Sleep Quality Index 
8. Functional Assessment of Cancer Therapy-Breast and Endocrine Symptoms 
9. Sunlight Assessment 
10. Block Calcium/Vitamin D screener 
11. Godin Exercise Leisure-time Questionnaire 
12. Medical Outcomes Study Social Support Survey 
13. Food Sources of Calcium 
14. FACT-Bone Pain 
15. Fruit, vegetable and fiber screener 
 

SAP_001.pdf: 
 
Protocol title: Safety, feasibility and efficacy of vitamin D supplementation in women 
with metastatic breast cancer (SAFE-D)  
 
NCT: 02186015 
 
Date: November 14, 2018 
 
 


 
Protocol title: Safety, feasibility and efficacy of vitamin D supplementation in women 
with metastatic breast cancer (SAFE-D)  
 
Principal Investigator: Patricia Sheean, PhD, RD  
 
Research Team: William Adams, MS; Cara Joyce, PhD, Sue Penckofer, PhD, RN; 
Ruta Rao, MD; Patricia Robinson, MD;  
 
Statistical Analyses Conducted  
Descriptive statistics were conducted to examine differences in sociodemographics, 
medical characteristics and dietary intake stratified by sufficient vs. insufficient serum 
25(OH)D at baseline. Statistical differences between groups were assessed with 
Wilcoxon rank sum tests for continuous variables and chi-square or Fisher’s exact test 
for nominal variables. Among those treated with 8 weeks of high dose cholecalciferol, 
changes from baseline were assessed with Wilcoxon signed rank tests for continuous 
scores. Analyses were performed with SAS version 9.4 (Cary, NC). A p value of <0.05 
was used to denote statistical significance and based on the exploratory nature of this 
study, a p value of <0.10 was used to designate statistical trends.