Clinical trial NCT01988090
Conditions: Breast Cancer
Keywords: Breast Cancer Hormone Receptor Positive Vitamin D
Sponsor: Mothaffar Rimawi
Start date: 2013-12-01; Completion date: 2018-12-10
Enrollment: 93 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being done to look at the difference, if there is a difference between two different doses of Vitamin D and the reduction of joint/muscle pain (arthralgia)that is caused by taking anti-estrogen medications (aromatase inhibitors) by breast cancer patients. The investigators hope to learn if taking a higher dose of Vitamin D is a good way to prevent aromatase inhibitor arthralgia (AIA).

Detailed description:
Treatments with anti-estrogen agents for hormone receptor positive breast cancer is the most efficacious of systemic therapies, with aromatase inhibitors (AI's) being considered the most active anti-estrogen therapy in early stage breast cancer. But, use of these treatments has been shown to cause musculoskeletal (joint/muscle) side effects that sometimes cause patients to discontinue the use of them. Also, Vitamin D deficiency is a well know cause of a wide array of musculoskeletal issues. There is evidence that Vitamin D supplementation may help prevent arthralgia while on AI's. Therefore, the investigators want to see if giving a higher dose of Vitamin D could decrease the incidence of AIA as compared to a standard dose of Vitamin D. The investigators believe that this could possibly result in patients continued treatment with AI therapy for hormone receptor positive breast cancer.

Arms: arm 1: 50,000 IU Vitamin D supplement arm 2: 800 IU Vitamin D Supplement
Interventions: intervention 1: 800 IU Vitamin D Supplement intervention 2: 50,000 IU Vitamin D supplement
Intervention descriptions: intervention 1: Standard Dose intervention 2: High Dose

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
A Randomized, Controlled Trial of High Dose vs. Standard Dose  
Vitamin D for Aromatase-Inhibitor Induced Arthralgia in Breast Cancer 
Survivors 
 
Protocol Number 
 
 H-33261 
 
Protocol Chair  
 
Mothaffar Rimawi, M.D. 
 
 
 
 
Baylor College of Medicine 
 
 
 
 
One Baylor Plaza BCM 600 
Houston, TX 77030 
Phone:  (713) 798-1311 
Fax:  (713) 798-8884 
Email: rimawi@bcm.edu 
 
IND Number: 120053 
NCT Number:  NCT01988090 
 
Additional Sites  
 
 
              Washington University 
Site PI:  Foluso Ademuyiwa, MD 
 
                
 
     


High Dose Vitamin D for AIA 
 
 
Rimawi 
A Randomized, Controlled Trial of High Dose vs. Standard Dose Vitamin D for Aromatase-
Inhibitor Induced Arthralgia in Breast Cancer Survivors 
 
- Protocol Revision Record – 
 
Original Protocol: 
 
April 18, 2013 
Revision 1: 
 
 
July 22, 2013 
Revision 2: 
 
 
September 3, 2013 
Revision 3:   
 
 
November 18, 2013 
Revision 4:   
 
 
July 14, 2015 
 
 


Vitamin D for AIA 
3 
 
TABLE OF CONTENTS 
 
1.  BACKGROUND ............................................................................................................................................ 5 
1.1 
TREATMENT OF HORMONE RECEPTOR POSITIVE BREAST CANCER..................................................................... 5 
1.2 
MUSCULOSKELETAL SIDE EFFECTS OF HORMONAL THERAPY ........................................................................... 6 
1.3 
MANAGEMENT OF AIA ......................................................................................................................... 8 
1.4 
VITAMIN D AND BREAST CANCER............................................................................................................. 9 
1.5 
VITAMIN D BACKGROUND ..................................................................................................................... 9 
1.6 
STUDY RATIONALE ............................................................................................................................. 10 
2. 
OBJECTIVES ........................................................................................................................................... 11 
2.1 
PRIMARY OBJECTIVE ........................................................................................................................... 11 
2.2 
SECONDARY OBJECTIVES ...................................................................................................................... 12 
2.3 
EXPLORATORY OBJECTIVE .................................................................................................................... 12 
3. 
STUDY DESIGN/SUMMARY ................................................................................................................... 12 
SCHEMA ........................................................................................................................................................ 14 
4. 
PARTICIPANT SELECTION ...................................................................................................................... 15 
4.1 
INCLUSION CRITERIA ........................................................................................................................... 15 
4.2 
EXCLUSION CRITERIA .......................................................................................................................... 15 
4.3 
INCLUSION OF UNDERREPRESENTED POPULATIONS ..................................................................................... 16 
5. 
REGISTRATION PROCEDURES ................................................................................................................ 16 
5.1 
GUIDELINES ...................................................................................................................................... 16 
5.2 
ELIGIBILITY EXCEPTIONS ....................................................................................................................... 17 
6. 
STUDY PROCEDURES ............................................................................................................................. 17 
6.1 
SCREENING AND BASELINE ASSESSMENTS ................................................................................................. 17 
6.2 
FOLLOW-UP AT WEEK 4 ...................................................................................................................... 18 
6.3 
FOLLOW-UP AT WEEK 12 .................................................................................................................... 18 
6.4 
FOLLOW UP AT WEEKS 24 AND 36......................................................................................................... 19 
6.5 
FOLLOW UP AT WEEK 52, AND END OF TREATMENT VISIT ............................................................................ 19 
6.6 
SAFETY FOLLOW-UP ........................................................................................................................... 20 
6.7 
UPON COMPLETION OF THE THERAPEUTIC REGIMEN, SUBJECTS WILL BE FOLLOWED FOR ADVERSE EVENTS FOR A PERIOD 
OF 30 DAYS AFTER THE LAST DOSE OF VITAMIN D ON STUDY.  PATIENTS WITH ABNORMAL LABORATORY OR CLINICAL FINDINGS 
THAT ARE BELIEVED TO BE TREATMENT RELATED WILL BE FOLLOWED UNTIL THE CONDITION RESOLVES, STABILIZES, OR UNTIL THE 
LABORATORY VALUES ARE NO LONGER CONSIDERED CLINICALLY SIGNIFICANT.  NEW ADVERSE EVENTS THAT OCCUR DURING THE 30 
DAY FOLLOW-UP PERIOD WILL ONLY BE RECORDED IF THE INVESTIGATOR BELIEVES THERE IS A REASONABLE POSSIBILITY THAT THE 
ADVERSE EVENT IS DRUG-RELATED.  THE SAFETY FOLLOW-UP MAY BE CONDUCTED BY A PHONE VISIT OR A CLINIC VISIT; IF 
CLINICALLY INDICATED, A CLINIC VISIT SHOULD BE PERFORMED ALONG WITH RELEVANT LAB WORK.  PER STANDARD OF CARE AND 
NCCN GUIDELINES, BONE DENSITY SCAN WILL BE REPEATED, AT THE TREATING PHYSICIAN’S DISCRETION, EVERY 1-2 YEARS WHILE 
THE PATIENT IS ON AI THERAPY.  PER NNCN GUIDELINES, PATIENT WILL HAVE DEXA SCAN EVERY 2 YEARS WHILE ON AI THERAPY, 
OR EVERY YEAR IF ACCELERATED BONE LOSS IS SUSPECTED, OR THERAPEUTIC INTERVENTION APPLIED.    DURATION OF FOLLOW-UP
 
20 


Vitamin D for AIA 
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6.8 
ON STUDY ASSESSMENTS AND PROCEDURES ............................................................................................ 20 
6.9 
AGENT ADMINISTRATION ..................................................................................................................... 21 
6.10 
COMPLIANCE .................................................................................................................................... 23 
6.11 
PROHIBITED THERAPIES ....................................................................................................................... 23 
6.12 
DISCONTINUATION OF TREATMENT ........................................................................................................ 23 
6.13 
WITHDRAWAL FROM STUDY ................................................................................................................. 24 
6.14 
CRITERIA FOR REMOVAL FROM THE STUDY ............................................................................................... 24 
6.15 
SUBJECT COMPENSATION ..................................................................................................................... 25 
7. 
DRUG FORMULATION/STORAGE/SUPPLY ............................................................................................. 25 
7.1 
VITAMIN D3, 5000 IU ....................................................................................................................... 25 
7.2 
VITAMIN D3, 2000 IU ....................................................................................................................... 25 
7.3 
CALTRATE-D, CALCIUM 600 MG & VITAMIN D3 800 IU ............................................................................ 25 
7.4 
DRUG ACCOUNTABILITY ...................................................................................................................... 25 
8. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................................................... 26 
8.1 
DOSE MODIFICATIONS/DELAYS ............................................................................................................. 26 
8.2 
SPECIAL CONSIDERATIONS.................................................................................................................... 26 
9. 
ADVERSE EVENTS & SAFETY MONITORING ........................................................................................... 26 
9.1 
GENERAL ......................................................................................................................................... 27 
9.2 
DEFINITIONS ..................................................................................................................................... 27 
9.3 
ANTICIPATED TOXICITIES ...................................................................................................................... 29 
9.4 
TOXICITY MANAGEMENT ..................................................................................................................... 29 
9.5 
ADVERSE EVENT FOLLOW-UP ................................................................................................................ 30 
9.6 
REPORTING PROCEDURES .................................................................................................................... 30 
10. 
CORRELATIVE/SPECIAL STUDIES ....................................................................................................... 32 
10.1 
GRIP STRENGTH ................................................................................................................................ 32 
11. 
SPECIMEN BANKING ......................................................................................................................... 32 
12. 
MEASUREMENT OF EFFECT ............................................................................................................... 32 
12.1 
DEFINITIONS ..................................................................................................................................... 32 
12.2 
MEASUREMENT OF AROMATASE INHIBITOR-INDUCED ARTHRALGIA ................................................................ 33 
12.3 
COMPLIANCE WITH AI THERAPY............................................................................................................. 34 
13. 
STATISTICAL CONSIDERATIONS ........................................................................................................ 34 
13.1 
STUDY DESIGN/ENDPOINTS .................................................................................................................. 34 
13.2 
SAMPLE SIZE/ACCRUAL RATE ............................................................................................................... 35 
13.3 
ELIGIBILITY EXCEPTIONS ................................................................................................................... 35 
13.4 
PRIMARY ENDPOINT ........................................................................................................................... 36 
13.5 
SECONDARY ENDPOINTS ...................................................................................................................... 36 
13.6 
EXPLORATORY ENDPOINTS ................................................................................................................... 36 
13.7 
FUTILITY ANALYSIS ............................................................................................................................. 36 
14. 
DATA AND SAFETY MONITORING ..................................................................................................... 37 
14.1 
DATA MANAGEMENT AND REPORTING.................................................................................................... 37 


Vitamin D for AIA 
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14.2 
MEETINGS ....................................................................................................................................... 38 
15. 
REGULATORY CONSIDERATIONS ....................................................................................................... 38 
15.1 
PROTOCOL REVIEW AND AMENDMENTS .................................................................................................. 38 
15.2 
INFORMED CONSENT .......................................................................................................................... 38 
15.3 
ETHICS AND GCP ............................................................................................................................... 39 
16. 
MULTI-CENTER GUIDELINES .............................................................................................................. 39 
16.1 
STUDY DOCUMENTATION .................................................................................................................... 39 
16.2 
RECORDS RETENTION.......................................................................................................................... 39 
16.3 
PUBLICATION .................................................................................................................................... 40 
17. 
WORKS CITED ................................................................................................................................... 40 
18. 
APPENDIX A:  HEALTH ASSESSMENT QUESTIONNAIRE (HAQ) ........................................................... 43 
APPENDIX B       STUDY CALENDAR ................................................................................................................ 46 
1.  BACKGROUND 
Breast cancer is the most common malignant disease in women in the Western world. In the U.S., 
SEER data states that over 207,000 women are diagnosed with invasive breast cancer every year, 
and almost 40,000 women will die of this disease (1).  Systemic treatment is the most active 
modality in reducing distant tumor recurrences and resulting mortality in early breast cancer.  
Specifically, endocrine therapy with anti-estrogen agents for hormone receptor positive breast 
cancer is the most efficacious of systemic therapies, with aromatase inhibitors being arguably the 
most active anti-estrogen therapy in early stage breast cancer (2).   
1.1 Treatment of Hormone Receptor Positive Breast Cancer 
Approximately 70% of newly diagnosed breast cancers are positive for hormone receptors 
(estrogen receptors, ER; progesterone receptors, PR). While tamoxifen was part of the standard of 
care for patients with hormone-responsive breast cancer, its use in the adjuvant setting has largely 
been replaced in postmenopausal women by the third generation aromatase inhibitors (AI’s) based 
on studies demonstrating superior efficacy of adjuvant AI’s in early breast cancer.  
The third-generation AI’s include non-steroidal aromatase inhibitors (NSAI’s) anastrozole 
and letrozole, as well as the steroidal aromatase inhibitor (SAI), exemestane. These AI’s suppress 
estrogen synthesis to nearly undetectable circulating levels by inhibiting the enzyme aromatase, 
thereby blocking the conversion of adrenal androgens to estrogens (3) (4).  The NSAI’s bind 
reversibly to the cytochrome P450 moiety of the aromatase enzyme, interfering with estrogen 
biosynthesis (5) whereas exemestane is a false substrate that binds irreversibly to the aromatase 


Vitamin D for AIA 
6 
 
enzyme, causing its inactivation (6). 
Several large trials have shown superiority of aromatase inhibitors over tamoxifen in early 
stage breast cancer in terms of disease free survival and recurrence.  The Arimidex, Tamoxifen, 
Alone or in Combination (ATAC) trial randomized 6186 post menopausal women with localized 
breast cancer to 5 years of anastrozole or 5 years of tamoxifen adjuvant therapy.  The group who 
received anastrozole demonstrated a significantly prolonged disease free survival, with 575 versus 
651 events (HR = 0.87 , 95% CI 0.78-0.97).  They also enjoyed longer time to recurrence (HR 0.79 
[0.70-0.90]) and a statistically significant 42% reduction in contralateral breast cancer (7).   
Similarly, the Intergroup Exemestane (IES) examined 4742 post-menopausal women 
receiving adjuvant tamoxifen for localized estrogen receptor positive breast cancer.  After taking 
tamoxifen for 2-3 years, 2632 women were randomized to switch to exemestane, and 2380 women 
continued to receive tamoxifen.  At three years after randomization, women who had been 
switched to exemestane had a 32% risk reduction for recurrence.  They also had improved disease 
free survival of 91.5%, compared to 86.8% in the tamoxifen group.  Distant disease was reduced by 
34% and contralateral breast cancer by 56% in the exemestane group (8).     
Finally, the Breast International Group (BIG) 1-98 was a randomized, phase 3 double-blind 
trial comparing tamoxifen monotherapy, letrozole monotherapy, and sequential treatment with 
both agents.  Despite 39.5% of women on tamoxifen monotherapy crossing over to letrozole, the 
letrozole monotherapy group experienced improved disease free survival of 87.9% as compared to 
84.6% in women assigned to the tamoxifen monotherapy arm (9).   
1.2 Musculoskeletal Side Effects of Hormonal Therapy 
Traditionally, Aromatase Inhibitor induced Arthralgia (AIA) has been somewhat difficult to 
both define and quantify.  Though a single, commonly accepted definition of AIA is lacking, patients 
who experience AIA most commonly describe joint pain and stiffness, predominantly affecting the 
hands, wrists, shoulders, and knees.  However, any joint may be affected.  Median time to onset of 
symptoms is 1.6 months. As part of the syndrome, patients may also describe morning stiffness, 
myalgia, tingling, numbness, decreased grip strength, and joint swelling (10) (11).  The clinical tool 
which is becoming the standard used in many trials (12) (13) (10) to evaluate AIA is the Health 
Assessment Questionnaire-II (HAQ-II).  It is commonly used in rheumatology literature, and has been 
substantiated across many trials.  This is a simple survey, which is a proven, reliable, and accurate 


Vitamin D for AIA 
7 
 
indicator of joint pains and consequent disabilities (14) (15).  Decreased grip strength has also been 
examined in a few small trials, and it has been found to correlate with symptoms of AIA as well as 
MRI changes in the joints (16) (17) (18).    
Across all of the aforementioned large adjuvant hormonal therapy trials, significantly more 
women who were taking aromatase inhibitors experienced arthralgia than those taking tamoxifen.  
In the ATAC trial, 35.6% of women in the anastrozole arm experienced arthralgia, compared with 
only 29.4% in the tamoxifen arm (p<0.0001) (7).  The IES trial showed a statistically significant 
difference in the incidence of arthralgia as well.  Five per cent of women in the exemestane group 
had arthralgia, and only 3.6% of women in the tamoxifen arm experienced this symptom (p=0.005) 
(8).  The BIG 1-98 study found a 34.7% incidence of arthralgia, myalgia, or both in the women who 
received letrozole, as compared to 30.1% in the tamoxifen group (p=0.05) (9).   
While it is clear that aromatase inhibitors cause more arthralgia than tamoxifen, the exact 
incidence of this adverse effect remains unclear, as none of the aforementioned trials were 
engineered to examine the incidence of AIA.  Thus, the measured incidence of arthralgia while on AI 
therapy varies widely among the large clinical trials.  One cross-sectional survey specifically assessed 
200 women for AIA via questionnaire.  They discovered a 47% prevalence of AI-related joint pain 
and 44% rate of joint stiffness (19).    
The significance of the arthralgia syndrome associated with AI therapy is clarified by looking 
at a small pilot study which prospectively evaluated 100 women on adjuvant AI therapy with serial 
questionnaires.  At a median of six months, 13% of these women discontinued aromatase inhibitor 
therapy because of arthralgia (10).  In larger studies, overall rates of non-adherence to AI therapy 
for any reason are even higher.  From reviewing pharmacy records of 12,000 patients, one 
researcher found the rate of adherence to adjuvant anastrazole therapy was only 50-68% at three 
years (20).  The joint pains, as they are one of the most common and troubling side effects of AI 
therapy, most likely play a significant role in patient’s non-adherence to medication.   
The significance of AIA, however, may extend beyond issues of quality of life and 
compliance.  It is possible that AIA is a marker of increased biologic effect.  Retrospective analysis of 
the ATAC trial suggests that women who develop new joint pains within three months of beginning 
endocrine therapy (either AI or tamoxifen) have a 40% reduction in the risk of breast cancer 
recurrence as compared to those women without arthralgia (21), similar to the increased efficacy 
seen in lung cancer patients who develop a rash with erlotinib.  Retrospective analyses of the TEAM 


Vitamin D for AIA 
8 
 
and BIG 1-98 trials have also found a correlation between the development of arthralgia on AI 
therapy and lower breast cancer recurrence risk, as compared to those who do not develop 
arthralgia (22) (23).  However, it should be noted that analysis of IES did not show the same 
correlation (24).  Clearly, more needs to be learned about the etiology and the significance of AIA.  
Further study of AIA could potentially lead to a better understanding of factors that predict disease 
recurrence.   
Many risk factors for developing arthralgia on AI’s have been postulated, but the mechanism 
is still not understood.  Both higher BMI and depressed mood have been associated with increased 
incidence of arthralgia while on AI’s in post-menopausal women.  Also, previous use of hormone 
replacement therapy, previous chemotherapy administration, and hormone receptor positivity have 
all been retrospectively associated with higher risk of developing new arthralgia while on aromatase 
inhibitor therapy.  Interestingly, women from North America or the UK were more likely to develop 
AIA compared to women from the rest of the world, though it is not clear why these geographic 
differences exist (25).   
1.3  Management of AIA 
In terms of treatment, the only intervention that has been shown to reduce AI-induced 
arthralgia in a randomized controlled trial is acupuncture, which has shown significantly decreased 
subjective pain scores and pain-related interference as compared to sham acupuncture (26).  
Exercise and NSAIDs are commonly utilized by oncologists to treat AIA, though quality evidence is 
lacking to support this approach.  Other treatments, such as steroids (27) and diuretics (28) have 
also been examined, but these studies have been plagued by small sample size, lack of 
reproducibility, and non-prospective design. 
There also may be some utility in simply switching AI’s.  The French ATOLL trial found that 
71.5% of women who discontinued anastrazole because of intolerable joint pains were actually able 
to tolerate and continue letrozole.  However, it should be noted that 74% of women still reported 
significant arthralgia after 6 months of letrozole therapy, but it was generally felt to be more 
tolerable than anastrazole by the majority of women (29). 
In one small, non-randomized trial of 27 patients, a short course of low dose prednisolone 
did show promise as a potentially effective treatment for AIA.  Patients with AIA were given 5 mg of 
prednisolone daily for one week, and 67% of patients reported immediate relief in joint pain, with 


Vitamin D for AIA 
9 
 
63% still reporting improvement at 1 month (27).  Retrospective data suggests that diuretics and 
bisphosphonates may play a role in reducing discomfort from AIA (28) (30).  In a single arm trial, 29 
women with AIA received duloxetine for 8 weeks, and 72% experienced at least a 30% reduction in 
average pain level (31).  While these results are interesting, all of these trials are plagued by small 
sample size, and none of them have been performed in a randomized controlled setting.  Thus, AIA 
is still very difficult for physicians to treat because there is no clearly effective management strategy.              
1.4 Vitamin D and Breast Cancer 
Vitamin D has recently begun to receive much attention because some data indicates that 
higher levels of vitamin D may correlate with lower breast cancer risk.  However, the Institute of 
Medicine recently released a report stating that the evidence for Vitamin D and breast cancer 
prevention is “inconsistent and insufficient to inform nutritional requirements” at this point (32).    
There is also some interesting data recently released which correlates higher baseline 
Vitamin D levels with decreased risk of distant recurrence in post-menopausal women, especially 
decreased risk of bone metastases (33).   
1.5 Vitamin D Background 
While the relationship of Vitamin D to breast cancer risk and recurrence clearly needs 
further study, Vitamin D deficiency is well known to cause a wide array of musculoskeletal issues, 
including diffuse skeletal pain and non-inflammatory arthritis.  For example, among 1993 post-
menopausal women from the Womens Health Initiative, low vitamin D levels were correlated with 
increased joint pain (34).  Furthermore, in non-cancer patients, these symptoms have resolved 
and/or improved with single high dose vitamin D3 at 150,000 IU orally (35) (36) (37).  
Optimal levels of Vitamin D are not completely agreed upon, as deficiency is usually defined 
as a serum 25-hydroxy vitamin D level <20 ng/mL, as supported by the Institute of Medicine (38).  
However, there is evidence to state that proximal muscle strength improves as vitamin D levels 
increase to >40 ng/mL (39).  Vitamin D insufficiency and deficiency are quite common among post-
menopausal breast cancer patients, ranging from 75-90% (33) in some reports, though vitamin D 
levels are known to vary based on geographic location.  However, the tie between post-menopausal 
women on AI therapy and low vitamin D levels is logical because estrogen and vitamin D are closely 
linked.  Estrogen increases activity of 1 alpha hydroxylase, which catalyzes conversion 25(OH)D to its 
active form, 1,25(OH)2D.  Estrogen also increases the activation of the Vitamin D receptor.  


Vitamin D for AIA 
10 
 
Therefore, it is reasonable to suppose that a low estrogen state, as is seen in women on AI therapy, 
could potentially decrease the amount of active Vitamin D available, and studies have corroborated 
this.  One retrospective analysis of the International Breast Cancer Intervention (IBIS-II) trial found 
that among 416 post-menopausal women who were at high risk of breast cancer, only 13% had 
adequate vitamin D levels (≥30 ng/mL), 41% had inadequate levels (20-30 ng/mL), and 46% were 
deficient or severely deficient (<20 ng/mL) (40).  Similarly, in the AZURE trial, only 10% of women 
had adequate Vitamin D levels of >30 ng/mL, even when seasonal variation was properly accounted 
for (33).  Clearly, Vitamin D deficiency is quite common among women internationally, and it merits 
further study.    
There is some preliminary evidence to suggest that Vitamin D supplementation may prevent 
arthralgia while on AI’s.  Sixty women who were beginning adjuvant AI therapy were enrolled in a 
small study which supplemented women with low baseline Vitamin D levels (≤40 ng/mL) with 
increased doses of vitamin D at 50,000 IU per week for 12 weeks.  They found that that the 
supplementation was effective in raising women’s Vitamin D levels, and higher Vitamin D level 
(25OHD > 66 ng/mL) correlated with less joint pain and disability from joint pain (12).   
In contrast, another prospective study with similar design only supplemented the women 
with vitamin D levels of <40 ng/mL with 16,000 IU of oral vitamin D3 every 2 weeks.  Half of the 
women failed to achieve Vitamin D levels >40 ng/mL at 3 months, and there was no improvement in 
joint pains (13).  Considering the somewhat disparate results of these two trials, it is clear that more 
needs to be understood regarding the role of vitamin D in AIA, the optimal dosing, and goal vitamin 
D levels.  Though there are some promising results in the literature, many more trials need to be 
done to further clarify the role which Vitamin D may play in Aromatase Inhibitor-Induced Arthralgia. 
1.6 Study Rationale 
As previously mentioned, Vitamin D deficiency is an exceedingly common, though relatively 
unexplored, condition among breast cancer patients.  This study aims to shed more light on the role 
of Vitamin D in the setting of AIA, and to see whether prophylactic vitamin D supplementation may 
decrease the incidence of AIA and, thus, also improve patient compliance with AI therapy.  Other 
studies have shown that Vitamin D supplementation may significantly improve AIA (12), though this 
is not clearly understood at this point.  Estrogen increases activity of 1 alpha hydroxylase, which 
catalyzes conversion 25(OH)D to its active form, 1,25(OH)2D.  Estrogen also increases the activation 
of the Vitamin D receptor.  Therefore, it is logical that a low estrogen state, as is seen in women on 


Vitamin D for AIA 
11 
 
AI therapy, could potentially decrease the amount of active Vitamin D available.  Vitamin D is known 
to inhibit release of inflammatory cytokines IL-1, IL-6, and TNF alpha from macrophages.  
Furthermore, in the non-breast cancer population, it has been proven that high dose vitamin D 
significantly decreases levels of TNF-α and IL-6 (41).  Inhibiting release of inflammatory cytokines, 
which may result from low estrogen and consequent low vitamin D levels, could potentially explain 
the etiology of AIA, if proven to be true.   
We propose to perform a randomized clinical trial in post-menopausal women with ER+ 
breast cancer, who are beginning adjuvant aromatase inhibitor therapy.  Half of the women will 
receive high dose Vitamin D (50,000 IU per week for 12 weeks, followed by 2000 IU daily for 40 
additional weeks), and the other half of women will receive standard dose Vitamin D (800 IU daily 
for 52 weeks).  The goal of this trial is to show us whether higher Vitamin D supplementation is a 
good preventative measure for AIA, and whether it is associated with increased AI compliance.   
 
Hypothesis 
Based on previous data from other trials mentioned above, high dose Vitamin D supplementation 
may decrease the incidence of AIA in the experimental arm as compared to the standard dose arm.   
We hypothesize that the women in the high dose Vitamin D arm will have significantly less 
aromatase inhibitor-induced arthralgia, as compared to the women on the control arm.  
Consequently, we further hypothesize that the women who are taking high dose Vitamin D will 
also have a significantly higher compliance rate with AI therapy than the women on the control 
arm.   
 
2. OBJECTIVES 
2.1 Primary Objective 
To evaluate whether women who are supplemented with high dose Vitamin D develop less 
Aromatase Inhibitor-Induced Arthralgia (AIA) than those women who receive standard dose 
Vitamin D.    


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2.2 Secondary Objectives 
2.2.1 
To assess whether high dose Vitamin D supplementation, as compared to standard 
dose, leads to improved compliance with aromatase inhibitor therapy. 
2.2.2 
To assess whether low baseline serum 25-hydroxyvitamin D levels are a risk factor for 
developing AIA 
2.3 Exploratory Objective 
2.3.1 
To study whether grip strength may serve as an accurate and reliable objective measure 
to complement the subjective complaint of AIA.  
2.3.2 
To investigate whether high dose vitamin D may be associated with lower breast cancer 
recurrence than standard dose Vitamin D 
3. STUDY DESIGN/SUMMARY 
This is a randomized, multi-center,  controlled, phase II study comparing high dose vitamin D vs. 
standard dose vitamin D for post-menopausal breast cancer patients who are beginning adjuvant 
aromatase inhibitor therapy.  The study is intended to be conducted in up to 5 centers within the 
U.S.A which are routinely engaged in the administration of aromatase inhibitor therapy for the study 
specified population.  All patients who are starting an AI in the adjuvant setting are eligible to 
participate in the study.   
In order to preserve power and compensate for the interim futility analysis which tends to  reduce 
power, the sample size of the study is increased from 88 per group to 93 per group, which is 186 
total if considering a 5% drop out rate.  A total of 186 patients at up to 5 centers will be randomized 
1:1 to receive either 50,000 International Units (IU) oral vitamin D per week for 12 weeks followed 
by 2000 IU daily for 40 weeks, or 800 IU Vitamin D daily for 52 weeks.  All women on both arms of 
the trial will also take calcium carbonate 600 mg daily.   
The primary endpoint for this study is development of AIA in each arm after 12 weeks of AI 
therapy, as determined by patient questionnaires.  Secondary endpoints include compliance with AI 
therapy, as well as correlation of low baseline vitamin D levels with development of AIA.  Grip 
strength is an exploratory endpoint.   
Throughout the 52 week study period, participating women will complete the questionnaire 
and grip strength measurement a total of three times in order to assess their arthralgia while on AI 
therapy.  Compliance with aromatase inhibitor (AI) therapy will also be assessed throughout the 


Vitamin D for AIA 
13 
 
study to determine if AI compliance is improved in women who are receiving Vitamin D. 
Additionally, women will also have periodic assessments of serum 25-hydroxyvitamin D to assess 
whether vitamin D levels correlate with AIA, and to ensure that calcium and 25(OH) D levels are 
within healthy ranges.   
 
 
 


Vitamin D for AIA 
14 
 
SCHEMA 
 
High Dose vs. Standard Dose Vitamin D for Aromatase Inhibitor-Induced Arthralgia 
 
 
High 
dose 
Standard Dose 
184 post-menopausal 
women beginning 
adjuvant AI therapy 
50,000 IU vitamin D3 
qweek x12 weeks 
+  
Calcium 600 mg daily 
2000 IU Vit D3 daily 
+ 
Calcium 600 mg daily 
X40 weeks 
800 IU Vit D3 &  
600 mg Calcium/day 
x52 weeks 


Vitamin D for AIA 
15 
 
4. PARTICIPANT SELECTION 
4.1 Inclusion Criteria 
4.1.1 
All participants must  be female and at least 21 years of age 
4.1.2 
Signed informed consent 
4.1.3 
Patients must have had histologically confirmed stage I-III breast carcinoma that is 
positive for Estrogen Receptor (ER) and/or Progesterone Receptor (PR). 
4.1.4 
Post-menopausal status defined by any of the following: 
• 
Age >60 years 
• 
History of bilateral oophorectomy 
• 
Serum estradiol and FSH concentrations in the post-menopausal range, along with 
either amenorrhea for 12 months or previous hysterectomy (If patient is <60 years 
old, post-menopausal status must have been confirmed PRIOR to chemotherapy, if 
chemotherapy was given) 
4.1.5 
Beginning adjuvant aromatase inhibitor therapy, with no previous use within the last 6 
weeks.  Patients may take anastrozole, letrozole, or exemestane, per the discretion of 
the treating physician and the patient.   
4.1.6 
Bisphosphonates are allowed, at the treating investigator’s discretion  
4.1.7 
Performance status (WHO/ECOG scale) 0-2. 
4.2 Exclusion Criteria 
4.2.1 
History of kidney stones 
4.2.2 
Hypercalcemia at baseline, defined as any corrected calcium greater than the 
laboratory’s normal parameters  
4.2.3 
History of either symptomatic hypercalcemia or hyperparathyroidism, at the treating 
investigator’s discretion 
4.2.4 
Baseline 25-hydroxyvitamin D level greater than 50 ng/mL 


Vitamin D for AIA 
16 
 
4.2.5 
Inability or unwillingness to comply with, or follow study procedures.  
4.2.6 
Currently taking Phenytoin or phenobarbital  
4.2.7 
Currently taking cholestyramine or orlistat 
4.2.8 
Malabsorption syndrome, such as Crohn’s disease 
4.2.9 
 History of chronic granulomata forming disorders, such as sarcoidosis or tuberculosis. 
4.2.10 History of chronic fungal infection or lymphoma 
4.3 Inclusion of Underrepresented Populations 
Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards 
race in the clinical trial outlined. By the nature of the trial, the majority of women will be 
older because aromatase inhibitors are intended only for post-menopausal women.  Due to 
the rate incidence of breast cancer in men and infrequent treatment with AI’s in this group, 
this trial is open to the accrual of women only. 
5. REGISTRATION PROCEDURES 
5.1 Guidelines  
Patients should be registered in the electronic database as soon as the patient has signed the 
informed consent.  Following registration, the patient’s enrollment status in the electronic database 
will be listed as pending. Prior to enrollment in the electronic database, the eligibility worksheet 
must be reviewed and signed by the study coordinator and a Breast Center physician investigator, in 
accordance with Lester & Sue Smith Breast Center clinical research standard operating procedures. 
Eligibility data will then be entered in the electronic database and the subject will be randomized. 
 
Study treatment may begin only after eligibility has been confirmed by both a study coordinator and 
a Breast Center physician.  Once eligibility has been reviewed, it is recommended that treatment 
begin within a timely manner.  Although there is no protocol-required timeframe, every effort will 
be made to ensure that study treatment begins within 7-14 days of subject enrollment. 


Vitamin D for AIA 
17 
 
5.2 Eligibility exceptions 
Any requests for protocol exceptions must be approved in writing by the protocol chair, Dr. 
Mothaffar Rimawi or his designee at the Lester & Sue Smith Breast Center.  Request for protocol 
exceptions must be made via email or fax to the lead study coordinator.  Protocol chair or her 
designee should be copied on all requests and associated correspondence.  Exceptions will be 
granted in very limited circumstances if the protocol chair or her designee determine that it is in the 
best interest of the patient to participate and that the goals of the study will not be affected. Once a 
determination has been made, the requesting physician will be notified in writing.  In the event that 
an eligibility exception is granted, the requesting physician must submit the exception to the Baylor 
College of Medicine IRB in accordance with institutional standard operating procedures. 
Although every effort should be made to comply with study calendar and procedures will be made, 
on occasion, the protocol chair or her designee may allow patients to go the study on whose 
baseline studies fall slightly outside the specified windows. This will not constitute a protocol 
exception and need not be reported to the IRB. 
6. STUDY PROCEDURES 
Patients enrolled on study will have the following study assessments and procedures performed as 
described.  For a summary of required assessments, please refer to the study calendar in Appendix 
B. 
6.1 Screening and Baseline assessments 
A signed, written informed consent must be obtained before any study-specific assessments are 
initiated.  Results from assessments performed prior to written consent as part of a patient’s routine 
diagnostic workup may be used for screening purposes. The following assessments will be obtained 
at screening, within 28 days prior to beginning study medication: 
§ 
Subject demographic information, to include age, ethnicity, and race 
§ 
Medical history, including past and current conditions, and past surgical history 
§ 
Whether patient has used Hormone Replacement Therapy (HRT), for how many years, and 
how long ago she stopped.   
§ 
Use of chemotherapy, including taxanes or not including taxanes 
§ 
Measurement of body weight, height, and Body Mass Index 
§ 
Completion of Health Assessment Questionnaire (HAQ-II) 


Vitamin D for AIA 
18 
 
§ 
Grip strength measurement 
§ 
Laboratory assessments to include: 
– Calcium level 
– Albumin level 
– Vitamin D level -- serum 25(OH)D   
– FSH, LH, and estradiol levels must be obtained if required as detailed above in 4.1.4 
to determine menopausal status.  Menopausal status should be interpreted by the 
treating physician and approved by study chair based on the cutoff values provided 
by the reporting laboratory.  
§ 
Review of all medications taken within 28 days of planned treatment start date 
§ 
Study coordinator will educate the patient about the importance of compliance with 
Aromatase Inhibitor therapy. 
§ 
If a Bone Mineral density test has not been completed within 3 months of starting AI 
therapy, a Bone Mineral Density test must be ordered as a screening assessment, and the 
test must be completed within 28 days of starting Aromatase Inhibitor therapy 
If the above studies are within acceptable parameters as defined by the eligibility criteria, the 
patient will be randomized to begin either high dose Vitamin D or standard dose Vitamin D, as 
described in Section 7.  
6.2 Follow-up at Week 4 
The following assessments should be performed at 4 weeks (28 days) from the start of study 
medication.  To allow for weekends, holidays, etc., study procedures may be completed within a 
window of +/- 5 business days.   
§ 
Laboratory assessments to include a calcium level, 25-hydroxyvitamin D level, and albumin. 
6.3 Follow-up at Week 12 
§ 
Measurement of body weight and BMI 
§ 
Laboratory assessments to include a calcium level, 25-hydroxyvitamin D level, and albumin. 
§ 
Patient is to complete the Health Assessment Questionnaire (HAQ-II) 
§ 
Study coordinator will perform grip strength measurement, using the Smedley 
dynamometer, as described in Section 6.8.2 Grip Strength Measurement.    
§ 
Record all concomitant medications added and/or changed. 
§ 
Assess compliance to aromatase inhibitor therapy, as outlined in Section 6.8.3 


Vitamin D for AIA 
19 
 
§ 
Assess compliance to vitamin D treatment, as outlined in Section 6.10 
§ 
Non-serious and serious adverse events should be recorded and graded appropriately as 
discussed in section 9.6. 
§ 
Administration of study medications will continue as described in Section 6.9. 
6.4 Follow up at Weeks 24 and 36 
§ 
Laboratory assessments to include a calcium level, 25-hydroxyvitamin D level, and albumin. 
§ 
Record all concomitant medications added and/or changed. 
§ 
Assess compliance to aromatase inhibitor therapy by counting remaining pills in bottle, as 
per Section 6.8.3 
§ 
Assess compliance to vitamin D treatment, as outlined in section 6.10 
§ 
Non-serious and serious adverse events should be recorded and graded appropriately as 
discussed in Section 9.6. 
§ 
Administration of study medications will continue as described in Section 6.9. 
6.5 Follow up at week 52, and End of Treatment Visit 
The following assessments should be performed within five to ten business days of the completion 
of study therapy.  End of treatment is defined as Week 52.  These assessments should also be 
performed for patients who discontinue treatment prematurely (unless otherwise noted below).   
 
§ 
Measurement of body weight and BMI 
§ 
Laboratory assessments to include calcium level, 25-hydroxyvitamin D, and albumin. 
§ 
Patient is to complete the Health Assessment Questionnaire (HAQ-II) 
§ 
Grip strength measurement 
§ 
Record all concomitant medications added and/or changed. 
§ 
Assess compliance to aromatase inhibitor therapy 
§ 
Access compliance to vitamin D and calcium treatment 
Non-serious and serious adverse events should be recorded and graded appropriately as discussed 
in section 9.6. 
At this point, patients will have completed study treatment and should proceed with the completion 
of their adjuvant therapy, as determined by the treating physician.  Patients may take Vitamin D at 
any dosage they wish, at the discretion of the patient and the treating physician.   


Vitamin D for AIA 
20 
 
6.6 Safety Follow-up 
6.7 Upon completion of the therapeutic regimen, subjects will be followed for 
adverse events for a period of 30 days after the last dose of Vitamin D on 
study.  Patients with abnormal laboratory or clinical findings that are 
believed to be treatment related will be followed until the condition 
resolves, stabilizes, or until the laboratory values are no longer considered 
clinically significant.  New adverse events that occur during the 30 day 
follow-up period will only be recorded if the investigator believes there is a 
reasonable possibility that the adverse event is drug-related.  The safety 
follow-up may be conducted by a phone visit or a clinic visit; if clinically 
indicated, a clinic visit should be performed along with relevant lab work.  
Per standard of care and NCCN guidelines, bone density scan will be 
repeated, at the treating physician’s discretion, every 1-2 years while the 
patient is on AI therapy.  Per NNCN guidelines, patient will have DEXA scan 
every 2 years while on AI therapy, or every year if accelerated bone loss is 
suspected, or therapeutic intervention applied.    Duration of Follow-up 
All subjects will be followed for breast cancer recurrence at approximately 6-month intervals from 
the completion of the study period (52 weeks) to the completion of the five years of adjuvant 
therapy.  Follow-ups may be conducted by phone, email, or clinic visit, and will be discontinued in 
the event of subject death, recurrence, loss to follow up after at least 3 documented attempts to 
contact her, or withdrawal of consent.     
6.8 On Study Assessments and Procedures 
6.8.1 
Health Assessment Questionnaire 
Each subject will be asked to complete the Health Assessment Questionnaire (HAQ-II) at baseline, 12 
weeks, and 52 weeks.  The questionnaire will be completed in the office, during the clinic visit, and it 
will be administered by the study coordinator.  Generally, the questionnaire can be completed in 
less than 5 minutes by most patients.  The questionnaire will be available in English, Spanish, and 
Vietnamese.    


Vitamin D for AIA 
21 
 
6.8.2 
Grip Strength Measurement 
At baseline, and 12 weeks, and 52 weeks, the study coordinator will measure the patients’ grip 
strength using the Smedley Dynamometer.  The study coordinator will be trained on using the 
dynamometer.  They will be instructed to take 3 consecutive grip strength measurements on each 
hand, and they will use and record the highest result for each hand.   
6.8.3 
Compliance with AI therapy 
Compliance with aromatase inhibitor therapy will be evaluated by a physical pill count at the 
scheduled clinic visits on Weeks 12, 24, 36, and 52.  Subjects will be instructed to bring their used 
bottles of aromatase inhibitor to each return visit, along with any unused tablets.  Study staff will 
count the number of remaining tablets at each visit to assess compliance.  In the event that the 
subject forgets to bring their used study meds to their clinic visit, compliance will be assessed by 
direct questioning of the subject.  In this case, subjects should be counseled to bring their used drug 
bottles to their next scheduled clinic appointment so that compliance may be confirmed by pill 
count.  Subjects should be instructed to report any missed doses of aromatase inhibitor to the study 
coordinator. 
      Compliance with the aromatase inhibitor will be calculated by the ratio of number of pills 
actually taken to the number of pills that should have been taken.  Compliance will be defined as a 
ratio ≥ 0.80.  Study staff should ensure subject understanding of dosing instructions for subjects 
whose compliance is less than 100%.  In addition, the importance of compliance with anticancer 
therapy should be reinforced.  In the case of non-compliance, the study coordinator will ascertain, 
from the patient, the main reason for the non-compliance, and this will be recorded as study data.   
      Subjects who miss doses as a result of physician-prescribed drug holidays will not be considered 
non-compliant.  Calculation of the compliance ratio should thus be adjusted such that the “number 
of pills that should have been taken” reflects the drug holiday.   
6.9 Agent Administration 
6.9.1 
Vitamin D3, 5000 IU 
One half of the patients will be randomized to receive Vitamin D3 at a dose of 50,000 IU weekly for 
12 weeks, followed by 2000 IU of vitamin D3 daily for 40 additional weeks.  Patients will receive high 
dose vitamin D through the study, via 5000 IU capsules, which are available over the counter.  They 


Vitamin D for AIA 
22 
 
will receive this study medication after all screening assessments have been completed, and 
eligibility has been confirmed by the study coordinator.   
 
Patients should be carefully instructed by study personnel on how to take Vitamin D3.  Patients will 
be instructed to take Vitamin D, 50,000 IU (10 capsules) PO on a weekly basis, on the same day each 
week, and at approximately the same time each dose.  Vitamin D should be taken shortly after a 
meal.  Patients may take concomitant medications along with their Vitamin D dose, provided that 
the medications do not interact with vitamin D absorption (e.g.cholestyramine, orlistat, phenytoin, 
or phenobarbital).  Vitamin D3 at 50,000 IU per week will be provided for the patient by the study.  
This cost has been accounted for in the budget.  
6.9.2 
Vitamin D3, 2000 IU 
After completing 12 weeks of high dose vitamin D, the patients randomized to this arm will then 
complete 40 additional weeks of 2000 IU daily.  The pills are available in 2000 IU strength, and 
the patients will take 1 pill daily, with food.  Again, study personnel will instruct patients on how 
to take vitamin D, with the same instructions and precautions provided above, in Section 6.9.1. 
 
Vitamin D3 at this dosage is available over the counter at any retail pharmacy.  Patients will 
be provided with Schiff Vitamin D3 2000 IU Dietary Supplements, which are available at 200 pills for 
$14.00.  The study will cover this cost, and the research coordinator will dispense the medication at 
clinic visits as necessary.     
6.9.3 
Caltrate-D 
The patients who are randomized to the standard dose Vitamin D arm will take 1 Caltrate-D pill 
daily.  Each pill contains 600 mg of Calcium and 800 IU of Vitamin D3.  Patients will be instructed to 
take one pill daily, with food.  Again, the medicine will be provided to them by the study, at no cost 
to the patient.  Study personnel will instruct patients on how to take vitamin D, with the same 
instructions and precautions provided above, in Section 6.9.1. 
6.9.4 
Calcium, 600 mg 
Patients on the high dose Vitamin D arm will be asked to take over-the-counter Calcium supplement, 
as is recommended as standard of care.  This will not be supplied by the study, but patients will be 
instructed to take NatureMade Calcium 600 mg dietary supplement tablets – 1 tablet daily.   


Vitamin D for AIA 
23 
 
6.10 Compliance 
Compliance with Vitamin D supplementation in both arms will be assessed via the research 
coordinator counting remaining pills in the bottle at specified visits when compliance is assessed.  
(Compliance with AI therapy and with vitamin D supplementation will be assessed at all the same 
visits).  Compliance will be defined as having taken ≥80% of expected doses of Vitamin D.   
6.11 Prohibited Therapies 
Patients may not take additional Calcium and Vitamin D aside from the study medications.  Patients 
who are on cholestyramine or orlistat will not be allowed on the trial.  Also, patients who are taking 
phenytoin or phenobarbital are not allowed on the trial either because of interaction between 
Vitamin D and anti-epileptic medications.   
6.12 Discontinuation of Treatment 
In the event that study treatment is discontinued prematurely, subjects should undergo the study 
procedures as described in Section 6.5.    NOTE: Subjects who discontinue study therapy will still be 
included in the overall evaluation of response (intent-to-treat analysis), regardless of the reason for 
therapy discontinuation. Study treatment may be discontinued for any of the following reasons.   
§ 
Breast cancer recurrence or new breast cancer 
§ 
Failure of the subject to attend the majority of scheduled visits.  The protocol chair or her 
designee will determine when non-compliance with clinic visits should lead to removal from 
study.  
§ 
Lost to follow-up 
§ 
Withdrawal of consent. 
§ 
Unacceptable major toxicity, as determined by the treating investigator.   
§ 
Intercurrent illness or condition that would, in the judgment of the treating investigator, 
affect assessment of clinical status to a significant degree or require discontinuation of study 
treatment. 
§ 
At subject’s own request. Note: The reason for discontinuation from the study must be 
documented.  


Vitamin D for AIA 
24 
 
§ 
Study is closed for any reason (e.g. new information shows that the patient’s welfare would 
be at risk if she continued study treatment). 
§ 
General or specific changes in the participant's condition which render the 
participant unacceptable for further treatment in the opinion of the treating 
investigator physician. 
§ 
25-hydroxyvitamin D level exceeds 120 ng/mL at any point during the study 
§ 
25-hydroxyvitamin D level is persistently >70 ng/mL, as outlined in Section 8.1. 
§ 
Corrected calcium level >11.0 mg/dL on any measurement during the study, or 
corrected calcium level >10.5 mg/dL on three consecutive measures, as outlined 
in Section 8.1. 
§ 
Symptomatic hypercalcemia which warrants discontinuation, at the discretion of 
the treating investigator physician, with symptoms including but not limited to 
confusion, lethargy, constipation, nausea/vomiting, abdominal pain, or muscle 
weakness. 
§ 
Development of symptomatic calcium-based renal stones 
6.13 Withdrawal from Study 
Subjects may be withdrawn from follow-up for the following reasons: 
§ Subject withdraws consent for follow-up. 
§ Subject is lost to follow-up (after at least three documented attempts to contact 
her). 
§ Study is terminated for any reason. 
§ Subject death 
6.14 Criteria for Removal from the Study 
Participants will be removed from study when any of the criteria listed in Section 6.12 applies.  All 
patients who are randomized in the study will be included in the overall evaluation of response 
(intent-to-treat analysis). All reasons for discontinuation of therapy should be documented clearly in 
the medical record. 


Vitamin D for AIA 
25 
 
6.15 Subject compensation  
Participation in this trial is entirely voluntary.  No cash compensation shall be provided for 
participants.  However, subjects may be given parking vouchers for study-specific visits, in 
accordance with Lester & Sue Smith Breast Center clinical research standard operating procedures. 
7. DRUG FORMULATION/STORAGE/SUPPLY 
7.1 Vitamin D3, 5000 IU 
Vitamin D3 at 5,000 IU strength is available over the counter at most retail pharmacies, and it will be 
supplied to patients through the study.  They will be instructed to take 10 capsules one day each 
week, as described above in section 6.9.1, so that total dose is 50,000 IU weekly.  The pills will be 
stored at controlled room temperature 15° to 30° C (59° to 86° F), in an appropriately labeled bin 
which is housed in a locked closet within the locked pharmacy.  
7.2 Vitamin D3, 2000 IU 
Vitamin D3 at 2000 IU strength is available over the counter at most retail pharmacies.  The patients 
on the high dose arm will be provided with this medication for weeks 13-52 of the study.  The pills 
will be stored at controlled room temperature 15° to 30° C (59° to 86° F), in an appropriately labeled 
bin which is housed in a locked closet within the locked pharmacy.  
7.3 Caltrate-D, Calcium 600 mg & Vitamin D3 800 IU 
The patients on the standard dose arm will be provided with this medication throughout the study.  
The pills will be stored at controlled room temperature 15° to 30° C (59° to 86° F), in an 
appropriately labeled bin which is housed in a locked closet within the locked pharmacy.  
7.4 Drug Accountability 
The investigator is responsible for accountability, reconciliation, and record maintenance of the 
study drugs (all doses of Vitamin D mentioned in sections 7.1-7.3).  In accordance with all applicable 
regulatory requirements, the investigator or designated site staff must maintain investigational 
product accountability records throughout the course of the study.  The responsible person(s) will 
document the amount of study drug supplied to and returned by patients. 
 


Vitamin D for AIA 
26 
 
8. DOSING DELAYS/DOSE MODIFICATIONS 
8.1 Dose Modifications/Delays 
For any patient in the study, if 25-hydroxyvitamin D level exceeds 120 ng/mL at any point, the 
patient will be taken off the study medication.  If the 25 (OH)D level is >90 ng/mL, we will hold the 
vitamin D supplementation for 4 weeks, and then recheck vitamin D level.  If it is <70 ng/mL after 4 
weeks, the patient may resume vitamin D at 50,000 IU every other week if the patient was on the 
lead-in phase of the high dose arm.  If the patient was on the continuation phase of the high dose 
arm, she would instead take 1000 IU/day.  If the patient was on the standard dose arm, she would 
take Caltrate-D once every other day.  If the 25-hydroxyvitamin D level did not fall to <70 ng/mL 
after 4 weeks of a drug holiday, then the vitamin D will be held for an additional 4 weeks.  At the 
end of this 8 week period, patients will resume reduced vitamin D dosing as described above if the 
level has fallen to <70 ng/mL.  However, if the level is still ≥70 ng/mL, then the patient will be taken 
off the study medication.   
Similarly, if the calcium level is >11.0 mg/dL at any time during the study, the patient will be taken 
off the study.  If the calcium level is between 10.5 and 11.0 mg/dL, the patient may follow the same 
vitamin D reduction schedule outlined above in which the vitamin D supplementation is held for 4 
weeks, and may only be resumed at half dose if the calcium level is within normal limits, according 
to reference lab values.  If the calcium level has not normalized after 8 weeks of drug holiday, then 
the patient will be taken off the study medication.     
8.2 Special Considerations 
The 25-hydroxyvitamin D levels which are checked in the study are not revealed to the patient and 
doctor unless they specifically request that information, or if any of the calcium or Vitamin D levels 
exceed the pre-specified threshholds laid out in Section 8.1.  However, if the physician or patient 
wishes to know her vitamin D level, they may obtain this information from the study coordinator.  
For those who are on the standard dose vitamin D arm and have vitamin D <20 ng/mL, the physician 
may choose to replace vitamin D levels with 4000 IU of vitamin D3 daily, beginning at any point after 
12 weeks of study enrollment.  Vitamin D level will be checked every 4 weeks until it is ≥30 mg/mL.  
At that point, the patient will resume Caltrate-D once daily for the remainder of the study period. 
9.   ADVERSE EVENTS & SAFETY MONITORING 


Vitamin D for AIA 
27 
 
9.1 General 
Adverse event collection and reporting is a routine part of every clinical trial. This study will use the 
descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
version 4.0 (CTCAE v4.0) that is available at http://ctep.cancer.gov/reporting//ctc.html.  
 
Information on certain adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections.  
 
Adverse events experienced by participants will be collected and reported from initiation of study 
medication, throughout the study, and within 30 days of the last dose of study medication. 
Participants who experience an ongoing adverse event related to a study procedure and/or study 
medication beyond 30 days will continue to be contacted by a member of the study team until the 
event is resolved, stabilized, or determined to be irreversible by the participating investigator.  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably be 
related to participation in this study. The investigator should notify the IRB and any other applicable 
regulatory agency of any unanticipated death or adverse event occurring after a participant has 
discontinued or terminated study participation that may reasonably be related to the study.  
9.2 Definitions 
9.2.1 
Adverse Event (AE) 
An adverse event is any undesirable sign, symptom or medical condition or experience that develops 
or worsens in severity after starting the first dose of study treatment or any procedure specified in 
the protocol, even if the event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests.  
9.2.2 
Serious adverse event (SAE) 
A serious adverse event is an undesirable sign, symptom, or medical condition which: 
§ 
is fatal or life-threatening; 


Vitamin D for AIA 
28 
 
§ 
requires or prolongs inpatient hospitalization; 
§ 
results in persistent or significant disability/incapacity; 
§ 
constitutes a congenital anomaly or birth defect; or 
§ 
jeopardizes the participant and requires medical or surgical intervention to prevent one of 
the outcomes listed above.  
§ 
Any other event, which, in the opinion of the investigator, could be considered serious. 
 
Events not considered to be serious adverse events are hospitalizations for: 
§ 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
§ 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
§ 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
§ 
respite care 
9.2.3 
Expectedness  
§ 
Expected:  Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an adverse event 
is considered expected when it appears in the current adverse event list, the Investigator’s 
Brochure, the package insert or is included in the informed consent document as a potential 
risk. 
§ 
Unexpected:  An adverse event is considered unexpected when it varies in nature, intensity 
or frequency from information provided in the current adverse event list, the Investigator’s 
Brochure, the package insert or when it is not included in the informed consent document 
as a potential risk 
9.2.4 
Attribution  
The investigator will determine the relationship of each adverse event, if any, to investigational 
treatment or study procedure.  Causality should be assessed using the following categories: 
Unrelated, Unlikely, Possible, Probable, or Definite.   
 


Vitamin D for AIA 
29 
 
The degree of certainty with which an adverse experience is attributed to drug treatment (or 
alternative causes, e.g. natural history of the underlying diseases, concomitant therapy, etc.) will be 
determined by how well the experience can be understood in terms of the following: 
§ 
Known pharmacology of the drug 
§ 
Reaction of similar nature being previously observed with this drug or class of drug 
§ 
The event having often been reported in literature for similar drugs as drug related (e.g. skin 
rashes, blood dyscrasia) 
§ 
The event being related by time to drug administration terminating with drug withdrawal 
(dechallenge) or reproduced on rechallenge. 
 
The investigator may change his/her assessment of causality in light of follow-up information.  All 
adverse events will be recorded, regardless of whether the event is thought to be related to 
investigational treatment.  Attribution will be assigned as follows: 
 
§ 
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. 
9.3 Anticipated Toxicities 
If Vitamin D levels are allowed to become too high, hypercalcemia is the most common side effect.  
Symptoms may include anorexia, nausea, vomiting, abdominal pain, confusion, lethargy, 
constipation, muscle weakness, weight loss, polyuria, kidney stones, and heart arrhythmias.   
9.4 Toxicity Management 
Calcium and 25-hydroxyvitamin D levels will be followed closely while the patients are on study to 
avoid hypervitaminosis D.  Levels of 25-hydroxyvitamin D and calcium will be monitored and 
managed as outlined in Section 8.1.  For corrected calcium level greater than 11 g/dL, management 
will be according to standard of care and the judgment of the treating physician. It is recommended 
that the patient be hydrated with one liter of IV normal saline, and given one dose of pamidronate 
at 90 mg IV, if renal function is within normal limits.  The use of calcitonin will be at the treating 


Vitamin D for AIA 
30 
 
physician’s discretion.  The patient will be followed closely and treated until the calcium level 
normalizes.  The patient will not be re-challenged with the study medication in this case.   
If the patient develops calcium kidney stones, she will also be taken off the study.  She will be 
referred to her primary care physician and/or urology for further management of the kidney stones.   
9.5 Adverse event follow-up 
Investigators should follow-up subjects with adverse events until the event has subsided 
(disappeared) or until the condition has stabilized.  Subjects will be followed for adverse events and 
serious adverse events for 30-days from the last dose of study drug.   
 
During the 30-day follow-up period, new onset, non-serious adverse events should only be recorded 
if, in the opinion of the investigator, there is a reasonable possibility the event is attributable to the 
investigational product.  All serious adverse events occurring within the 30-day follow-up period 
must be reported, regardless of suspected causality. 
9.6 Reporting Procedures 
9.6.1 
General 
Adverse events will be captured in both the source documents and on the appropriate study-specific 
case report forms (CRFs).  Given that each of the medications being utilized in this trial has a well-
established safety profile, this protocol will utilize targeted AE reporting for all non-serious adverse 
events, as described below. 
9.6.2 
     AE reporting requirements 
▪ AE of any grade that requires a modification to treatment (e.g. dose modification, dose 
delay, or drug discontinuation) 
▪ All grade 3 and 4 AEs, regardless of causality 
▪ Any clinically significant laboratory abnormality, as defined in section 8.1 
▪ All serious adverse events (SAEs), as defined in section 8.1 
  
9.6.3 
Serious Adverse Events 
Any serious adverse events that occur during the clinical study or within 30 days of receiving the last 
dose of study medication, whether or not related to the study drug, must be reported by the 


Vitamin D for AIA 
31 
 
investigator. In addition, any SAEs which occur as a result of protocol specific diagnostic procedures 
or interventions must also be reported. 
 
All serious adverse events must be reported to the PI within 1 business day of becoming aware of 
the event. The protocol chair will then report SAEs to the Baylor College of Medicine IRB, in 
accordance with standard operating procedures.  Events should be reported using a MedWatch 
form (FDA Form 3500), which is available for download on the FDA website.   
 
The SAE report should comprise a full, written summary detailing relevant aspects of the adverse 
events in question.  Where applicable, information from relevant hospital case records and autopsy 
reports should be included.  Follow-up information and follow-up reports should be forwarded to all 
appropriate entities within 24 hours.  
 
Instances of death, if brought to the attention of the investigator AT ANY TIME after cessation of 
study medication, and linked by the investigator to a previous clinical trial, should be reported to the 
FDA. 
 
The PI will disseminate information regarding serious adverse events to the participating 
investigators within 5 days of review of the information by the Protocol Chair (or designee in the 
event of extended absence) only in the case that the event(s) is believed to be related (i.e., possibly, 
probably, or definitely) to the study medication.   
9.6.4 
Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current institutional 
standards. If an adverse event requires modification of the informed consent, these modifications 
will be provided to the IRB with the report of the adverse event. If an adverse event requires 
modification to the study protocol, these modifications will be provided to the IRB as soon as 
possible. 
9.6.5 
Food and Drug Administration (FDA) 
In this trial, unexpected adverse events believed to be definitely, probably, or possibly related to the 
medications will be reported to the Food and Drug Administration via MedWatch (using the online 


Vitamin D for AIA 
32 
 
form available at https://www.accessdata.fda.gov/scripts/medwatch/; by telephone 1-800-FDA-
1088; or by fax 1-800-FDA-0178.  FDA Form 3500A — Mandatory Reporting, available at: 
 http://www.fda.gov/medwatch/report/hcp.htm).  
 
10.  CORRELATIVE/SPECIAL STUDIES 
10.1 Grip Strength 
To further investigate whether grip strength may serve as a simple, objective measure of AIA, we 
will measure grip strength at baseline, week 12 and week 52 visits (see study Calendar in Appendix 
B), and see whether changes in grip strength do correlate with changes in joint pain, as represented 
in the HAQ score.  Research coordinators will measure grip strength as outlined in Section 6.8.2.    
11.  SPECIMEN BANKING 
Any leftover study blood samples may be stored for future research studies.  The subjects will 
consent to the future use of samples in the consent form for the study.  All samples will be stored 
indefinitely in the Lester & Sue Smith Breast Center Tumor Bank, located at One Baylor Plaza, 
Houston TX 77030.  Samples will not contain any traditional patient identifiers; however, samples 
will be coded such that specimens are traceable back to the patient.  The link between the specimen 
code and the patient will be maintained in a secure area, accessible only to the Tissue Bank 
Coordinator.  Samples will only be released for use in future studies after approval by the protocol 
chair and other regulatory bodies, as appropriate.  The samples will not be sold to third parties.   
12.  MEASUREMENT OF EFFECT 
The primary assessments for this study will be the average score on the Health Assessment 
Questionnaire (HAQ-II), as well as the score from the visual analog scale.   
12.1 Definitions 
12.1.1 Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their 
first treatment with Vitamin D.   
12.1.2 Evaluable for response: All the patients who have been randomized will be considered 
evaluable for response, regardless of how much treatment they have received, 


Vitamin D for AIA 
33 
 
consistent with an intention to treat analysis. These patients will have their response 
classified according to the definitions stated below.   Any patient who began the study 
medication, but does not complete the HAQ at 12 weeks, will be deemed to be a study 
failure (i.e. the development of AIA will be assumed), consistent with an intention to 
treat analysis.    
12.2 Measurement of Aromatase Inhibitor-Induced Arthralgia 
    Many trials which specifically examine AIA or other joint pathologies use a widely validated clinical 
tool termed the Health Assessment Questionnaire (HAQ-II).  It is commonly used in rheumatology 
literature, and has been substantiated across many trials.  This is a simple survey, which is a proven, 
reliable, and accurate indicator of joint pains and consequent disabilities (14) (15).  An abbreviated 
version of the HAQ-II, which takes about 5 minutes to complete, will be used in the study (see 
Appendix A). 
 
This questionnaire asks 20 questions in 8 categories of functioning:  dressing, rising, eating, 
walking, hygiene, reach, grip, and usual activities.  For each question, the patient is scored on a scale 
of 0-3, depending on how much difficulty they have performing the task.  A score of 0 correlates 
with no difficulty at all, and a score of 3 denotes that the patient is unable to do the task.  The 
highest numerical score from each category is used, and the average of these 8 numbers is the 
composite score on the HAQ-II.  Scores of 0-1 are considered to represent mild to moderate 
difficulty, 1-2 represents moderate to severe disability, and 2-3 represents severe to very severe 
disability.  Average score in a population based study is 0.49, whereas patients with osteoarthritis 
and rheumatoid arthritis have average scores of 0.8 and 1.2, respectively.  Most investigators agree 
that “minimal clinical important difference” is 0.2 (42).  Thus, the study uses this as a cut-off point.   
The visual analog scale is the other major component of the HAQ-II.  In this, the patient is 
asked to mark, with a vertical line, where their pain lies on a horizontal line which is 15 cm long, 
with the far left side of the line representing no pain at all, and the far right side representing 
unbearable pain.  To obtain the individual’s score, the distance between the far left side of the line 
and the patient’s mark is multiplied by 0.2. This converts the number of centimeters into the 
appropriate score and will yield a value from 0 to 3. 
 
For the purposes of this study, AIA will be defined as any of the following criteria:  1) 
increase in HAQ-II score from baseline by 0.2 or greater; or 2) increase in visual analog pain score by 
0.3 or greater.  The HAQ-II questionnaire and its visual analog pain score are used in the definition of 


Vitamin D for AIA 
34 
 
AIA because the questionnaire has been validated through many other studies which examine joint 
pain, and it is very simple to do in the office in less than 5 minutes.  Though grip strength will be 
measured at various time points throughout the study, it will only be used in the exploratory 
analysis to see whether it may be an appropriate measure for AIA.  Grip strength measurement is a 
relatively easy, inexpensive, objective criteria which may help to more clearly define AIA.  This data 
will be very useful in the future, as it may serve to support a clearer, more objective definition of AIA 
for use in future studies, and for use in clinical practice.  
12.3  Compliance with AI therapy 
 
Compliance with aromatase inhibitor therapy will be evaluated by a physical pill count at the 
scheduled clinic visits on Weeks 12, 24, 36, and 52.  Subjects will be instructed to bring their used 
bottles of aromatase inhibitor to each return visit, along with any unused tablets.  Study staff will 
count the number of remaining tablets at each visit to assess compliance.  In the event that the 
subject forgets to bring their used study meds to their clinic visit, compliance will be assessed by 
direct questioning of the subject.  In this case, subjects should be counseled to bring their used drug 
bottles to their next scheduled clinic appointment so that compliance may be confirmed by pill 
count.  Subjects should be instructed to report any missed doses of aromatase inhibitor to the study 
coordinator. 
 
Compliance with the aromatase inhibitor will be calculated by the ratio of number of pills 
actually taken to the number of pills that should have been taken.  Compliance will be defined as a 
ratio ≥ 0.80.  Study staff should ensure subject understanding of dosing instructions for subjects 
whose compliance is less than 100%.  In addition, the importance of compliance with anticancer 
therapy should be reinforced.  In the case of non-compliance, the study coordinator will ascertain, 
from the patient, the main reason for the non-compliance, and this will be recorded as study data.   
 
Subjects who miss doses as a result of physician-prescribed drug holidays will not be 
considered non-compliant.  Calculation of the compliance ratio should thus be adjusted such that 
the “number of pills that should have been taken” reflects the drug holiday.   
13. STATISTICAL CONSIDERATIONS 
13.1 Study Design/Endpoints   
The primary endpoint will be development of aromatase inhibitor induced arthralgia.  Secondary 
endpoints will be compliance with aromatase inhibitor therapy and baseline vitamin D level.  


Vitamin D for AIA 
35 
 
Exploratory endpoints will be grip strength and breast cancer recurrence.  Women on the study will 
be randomized to receive either high dose vitamin D or standard dose vitamin D for a total of 52 
weeks (see attached Schema).  All women will have their arthralgia and vitamin D levels assessed 
periodically throughout the study.   
13.2 Sample Size/Accrual Rate 
The primary objective of this study is to determine if supplementation of high dose Vitamin D 
prevents AIA in women being treated with adjuvant aromatase inhibitors.  The Health Assessment 
Questionnaire II (HAQ-II) will be used to assess joint pain symptoms.  Previously published estimates 
of AIA incidence showed that 33% of women on standard dose of vitamin D, and 19% of women on 
a high dose of vitamin D, developed AIA (43).  Assuming a one-sided test with α=0.10, β=0.20, we 
would need 93 women in each arm to detect a different rate of AIA development using the Chi- 
square test.  Assuming 5% dropout rate in the first 12 weeks, we will accrue 93 women to each arm, 
for a total of 186 women.  Sample size calculations were conducted using nQuery Advisor 7.0, 
Statistical Solutions, USA.  Given that there are over 8000 office visits each year in our Baylor Clinic 
and Smith Clinic, we should easily be able to recruit an average of 4-6 women/month to the study, 
which would allow us to complete accrual in approximately 3 years.   
13.3  Guidelines for Lead Institution and Other Site Institutions 
 Patients should be registered in the electronic database, ONCORE as soon as the patient has signed 
the informed consent. Following registration, the patient’s enrollment status in the electronic 
database will be listed as pending. Prior to randomization the eligibility criteria must be reviewed 
and confirmed by the site PI and the coordinating center.  Eligibility data will then be entered in the 
electronic database and the subject will be randomized. Study treatment may begin only after 
eligibility has been confirmed by both a site PI and the coordinating center. Once eligibility has been 
reviewed, it is recommended that treatment begin within a timely manner.  
13.3 Eligibility exceptions  
Any requests for protocol exceptions must be approved in writing by Dr. Mothaffar Rimawi at the 
Lester & Sue Smith Breast Center. Request for protocol exceptions must be made via email or fax to 
the lead study coordinator. Both Dr. Rimawi and the local PI should be copied on all requests and 
associated correspondence. Once a determination has been made, the site study coordinator and 
local PI will be notified in writing. In the event that an eligibility exception is granted by the 


Vitamin D for AIA 
36 
 
coordinating center, the local site must submit the exception to their local IRB in accordance with 
institutional standard operating procedures. 
13.4 Primary Endpoint 
Descriptive and summary statistics will be computed for all demographic and clinical data in each 
treatment group.  The HAQ-II will be used to assess joint pain symptoms; a higher score indicates 
more severe joint pain.  Scores will be evaluated for the development of AIA between baseline and 
Week 12, as well as between baseline and Week 52, though development of AIA at 12 weeks will be 
the primary endpoint.  The scores will be dichotomized as “development of AIA” (as defined above, 
in Section 12.2) or “no development of AIA.”  Group differences in AIA rate will be assessed using 
the Chi-square test.  Development of AIA at week 12 will be used to test the primary objective.  The 
week 52 data will be measured and reported as well.  As exploratory analyses, development of AIA 
will be assessed using logistic regression, adjusting for potential confounders such as age at 
diagnosis, race/ethnicity, BMI, receipt of chemotherapy, taxane use, and use of hormone 
replacement therapy.  All statistical tests are one-sided with α =0.10 as the level of significance.   
13.5 Secondary Endpoints 
Compliance will be determined via counting remaining pills in patient’s bottles at weeks 12, 24, 36, 
and 52 weeks.  Compliance rate over 52 weeks of AI therapy will be compared between the two 
arms using longitudinal data analysis.  The association between low baseline vitamin D levels and 
AIA will be assessed using the multivariate logistic regression model with adjusting for treatment 
effect and other confounding factors.  
13.6 Exploratory Endpoints 
For each patient on the study, grip strength will be correlated with AIA score using logistic 
regression analysis and Spearman correlation at three time points throughout the study – baseline, 
week 12, and week 52.    At five years, we will also compare breast cancer recurrence rates in each 
arm using Kaplan-Meier survival analysis and log-rank test.   
13.7 Futility Analysis 
One interim analysis will be added to the study. It is expected to take place half-way through 
the study after 46 patients in each of the treatment group are enrolled and evaluable for the 
primary endpoint. The purpose of the interim analysis is to allow the study to stop early for lack of 
efficacy (futility). A non-binding O’Brien-Fleming spending function is used to calculate the futility 
boundary. Calculations were performed using nQuery Advisor + nTerim 3.0 (Statistical Solutions. 
Boston, MA).  


Vitamin D for AIA 
37 
 
The following table summarizes the futility boundary at each analysis when 50% and 100% 
patients are enrolled and evaluable at the interim analysis and the final analysis. The futility 
boundary in the term of p-value scale at the interim analysis is calculated as p=0.47 (or Z=0.076). If 
the one-tailed p-value exceeds 0.47, it will be recommended that the trial stop for futility.  
Looks  
Information  
n per group 
Futility Boundary  
(Z value) 
Futility Boundary  
(one-tailed p value) 
1 
50% 
46 
0.076 
0.47 
2 
100% 
93 
1.28 
0.05 
 
In order to preserve power and compensate for the interim futility analysis which tends to 
reduce power, the sample size of the study is increased from 88 per group to 93 per group, which is 
196 total if considering a 5% drop out rate.  
 
14. DATA AND SAFETY MONITORING 
14.1 Data Management and Reporting 
All patients who received any amount of study drug will be included in the safety analysis.  Subjects 
will be monitored at each clinic visit and at any contact with the subject throughout the study for 
the occurrence of AEs and SAEs. The investigator or site staff will inquire about the occurrence of 
AEs/SAEs at weeks 12, 24, 36, and 52.  Adverse events will be graded according to the NCI Common 
Terminology Criteria v. 4.0.   All relevant AE's, as described in Section 9.6, that occur during active 
treatment will be recorded in subject source documents and on CRFs, regardless of relationship to 
investigational treatment.  Non-serious adverse events that occur within the 30 day follow-up 
period will only be recorded on the CRFs if the investigator believes there to be a possible 
relationship to study medication.   Serious adverse events should be recorded, regardless of 
relationship to drug. 
Safety analyses will include summaries of adverse event rates (both frequency and incidence tables), 
baseline laboratory parameters and changes from baseline, frequency of CTC toxicity grades for 
both laboratory and non-laboratory data. The investigators and others responsible for patient care 
at individual sites should institute any supplementary investigations of major adverse events based 
on their clinical judgment of the likely causative factors. 


Vitamin D for AIA 
38 
 
14.2 Meetings  
We will utilize the Data and Safety Monitoring Plan of the Dan L. Duncan Cancer Center at Baylor 
College of Medicine. During the clinical trial, clinical data on all participants enrolled on the study 
will be reviewed in our monthly breast center Data and Safety Monitoring Meeting.  
We will have the trial reviewed at our Data Review Committee which will review accruals, serious 
adverse events, and cumulative toxicity data. The DRC will make recommendations about safety and 
tolerability. 
15.  REGULATORY CONSIDERATIONS 
15.1 Protocol Review and Amendments 
 
Information regarding study conduct and progress will be reported to the Institutional 
Review Board (IRB) per the current institutional standards of each participating center.  Any changes 
to the protocol will be made in the form of an amendment and must be approved by the IRB of each 
institution prior to implementation.  The Protocol Chair (or his designee) is responsible for the 
coordination and development of all protocol amendments, and will disseminate this information to 
the participating centers. 
15.2 Informed Consent 
 
An investigator will explain to each subject the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved and any 
discomfort it may entail.  Each subject will be informed that participation in the study is voluntary, 
that s/he may withdraw from the study at any time, and that withdrawal of consent will not affect 
her subsequent medical treatment or relationship with the treating physician(s) or institution.  The 
informed consent will be given by means of a standard written statement, written in non-technical 
language, which will be IRB approved.  The subject should read and consider the statement before 
signing and dating it, and will be given a copy of the document.  No subject will enter the study or 
have study-specific procedures done before his/her informed consent has been obtained. 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written informed consent document (or a separate document to be given in conjunction with the 
consent document) will include a subject authorization to release medical information to the study 
investigator and supporting agencies and/or allow these bodies, a regulatory authority, or 


Vitamin D for AIA 
39 
 
Institutional Review Board access to subjects’ medical information that includes all hospital records 
relevant to the study, including subjects’ medical history. 
 
15.3 Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
16. MULTI-CENTER GUIDELINES 
16.1 Study Documentation  
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Coordinating Center. The required documents include, but are not 
limited to the following: local IRB approvals (i.e., protocol, consent form, amendments, patient 
brochures and recruitment material, etc.), IRB membership rosters, summary of unanticipated 
problems or protocol deviations, and documentation of expertise of the investigators. The 
Coordinating Center will provide each participating site with a comprehensive list of the 
necessary documents. It is the responsibility of the participating sites to maintain copies of all 
documentation submitted to the Coordinating Center. 
 
The requirements for data management, submissions, and monitoring are outlined below. 
 
All data collected will be entered by the participating site into the Coordinating Center 
Electronic Database (eCRF), via ONCORE. 
16.2 Records Retention  
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location. Records must be maintained for at least 5 years following 


Vitamin D for AIA 
40 
 
the conclusion of the study, or in accordance with institutional policy, whichever is longer. The 
Coordinating Center will inform the investigator at each site at such time that the records may 
be destroyed. 
16.3 Publication  
It is understood that any manuscript or releases resulting from the collaborative research will 
be circulated to all participating sites prior to submission for publication or presentation. 
 
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management of AI associated joint symptoms in women with early stage breast cancer. Journal 
of Clinical Oncology. March 2010;28(7):1154-1160. 
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aromatase inhibitor-induced arthralgia in patients with breast cancer. Anticancer Res. June 
2012;32(6):2331-36. 
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29. Briot K, Tubiana-Hulin M, Bastit L, Kloos I, Roux C. Effect of a switch of aromatase inhibitors on 
musculoskeletal symptoms in postmenopausal women with hormone-receptor-positive breast 
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30. Muslimani A, Spiro T, Chaudhry A, Taylor H, Jaivesimi I, Daw H. Aromatase Inhibitor related 
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32. Chlebowski R. Vitamin D and breast cancer: interpreting current evidence. Breast Cancer Res 
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33. Coleman R, Rathbone E, Marshall H, Wilson C, Brown J. Vitamin D, but not bone turnover 
markers, predict relapse in women with early breast cancer: an AZURE translational study. Paper 
presented at: Cancer Res, 2012. 
34. Chlebowski R, Johnson K, Lane D, et al. 25-hydroxyvitamin D concentration, vitamin D intake and 
joint symptoms in postmenopausal women. Maturitas. Jan 2011;68(1):73-8. 
35. Heidari B, Shirvani J, Firouzjahi A, Heidari P, Hajian-Tilaki K. Association between nonspecific 
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importance of diagnosis and treatment of hypovitaminosis D. BMC Fam Pract. 2006;7:4-11. 
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National Academies Press; 2011. 
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associated with better lower extremity function in both active and inactive persons aged >60 
years. Am J clin Nutr. Sep 2004;80(3):752-58. 
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aromatase 
inhibitors 
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symptoms: 
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chemoprevention study using anastrazole. Breast Cancer Res Treat. April 2012;132(2):625-29. 
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markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation. 
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42. Bruce B, Fries J. The Stanford Health Assessment Questionnaire: Dimensions and Practical 
Applications. Health and Quality of Life Outcomes. June 2003;1(20):1-6. 


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43 
 
43. Khan Q, Reddy P, Kimler B, et al. Effect of Vitamin D supplementation on serum 25 hydroxy 
vitamin D levels, joint pains, and fatigue in women starting adjuvant letrozole treatment for 
breast cancer. Breast Cancer Research and Treatment. 2010;119:111-118. 
44. Presant C, Bosserman L, Young T, et al. Aromatase inhibitor-associated arthralgia and/or bone 
pain: frequency and characterization in non-clinical trial patients. Clin Breast Cancer. Oct 
2007;7(10):775-8. 
45. Crew K, Capodice J, Greenlee H, et al. Randomized, Blinded, Sham-Controlled trial of 
acupuncture for the management of AI associated joint symptoms in women with early stage 
breast cancer. Journal of Clinical Oncology. March 2010;28(7):1154-1160. 
46. Bruce B, Fries J. The Stanford Health Assessment Questionnaire: dimensions and practical 
applications. Health Qual Life Outcomes. June 2003;1(20). 
47. van Groen M, ten Klooster P, Taal E, van de Laar M, Glas C. Application of the health assessment 
questionnaire disability index to various rheumatic diseases. Qual Life Res. Nov 2010;19(9):1255-
63. 
 
18. Appendix A:  Health Assessment Questionnaire (HAQ) 


Vitamin D for AIA 
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Vitamin D for AIA 
45 
 
 
 
 
 


Vitamin D for AIA 
Protocol version: 14-JUL-2015 
Page 46 of 47 
 
 
APPENDIX B       STUDY CALENDAR 
Study Procedure 
Baseline 
(- 28 d) 
Week 
4 
Wk 12 
W 
24 
W 
36 
W 
52 
EOT 
Safety Follow-up2 
(+/- 7 d) 
Follow-up for 
recurrence3 
(+/- 30 d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Body weight measurement 
X 
 
X 
X 
X 
X 
X 
 
 
Health Assessment 
Questionnaire 
X 
 
X 
 
 
X 
X 
 
 
Grip Strength Measurement 
X 
 
X 
 
 
X 
X 
 
 
Review concomitant meds 
X 
 
X 
X 
X 
X 
X 
 
 
Bone Mineral Density Test4 
X 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
 
 
X 
X 
X 
X 
X 
X 
 
Assess compliance1 
 
 
X 
X 
X 
X 
X 
 
 
Assess disease & vital status 
 
 
 
 
 
 
 
 
X 
Calcium, Albumin, and 
25(OH) Vit D levels 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Compliance assessment as determined by pill count and/or pill diary. 
2. 
A safety follow-up should be performed 30 days after the last dose of study medication, even in the event of early discontinuation.  Physical exam and  
laboratory assessments need only be performed if clinically indicated.  
3. 
Recurrence follow ups will be performed every 6 months for the 4 years following the completion of the 52 week study period.   


Vitamin D for AIA 
Protocol version: 14-JUL-2015 
Page 47 of 47 
 
Study Procedure 
Baseline 
(- 28 d) 
Week 
4 
Wk 12 
W 
24 
W 
36 
W 
52 
EOT 
Safety Follow-up2 
(+/- 7 d) 
Follow-up for 
recurrence3 
(+/- 30 d) 
4. 
  The Bone Mineral Density test must be ordered as a screening assessment, and results must be available within 28 days of starting AI therapy.  If 
not completedwithin 28 days, patient will be taken off trial.