A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase Inhibitors (AI) Associated Musculoskeletal Symptoms in Women With Early Stage Breast Cancer
Phase: NA
Conditions: Relief of Joint Pain
Sponsor: Texas Tech University Health Sciences Center, El Paso

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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Title: A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer 
 
Principal Investigator: 
Zeina Nahleh, M.D., F.A.C.P. 
Professor of Medicine and Biomedical Sciences 
Chief, Division of Hematology-Oncology 
Department of Internal Medicine 
Co-Director, Garbar Breast Care Center 
Paul L. Foster School of Medicine 
4800 Alberta Avenue 
El Paso, TX  79905 
(915) 215-5195 (Office) 
 
(915) 545-6634 (Fax) 
Zeina.nahleh@ttuhsc.edu 
 
 
Co-Investigators: 
Rosalinda Heydarian, ANP 
TTUHSC-PLFSOM 
Department of Internal Medicine 
 
Sumit Gaur, M.D. 
Department of Internal Medicine 
 
RESEARCH SUPPORT STAFF: 
Alok Dwivedi, Ph.D., Biostatistician 
TTUHSC-PLFSOM 
Department of Biostatistics 
 
Cecilia Ochoa, M.P.H., Study Coordinator 
Cancer Clinical Research Core 
TTUHSC 
 
Danielle Liss, B.S., Study Coordinator 
Cancer Clinical Research Core 
TTUHSC 
 
Luis Sanchez, B.A., Research Assistant 
Cancer Clinical Research Core 
TTUHSC 
 
Aleli Campbell, M.S., Study Coordinator 
Cancer Clinical Research Core 
TTUHSC 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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Table of Contents 
 
 
 
 
 
 
 
 
 
Page 
 
Summary...………………………………………………………………………………..3 
 
Schema.……………………………………………………………………………………4 
 
1.0  Objectives .……………………………………………………………………………......5 
 
2.0 Background ……………………………………………………………………………..5-8 
 
3.0  Drug Information ………………………………………………………………………8-10 
 
4.0  Eligibility Criteria……………………………………………………………………..10-12 
 
5.0  Treatment Plan ………………………………………………………………………13-15 
 
6.0 Documentation…………………………………………………………………………...15 
 
7.0 Toxicities to be Monitored and Dosage Modifications……………………………….16 
 
8.0 Criteria for Evaluation and Endpoint Definitions………………………………….17-18 
 
9.0 Statistical Considerations…………………………………………………………..18-19 
 
10.0 References……………………………………………………………………………20-21 
 
11.0 Appendix……………………………………………………………..……………22-42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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SUMMARY 
 
Significant aromatase inhibitor (AI)-associated toxicity, affects as many as 50% of patients with 
breast cancer leading to early discontinuation of this life-saving cancer treatment. No effective 
pharmacologic therapy has yet been identified for management of these symptoms, as many 
patients do not experience relief of symptoms with analgesic therapy. Improvement in 
treatment-related symptoms is needed and may improve compliance with AI therapy, and 
thereby lead to improved breast cancer outcomes. Vitamin B12, whether as injection or oral 
forms, has been used as a naturopathic product to provide relief for joint pain caused by 
arthritis. Vitamin B12, in addition to its neurological and hematological functions, 
suppresses the cytokine production of T lymphocytes at articulation lesion sites which might 
explain, in part, its reported benefit in arthritis. This effect has not been studied in the setting of 
Aromatase Inhibitor-associated Musculoskeletal Symptoms (AIMSS). However, patients who 
use vitamin B12 report anecdotally that they feel relief from AIMSS.  We are proposing a 
Phase II open label, single arm clinical trial of Vitamin B12 2500 mcg daily to evaluate the 
benefit of vitamin B12 for management of (AIMSS) and other related symptoms that can 
impact quality of life. We will also perform exploratory correlative studies for hypothesis 
generation. 
 
Inclusion of Women and Minorities 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects. The anticipated accrual in the ethnicity/race and 
sex categories is shown in the table below. Aromatase inhibitors are not used in men with 
breast cancer; therefore, men will not be included in this study. 
 
Ethnic Category 
 
Females 
Males 
Total 
Hispanic or Latino 
30 
0 
30 
Not Hispanic or Latino 
5 
0 
5 
Total Ethnic 
35 
0 
35 
 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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SCHEMA 
 
Enrollment/Informed Consent obtained  
 
 
 
 
 
 
Women with hormone receptor-positive breast cancer who are receiving AIs and report average 
pain of at least 4 (out of 10) on the BPI-SF that has started or increased since initiation of AI 
treatment 
 
 
 
 
 
 
Days 0, 45, AND 90: 
Staff administered assessments and patient-completed questionnaires via an iPad or 
if unavailable via paper copies 
(FACT-ES, BPI-SF, Assessment of AI Adherence, Demographics, and Supplemental Agents 
Reporting Form, AE assessment at day 45 and 90) 
 
 
 
 
 
 
Days 0, 45, AND 90: 
Blood collection to test CRP, Vitamin B12, MMA, and homocysteine levels before protocol 
treatment, at day 45, and at day 90 
 
 
 
 
 
 
 
Oral Intake of Vitamin B12 Daily X 90 days 
 
 
 
 
 
 
 
 
Day 90 (at 12 weeks): 
COMPLETION OF STUDY TREATMENT 
 
 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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1.0 
OBJECTIVES 
 
1.1 Primary Objective 
 
To assess whether daily oral Vitamin B12 decreases average joint pain in women 
with Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), as 
measured at baseline, day 45 (+/- 10 days) and day 90 (+/- 10 days) by the 
modified Brief Pain Inventory Short Form (BPI-SF). 
 
1.2 Secondary Objectives 
 
a. To investigate whether daily vitamin B12 improves functional quality of life as 
measured at baseline, at day 45 (+/- 10 days), and at day 90 (+/-10 days) by the 
Functional Assessment of Cancer Therapy-Endocrine Scale (FACT-ES); 
 
b. To explore the impact of treatment on serum inflammatory cytokine levels (C- 
REACTIVE PROTEIN) between baseline, day 45 (+/-10 days), and day 90 (+/- 10 
days) of treatment. 
 
2.0 
BACKGROUND 
 
Almost 180,000 women are diagnosed with breast cancer each year in the United States (1).  
The incidence of breast cancer increases with age; approximately 75% of patients are 
postmenopausal at the time of diagnosis. In addition, hormone receptors (HR) are 
over expressed on 80% of breast cancer tumors in postmenopausal women.  
Therefore, more than 100,000 postmenopausal women who are diagnosed with breast 
cancer each year in this country are potential candidates for anti-endocrine breast cancer 
therapy. 
 
Two classes of anti-endocrine therapies are used for treatment of HR-positive breast 
cancer: tamoxifen and the aromatase inhibitors (AIs).  AIs can only be used to treat 
postmenopausal women because they are ineffective in women with functional ovaries. 
Because of their superior efficacy, AIs are increasingly used for adjuvant treatment of 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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postmenopausal women with HR- positive breast cancer.  Based  on  currently  available  
data,  women  are  treated  with  either tamoxifen or AI therapy for 5 years, although studies 
are underway to determine if treatment should be continued for a longer period of time. 
 
AI-associated Musculoskeletal Symptoms (AIMSS) 
It has been increasingly recognized that arthralgias are a significant AI-associated toxicity, 
affecting as many as 50% of patients (2, 3). No factors associated with breast cancer 
treatment (such as chemotherapy) or co-morbid conditions (such as diabetes or body mass 
index) have been clearly shown to be predictive of the development of arthralgias (3). The 
etiology of AI-associated musculoskeletal symptoms remains elusive.  The hypotheses 
include direct effects of estrogen deprivation on bone, neurohormonal changes which result in 
change of pain sensitivity, and immune system changes resulting in alteration of circulating or 
local inflammatory cytokine concentrations. 
 
A greater than 20% treatment discontinuation rate due to AI-associated arthralgias in a 
prospective trial of AI therapy was reported (4, 5). Based on the number of patients treated 
with aromatase inhibitor therapy and the incidence of musculoskeletal symptoms that occur 
with therapy, as many as 40,000 women are affected by this toxicity in the United States 
annually. More importantly, up to 20,000 women discontinue these potentially life-saving 
medications because of intolerable arthralgias and myalgias. 
 
No effective pharmacologic therapy has yet been identified for management of these 
symptoms, as many patients do not experience relief of symptoms with analgesic therapy. The 
current treatment for AIMSS is limited to oral analgesics and exercise, however, neither 
intervention has optimal effect, and long term use of oral analgesics is problematic.   
 
Currently a phase III trial is ongoing nationwide S1202, “A Randomized Placebo-Controlled 
Phase III Study of Duloxetine for Treatment of Aromatase Inhibitor-Associated Musculoskeletal 
Symptoms in Women with Early Stage Breast Cancer.”  Our site at Texas Tech University 
Health Sciences Center El Paso (TTUHSC-EP) is participating in this study. However, it is 
limited to English speaking patients only; therefore the majority of our breast cancer patients are 
not able to participate in this clinical trial.  Also, those who qualify have been reluctant to 
participate due to the significant and serious side effects listed for Duloxetine, including death.   

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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Testing Vitamin B12 for the treatment of AIMSS 
We are proposing to study the effect of Oral Vitamin B12 on reducing the symptoms of AIMSS. 
Vitamin B12, whether as injection or oral forms, has been used as a naturopathic product to 
provide relief for joint pain caused by arthritis (6). Preclinical data suggests that in vitro, Vitamin 
B12 suppresses the cytokine production of T lymphocytes which are expressed also in vivo in 
patients with rheumatoid arthritis, especially at articulation lesion sites (7). This might explain 
the anecdotal benefit reported in patients with arthritis. We are proposing a  Phase II open-
label clinical trial of Vitamin B12  2500 micrograms per da y over the course of 90 days 
(+/- 10 days) to assess the impact on  postmenopausal women who have been treated 
with AI therapy for at least 2 weeks and who have developed new or worsening pain 
after starting AI therapy (details below). Although there are minimal data to suggest that 
women with AIMSS have altered levels of circulating inflammatory markers prior to therapy, 
we would explore whether it is possible that treatment with vitamin B12 could impact serum 
concentrations of pro- or anti-inflammatory factors, such as C-Reactive Protein (CRP) 
or that subsets of women who have altered levels prior to treatment initiation could be more 
likely to benefit. 
 
One of the reasons for our decision to explore the possible beneficial effect of vitamin B12 to 
treat AIMSS is our experience at the TTUHSC-EP Garbar Breast Care Center, where we 
conducted a pilot study to evaluate quality of life (QOL) in breast cancer survivors. Our findings 
support that QOL levels appear to be lower in women taking AIs.  The study included patients 
with breast cancer who were within the first 5 years post-diagnosis after having completed 
surgery/chemotherapy/radiation therapy (Figure 1). We assessed their quality of life (QOL) 
using a multi-purpose health related QOL questionnaire, the SF-36.  The
 
SF-36 scores were 
analyzed as two summary scales—one for physical health called the SF-36 Physical 
Component Summary (PCS) and a second for mental health called the Mental Component 
Summary (MCS). We noted the following: 60% of breast cancer survivors are receiving or have 
received anti-endocrine “hormonal therapy” and all patients had a low mean PCS at 40.4 and a 
mean MCS at 47.8, both lower than U.S. norm and values in other breast cancer survivors. 
Also, there was a lower Mental QOL in patients receiving or who have received hormonal 
therapy. The difference in the means for MCS was found to be statistically significantly lower 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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according to hormonal therapy status, 45.48 versus 51.5, p=0.006 (manuscript submitted under 
peer review). 
 
Figure 1. Patient Characteristics in the Pilot study conducted at the Garbar 
Breast Care Center-TTUHSC-EP (Manuscript in peer review) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.0 
DRUG INFORMATION 
Vitamin B-12 (or cobalamin) is one of multiple vitamins that belong to a family of vitamins known 
as the B vitamins. Vitamin B12 is water soluble and can’t be made in the body, therefore, it must 
be obtained by food or supplements. Dietary sources are found primarily in animal-derived 
foods such as dairy, eggs, meat, poultry and fish. Vitamin B-12 plays an essential role in a 
variety of bodily processes such as development and maintenance of red blood cells, nerve 
Variable 
N (%) 
Age [mean (SD) years]
57.75 
(10.03) 
Duration of diagnosis [median (IQR) years] 
2.00 (1, 4) 
Stage 
        I 
33 (32.35) 
        II 
47 (46.08) 
        III 
22 (21.57) 
Chemotherapy received
        Yes 
69 (67.65) 
        No
33 (32.35) 
  
  
Hormonal therapy received
  
        Yes 
61 (60.40) 
        No
40 (39.60) 
Language 
       English 
23 (22.55) 
       Spanish 
79 (77.45) 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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cells, normal covering (myelination) of nerve cells,  cellular metabolism, DNA and RNA 
synthesis and energy production. 
 
Deficiencies in Cobalamin (Cbl) can lead to altered neurological and hematological functioning. 
Neurological deficiencies may affect the central and peripheral nervous systems and may 
manifest in the body as depression, cognitive difficulties, memory loss, paranoia, peripheral 
neuropathy and decreased sensation in peripheral nerves (8). Other symptoms include 
weakness and fatigue.  Interestingly, 7-30% people over the age of 60 have vitamin B12 
deficiency, yet their presentation is ‘subclinical’ also known as ‘functional cobalamin deficiency’ 
(9, 10). That is, though blood analysis may reflect that levels of vitamin B12 that are in the low  
normal range, levels of cobalamin metabolites such as methylmalonic acid (MMA) or 
homocysteine are elevated and may be the first sign of deficiency (10).   
 
Risk factors in developing Vitamin B12 deficiency include: strictly vegetarian or vegan diets, 
excessive alcohol intake, atrophic gastritis, Helicobacter pylori infections, intestinal pathology 
and certain medications. Older adults are at risk for developing deficiency due to atrophic 
gastritis which decrease the production of gastric acids that are essential in the digestion of 
meat derived foods and subsequent absorption of the vitamin. Vitamin B12 is absorbed in the 
small intestine therefore illness or surgery of the small intestine, bariatric surgery or gastrectomy 
may also lead to deficiency (11). Defining deficiency is another task for the clinician as there are 
various interpretations of lab results. Serum Vitamin B12 concentrations of 150-160 pmol/L are 
indicative of overt deficiency (11).  
 
There is no consensus regarding how best to measure vitamin B12 deficiency as some studies 
use only serum Vitamin B-12 levels, while other studies use serum B12 levels in conjunction 
with methylmalonic acid (MMA) levels. Methylmalonic acid is considered highly sensitive and 
specific marker to determine vitamin B12 deficiency. As previously mentioned, many patients 
are identified with subclinical vitamin B12 deficiency which can be found in patients with 
cobalamin levels <200 ng/L (12). Supplementation of Vitamin B12 is a low risk endeavor since 
there is no Tolerable Upper Intake Level (UL) (11).  
 
Vitamin B12 comes in a variety of forms including: Cyanocobalamin, Methylcobalamin, 
hydroxocobalamin and adenosylcobalamin.  When ingested, cyanocobalamin is converted to 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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other forms of the vitamins in the liver. The conversion starts with hydroxocobalamin then into 
methylcobalamin and adenosylcobalamin which are stored in the liver. All forms of vitamin B12 
are deemed safe as the risk of toxicity with the vitamin is very low because it is water-soluble 
and so easily removed from the body. The vitamin B12 form known as cyanocobalamin is 
inexpensive and readily available at pharmacies, health food stores or grocery stores. 
 
The dose of Vitamin B12 as recommended by RDA is 2.4 mcg/dl for the general population 51 
years and older (13).  One often used method of vitamin B12 replacement in deficient patients is 
parenteral injection of the vitamin, in spite of the fact that oral Vitamin B12 is available. One 
review of the literature cited two randomized controlled trials that compared oral versus 
parenteral vitamin B12 administration. Though the number was small, the outcomes of both 
studies indicate that oral Vitamin B12 in doses ranging from 1000-2000 mcg is as effective as 
parenteral Vitamin B12 (14). 
 
How supplied? 
 
We will use 1 tablet of vitamin B-12 2500 mcg for sublingual (SL) consumption. 
 
This product is usually stored at room temperature between 59-86 degrees F (15-30 
degrees C) away from light and moisture.  
 
Certain medications can decrease the absorption of vitamin B12, including: colchicine, 
metformin, extended-release potassium products, antibiotics (such as gentamicin, 
neomycin, tobramycin), anti-seizure medications (such as phenobarbital, phenytoin, 
primidone), medications to treat heartburn (such as H2 blockers including 
cimetidine/famotidine, proton pump inhibitors such as omeprazole/lansoprazole). The 
vitamin B12 tablet will be taken sublingually, 1 hour after meals in AM, daily for 90 days 
(+/- 10days). 
 
4.0 ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be 
considered eligible for participation.   
 
A. Disease Related Criteria 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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1. Patients must be women with histologically confirmed estrogen receptor (ER) 
and/or progesterone receptor (PgR) positive invasive carcinoma of the breast 
(Stage I-III) with no evidence of metastatic disease (M0). 
2. Patients must have completed mastectomy or breast sparing surgery, and must 
have recovered from all side effects of the surgery. Patients should have 
recovered from all Grade 2 or higher side effects of chemotherapy and/or radiation 
therapy with the exception of alopecia and peripheral neuropathy. Concurrent 
bisphosphonate and trastuzumab therapies are allowed. 
 
B. Clinical/Laboratory Criteria 
 
1.  Patients must be post-menopausal, as defined by at least one of the following: 
a.  ≥ 12 months since the last menstrual period OR 
b.  Prior bilateral oophorectomy OR 
c.  Previous hysterectomy with one or both ovaries left in place (or previous 
hysterectomy in which documentation of bilateral oophorectomy is 
unavailable) AND (unless ≥ 60 years of age) FSH values consistent with the 
institutional normal values for the post-menopausal state. 
 
2. Patients must currently be taking one of the following aromatase inhibitor (AI) 
doses for at least 14 days prior to registration and plan to continue for at least 
an additional 180 days after registration: 
a. 
Anastrozole (Arimidex®) 1 mg daily OR 
b. 
Letrozole (Femara®) 2.5 mg daily OR 
c. 
Exemestane (Aromasin®) 25 mg daily 
 
3. Patients must have aromatase inhibitor (AI) associated musculoskeletal symptoms 
that began or increased after starting AI therapy. New musculoskeletal pain must 
not be due specifically to fracture or traumatic injury. 
 
4. Patients must have completed the Brief Pain Inventory-Short Form (BPI- SF) v i a  
a n  i P a d  o r  i f  u n a v a i l a b l e  o r  d u e  t o  t e c h n i c a l  

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Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
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d i f f i c u l t i e s  v i a  p a p e r  c o p i e s within 7 days after enrollment. Patients 
must have an “average pain” of at least 4 on the BPI-SF (item #5). 
 
5.  Patients must have Zubrod performance status of 0-2. 
 
6.  Patients must have no known allergy or hypersensitivity to vitamin B12. 
 
 
7. Patients must not have any contraindicated concurrent illnesses including: 
a. History of alcohol or other substance abuse or dependence within 365 days prior 
to enrollment. 
b. Chronic liver disease. 
c. End stage renal disease. 
 
8. Patients who are receiving treatment with narcotics, tramadol, gabapentin, and/or 
pregabalin must have been taking a stable dose for at least 30 days prior to 
registration. 
  
9. Patients must be able to complete study questionnaires in English or Spanish, which 
will be given via an iPad or if unavailable or due to technical difficulties via paper 
copies. 
 
10.  Patients who are currently taking vitamin B12 or a multivitamin containing vitamin 
B12 will be able to participate in the study after having stopped taking the vitamin B12 
or the multivitamin containing the B12 for two weeks. 
 
C. Specimen Submission Criteria 
 
1. Patients must be willing to submit blood samples for laboratory testing [to test for 
Serum Vitamin B12, C-Reactive Protein (CRP), homocysteine level, and Methyl 
Malonic Acid (MMA)]. Baseline samples must be obtained prior to beginning 
protocol treatment. 
 
D. Regulatory Criteria 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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1. All patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give written informed 
consent in accordance with institutional and federal guidelines. 
 
 
5.0 TREATMENT PLAN 
This is a single arm study; therefore, all patients enrolled will take 1 tablet of Vitamin B12 2500 
mcg, 1 hour after meals in AM, daily for 90 days (+/- 10 days). As it is a single arm study, there 
will be no control group.  Patients will be provided with a calendar to keep track of their intake. 
Each patient will receive 2 bottles (each containing 60 tablets) total over the course of 90 days. 
 
5.1 Study Plan 
Breast cancer patients seen at the Garbar Breast Care Center during their routine follow-up 
visits with their medical oncologist will be screened and referred to the clinical research 
coordinator.  Patients will have a general physical exam (including a record of their height and 
weight). The study coordinator will explain the study to the patient, answer their questions 
related to the study and obtain written consent and enroll them into the study.  Consented 
patients will then be required to complete the Brief Pain Inventory Short Form questionnaire, 
which will be administered via an iPad or if the iPad is unavailable, it will be administered via 
paper copies. The referring medical oncologist will then verify that the patient had an “average 
pain” score of at least 4 on the BPI-SF to confirm eligibility criteria. Once this information has 
been confirmed, the clinical research coordinator will proceed administering the remaining 
questionnaires via an iPad but if the iPad is unavailable or due to technical difficulties, they will 
be administered via paper copies, the FACT-ES questionnaire, the AI Adherence Assessment, 
and the Demographics questionnaires.  Additionally, with the patient’s assistance, the study 
coordinator will fill out the Agent Reporting Questionnaire also via an iPad or if unavailable via 
paper copies.  
 
Initial Visit 
Within 10 days of signing the consent form, the patient will be scheduled for their 
Initial/baseline visit, which will include the following: 
1. Blood collection for laboratory testing: 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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a. Serum B12 levels 
b. C-Reactive Protein (CRP) 
c. Homocysteine level 
d. Methylmalonic Acid (MMA) 
 
2. Administration of questionnaires via iPad or if unavailable via paper copies, which will 
include the following: 
a. Brief Pain Inventory – Short Form survey 
b. FACT-ES Trial Outcome Index (Version 4) 
c. “Questionnaire to Assess Adherence to Aromatase Inhibitors” (AI). 
d. Demographics Questionnaire 
e. Supplemental Agents Reporting Form (to be filled out by the clinical research 
coordinator) 
It should take approximately 20-25 minutes to complete the questionnaires. 
 
3. Dispensing of Vitamin B12 - The patient will be provided with a bottle containing 60 
tablets of vitamin B12 2500 mcg and instructed to take 1 tablet sublingually, 1 hour after 
their morning meal for the next 45 days (+/- 10 days) 
 
4. Intake Calendar for Vitamin B12 - The patient will be provided with a vitamin B12 intake 
calendar and instructed to record on the calendar the days that they take the vitamin 
B12 tablet. 
 
5. Intake Calendar for AI - The patient will be provided with an AI intake calendar and 
instructed to record on the calendar the days that they take the AI tablet. 
 
6. Instructions for Follow-Up Visit - The patient will be instructed to bring their vitamin B12 
bottle and both of their intake calendars to their follow-up visit on day 45 (+/- 10 days). 
 
Follow-up Visits 
The patient will be asked to return for follow-up visits on day 45 (+/- 10 days) and on day 90 
(+/- 10 days). Follow-up visits will consist of the following: 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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1. Blood collection for laboratory testing which will be performed at the University Medical 
Center Outpatient Laboratory: 
a. Serum B12 levels 
b. C-Reactive Protein (CRP) 
c. Homocysteine level 
d. Methylmalonic Acid (MMA) 
 
2. Administration of questionnaires via iPad or if unavailable via paper copies, which will 
include the following: 
a. FACT-ES Trial Outcome Index (Version 4) 
b. (BPI-SF) questionnaire 
c. “Questionnaire to Assess Adherence to Aromatase Inhibitors” (AI) 
(Administered only at baseline and on Day 90 +/- 10 days, not to be 
administered at Day 45) 
d. Supplemental Agents Reporting Form (to be filled out by the clinical research 
coordinator with assistance from the patient) 
e. The Adverse event summary form will be also administered on days 45 and 90 
(+/-10 days) (to be filled out by the clinical research coordinator with assistance 
from the patient) 
 
It should take approximately 20-25 minutes to complete the questionnaires. 
 
3. Vitamin B12, Intake Calendars, and Swift Pay Card - On day 45 (+/- 10 days), the 
study coordinator will give the patient a new bottle of Vitamin B12, two new intake 
calendars, one for the Vitamin B12 and another for the aromatase Inhibitor, and a $25 
Swift Pay card. 
 
4. Pill Count - The study coordinator will collect the bottles of Vitamin B12 from the 
patient, perform a pill count, and record the information on the Investigational Agent 
Accountability Record on day 45 (+/- 10 days) and day 90 (+/- 10 days). 
 
5. Intake Calendars - The study coordinator will collect the Vitamin B12 intake calendar 
and the AI intake calendar on days 45 (+/- 10 days) and 90 (+/- 10 days). 

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Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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6.0 DOCUMENTATION 
Drug compliance will be recorded by patients in the Intake Calendar. The clinical research 
coordinator will review and ascertain patient adherence with protocol therapy at the end of 
treatment for each visit. Note that the Vitamin B12 and AI Intake Calendars will be provided 
only as a tool for tracking patient compliance.  Counts of tablets remaining in the Vitamin B12 
bottles will be recorded on the Investigational Agent Accountability Record.  Adverse events 
will be assessed and recorded on the Adverse Event Summary Form during each study visit.  
Use of pain medications, steroids, physical therapy, and acupuncture will be recorded on the 
Supplemental Agents Reporting Form. 
 
The clinical research coordinator will also complete the Cover Sheet for Patient-Completed 
Questionnaires at each visit to indicate whether or not the patient completed the 
questionnaires, if the patient required assistance and the method for completing the 
questionnaires.  If one or more of the questionnaires was not completed, an overall reason will 
be indicated on the Cover Sheet. 
 
7.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
1 
NCI Common Terminology Criteria for Adverse Events 
 
The CTEP Version 4.0 of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) will be utilized for AE reporting.  The CTEP 
CTCAE Version 4.0 is identified and located at the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTEP 
Version 4.0 of the CTCAE. 
 
2 
General Considerations 
 
Patients who are taking narcotics, tramadol, gabapentin, and/or pregabalin at 
study enrollment should continue to take a stable dose of medication. Dose 
increases for these medications should be discouraged. 

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Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
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Patients who need additional analgesic medication during study participation 
are requested to take acetaminophen. Patients should not undergo therapy 
with other treatment modalities such as physical therapy, acupuncture, 
systemic steroids, or intra- articular steroid injections during study 
participation unless medically necessary. Usage of all medications and other 
therapies for treatment of pain should be documented. 
 
3 
Dose Modifications 
 
No dose modifications of Vitamin B12 are allowed. Follow-up will be conducted 
at the intervals specified in the protocol. 
 
 
8.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
1 
Primary Outcome 
Reduction in average joint pain according to the Brief Pain Inventory – Short 
Form (BPI- SF) average pain score. This item has a scale of 0 to 10 with 0 
indicating “No pain” and 10 indicating “Pain as bad as you can imagine” 
[assessed within 10 days prior to study enrollment, at Days 45 (+/- 10 days) 
and at Day 90 (+/- 10 days)]. 
 
2 
Main Secondary Outcome 
 
Reduction in worst joint pain according to the BPI-SF worst (maximum) pain 
score at day 90 (+/- 10 days). This item has a scale of 0 to 10 with 0 indicating 
“No pain” and 10 indicating “Pain as bad as you can imagine”. 
 
3 
Performance Status 
 
Participants will be graded according to the Zubrod performance 
status scale. 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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 POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance 
without restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry 
out any work activities; up and about more than 50% of 
waking hours. 
 
3 
 Capable of limited self-care, confined to bed or chair more 
than 50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; 
totally confined to bed or chair. 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
1.0 Primary Endpoint 
 
The primary endpoint is improvement in the BPI-SF scale. Joint pain will be 
assessed using “average pain” according to the BPI-SF. Enrollees must 
currently be taking AIs and must exhibit joint pain with a minimum BPI-SF 
average pain score of 4; scores of 4 to 10 are considered to reflect moderate to 
severe pain. (15) 
 
    2.0 Secondary Endpoints 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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Version: 02.19.16 
The following secondary analyses will be conducted: 
a. 
Improves  functional  quality  of  life  as  measured  by  the  Functional 
Assessment  of  Cancer  Therapy-Endocrine  Scale  (FACT-ES).(16,17)  
b.        Decreases the use of supplemental agents. 
 
A. Sample Size: The improvement in BPI-SF worst pain scores and pain severity scores were 
observed in between 70% to 90% in a study of comparing the effect of acupuncture for the 
management of Aromatase Inhibitor–Associated Joint Symptoms in women with early-stage 
breast cancer (18).  We expect at least 20% improvement in BPI-SF pain scores (less than 
half of the estimated effect with acupuncture) with a common standard deviation of 30% (a 
conservative estimate based on a published study). Using this information, we need at least a 
total of 30 patients to achieve more than 85% power to detect the differences in BPI-SF pain 
scores relative to baseline using a two tailed paired t-test with 5% level of significance.  After 
accounting for 15% dropouts, we estimated to include at least 35 patients in the study.    The 
sample size estimate was calculated using PASS 12 (19).  
 
B. Data Analysis:  Data will be described using appropriate summary measures.  The 
difference in mean pain scores between pre and post treatment with 95% confidence interval 
(CI) will be estimated.  A paired t-test will be used to determine the significant effect of Vitamin 
B12 on pain scores and quality of life scores.  Further, the pain scores will be categorized and 
compared from the baseline using Mc Nemar’s test.  Pearson’s correlation analysis will be 
carried out between quality of life scores and pain scores.  Heterogeneity effect of the 
treatment on the pain scores will be examined using cluster analysis.  P-values less than 5% 
will be considered significant results. All statistical analyses will be carried out using SAS 9.3. 
 
 
 
 
 
 
 
 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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Version: 02.19.16 
10.0 
REFERENCES 
 
1. American 
Cancer 
Society. 
http://www.cancer.org/downloads/STT/BCFF-Final 
.pdf. 
Accessed February 16, 2015 
 
2.  Crew KD, Greenlee H, Capodice J, et al. Prevalence of joint symptoms in 
postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin 
Oncol 25:3877-83, 2007 
 
3. Henry NL, Giles JT, Stearns V. Aromatase inhibitor-associated 
musculoskeletal 
symptoms: etiology and strategies for management. Oncology (Williston Park) 22:1401-8, 
2008 
 
4. Henry NL, Giles JT, Ang D, et al. Prospective characterization of musculoskeletal 
symptoms in early stage breast cancer patients treated with aromatase inhibitors. 
Breast Cancer Res Treat 111:365-372, 2008 
 
5. Henry NL, Azzouz F, Desta Z, et al. Predictors of aromatase inhibitor discontinuation 
due to treatment-emergent symptoms in early-stage breast cancer. J Clin Oncol, epub Feb 
13, 2012. 
 
6. http://www.progressivehealth.com/joint-pain-b12.htm, accessed February 15, 2015 
 
7. Yamashiki M, Nishimura A, Kosaka Y. Effects of methylcobalamin (vitamin B12) on in vitro 
cytokine production of peripheral blood mononuclear cells. Journal of Clinical and 
Laboratory Immunology. 1992;37(4):173–182 
 
8. Leishear, K., et al The Relationship of Vitamin B12 and Sensory and Motor Peripheral 
Nerve Function in Older Adults. J. Am. Geriatr Soc. 2012 June; 60(6): 1057-1063. 
 
9. McCaddon, A. Vitamin B12 in neurology and ageing; Clinical and genetic aspects. 
Biochimie 95 (2013):1066-1076 
 
10. Solomon, L.R. Functional cobalamin (vitamin B12) deficiency: role of advanced age and 
disorders associated with increased oxidative stress. European Journal of Clinical 
Nutrition (2015), 1-6. 
 
11. Park, S. and Johnson, M.A. What is an adequate dose of oral vitamin b12 in older people 
with poor vitamin B12 status? Nutrition Review. 2006, 64(8):373-378 
 
12. Carmel, R. How I treat cobalamin (Vitmain B12) deficiency. Blood. 2008. Sep 15; 112(6): 
2214-2221. 
 
13. National Institutes of Health. Vitamin B12. 2011. http://ods.od.nih.gov/factsheets/list-
VitaminsMinerals/ 
 
14. Vidal-Alaball,J., et al. Cochrane Database Syst Rev, 2005. Jul 20;(3): CD004655. 
 
15. Serlin RC, Mendoza TR, Nakamura Y, et al, When is cancer pain mild, moderate or 
severe? Grading pain severity by its interference with function. Pain 61:277-84, 1995. 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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Version: 02.19.16 
16.  Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy 
Scale: Development and validation of the general measure. J Clin Onc 11:570-79, 1993. 
 
17.  Fallowfield LJ, Leaity SK, Howell A, et al. Assessment of quality of life in women 
undergoing hormonal therapy for breast cancer: validation of an endocrine symptom 
subscale for the FACTB. Breast Cancer Res Treat 55:189-99, 1999. 
 
18. Crew  KD,  Capodice  J,  Greenlee  H,  et  al,  Randomized,  blinded,  sham-controlled  
trial  of acupuncture for the management of aromatase inhibitor-associated joint 
symptoms in women with early-stage breast cancer. J Clin Oncol 28:1154-1160, 2010. 
 
19. Hintze, J. (2013). PASS 12. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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APPENDIX 
I. 
Study Calendar 
II. 
Brief Pain Inventory – Short Form Questionnaire 
III. 
Demographics Questionnaire 
IV. 
FACT-ES Questionnaire (Version 4) 
V.  
Aromatase Inhibitor Adherence Questionnaire 
VI.  
Supplemental Agents Reporting Form 
 
VII.  
Vitamin B12 Intake Calendar 
 
VIII.  
Aromatase Inhibitor Intake Calendar 
 
IX.  
Investigational Agent Accountability Record 
 
X.  
Coversheet for Patient Completed Questionnaires 
 
XI.  
Adverse Event Summary Form 
 
XII. 
Eligibility Criteria Checklist 
 
XIII. 
Laboratory Results Form

 
Version 1.0 
5/20/2015 
I. 
Study Calendar 
α 
π 
√ 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk
Wk
Wk 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
REQUIRED STUDIES 
PRE 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
  
STUDY
1 
8 
15 
22 
29 
36 
45(+/- 
10 
DAYS) 
50 
57 
64 
71 
78 
90 (+/- 
10 
DAYS)
Informed Consent Signed* 
X 
  
  
 
  
  
  
 
  
  
  
  
  
 
PATIENT COMPLETED 
QUESTIONNAIRES 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Brief Pain Inventory-Short Form 
(BPI- SF) 
X ~ 
  
  
  
  
  
  
X  
  
  
  
  
  
X 
Demographics Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-ES Questionnaire (Version 4) 
 
X  
  
  
  
  
  
X 
  
  
  
  
  
X 
Aromatase Inhibitor Adherence 
Questionnaire 
 
 X 
 
 
 
 
 
 
 
 
 
 
 
X 
Supplemental Agents Reporting 
Form Ф 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
LABORATORY 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum vitamin B12 
 
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
C-reactive Protein (CRP) 
 
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
Homocysteine 
 
X 
X 
X 
Methyl Malonic Acid (MMA) 
 
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Dispense one bottle of 60 tablets of 
Vitamin B12 2,400 mcgº   
  
X 
  
  
  
  
X 
  
  
  
  
  
Collect bottle of vitamin B12 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
Investigational Agent Accountability 
Record Ф 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Adverse Event Summary Form Ф 
  
 
  
  
  
  
  
X 
  
  
  
  
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INTAKE CALENDARS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Provide patient with Vitamin B12 
and AI intake calendars 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Collect Vitamin B12 and AI intake 
calendars 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 

“A Single Arm Phase II Study of Oral Vitamin B12 for the Treatment of Aromatase 
Inhibitors (AI)-Associated Musculoskeletal Symptoms (AIMSS) in Women with Early 
Stage Breast Cancer” 
 
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Study Calendar Footnotes 
 
α  Baseline questionnaires and blood draw must be completed prior to starting the vitamin B12. 
π  Assessments must be completed during Day 35-55. 
√  Assessments must be completed during Day 80-100.
*  
A statement that arthralgias started or worsened since initiation of adjuvant AI therapy must be 
documented in the patient’s medical record at pre-study and prior to signing consent form. 
~ 
Must be performed within 7 days prior to enrollment. 
º  
Patient is to take study drug daily. 
Ф   Form to be filled out by Clinical Research Coordinator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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