A Pilot Study of Vitamin D Replacement in Patients With Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia With Low Vitamin D Levels
Phase: NA
Conditions: Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, Untreated Chronic Lymphocytic Leukemia, Vitamin D Deficiency
Sponsor: University of Nebraska

 
 
Clinical Trials Office | Oncology and Hematology 
 
 
 
Official Study Title: 
A Pilot Study of Vitamin D Replacement in Patients with Non-Hodgkin’s Lymphoma or Chronic Lymphocytic 
Leukemia with Low Vitamin D Levels 
 
 
ClinicalTrials.gov Identifier (NCT Number): 
NCT02553447 
 
 
Protocol ID: 
IRB #0556-15-FB 
 
 
Sponsor / Institution: 
University of Nebraska Medical Center 
 
 
Principal Investigator: 
Julie M. Vose, MD 
 
 
Document Type: 
Study Protocol 
 
 
Protocol version & Date: 
Protocol Version 6.4, Dated 01Dec2023 
 
  
                      
                   
 
 
 
 
 
 
 
 
 

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A Pilot Study of Vitamin D Replacement in Patients with Non-Hodgkin’s Lymphoma or 
Chronic Lymphocytic Leukemia with Low Vitamin D Levels 
Principal Investigator: 
Julie M. Vose, MD 
University of Nebraska Medical Center 
Phone: 402-559-6519 
Email: jmvose@unmc.edu 
 
 
Statistician: 
Lynette Smith, PhD - University of Nebraska Medical Center 
 
Participating Affiliate Regional Institutions: 
Cotton O'Neil Clinic and Stormont Vail Hospital 
 
 
 
 
IND EXEMPT 
CT.gov #: NCT02553447 
CTRP #:  NCI-2015-01502 
 
Protocol Version 3.0, Dated 23Sep2015 
Protocol Version 4.0, Dated 31May2016 
Protocol Version 4.1, Dated 27Dec2016 
Protocol Version 5.0, Dated 27Feb2018 
Protocol Version 6.0, Dated 24Apr2019 
Protocol Version 6.1, Dated 31Mar2020 
Protocol Version 6.2, Dated 04May2021 
Protocol Version 6.3, Dated 15Aug2023 
Protocol Version 6.4, Dated 01Dec2023 

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ABSTRACT: 
Title: A Pilot Study of Vitamin D Replacement in Patients with Non-Hodgkin’s Lymphoma and 
Chronic Lymphocytic Leukemia with Low Vitamin D Levels 
Objectives: To evaluate the Primary End Point, the 3 year progression-free survival (PFS), 
defined as time from the time of study entry of "watch and wait" patients or newly diagnosed 
NHL or CLL until relapse, progression, starting new therapies or death from any cause. To 
evaluate changes in the levels of serum vitamin D levels during therapy with daily oral 
Vitamin D supplementation. To evaluate the Secondary End Point, the overall survival (OS), 
defined as defined as time from the time of study entry of "watch and wait" or newly 
diagnosed NHL or CLL until death from any cause. 
Eligibility: Patients with histologically confirmed newly diagnosed or previously untreated 
(patients may be under no treatment “wait and watch” or have received two cycles of 
chemotherapy or localized radiation therapy before informed consent) non-Hodgkin’s lymphoma 
(NHL) or chronic lymphocytic lymphoma (CLL) with low vitamin D levels. 
Intervention: All patients will have a serum 25-hydroxyvitamin D [25(OH) D] drawn at time of 
enrollment 
Subjects with a normal level of serum Vitamin D 30-100 ng/ml at time of enrollment will be 
automatically enrolled in the controlled group and will be followed only for long-term 
progression free survival and outcome. No further evaluation of serum 25-hydroxyvitamin D 
[25(OH) D] will be obtained. 
Subjects found to have low levels of serum Vitamin D <30 ng/ml at time of enrollment will 
be randomized on a 1:1 basis to receive vitamin D 5000 IU daily (Higher Dose Cohort) or 
vitamin D 1000 IU daily (Lower Dose Cohort) stratified by disease group (aggressive NHL or 
indolent NHL/CLL). 
Evaluation: Serum 25-hydroxyvitamin D levels will be assessed at baseline, 6 months from 
baseline, 12 months from baseline, and then year 2 and 3. If subject is at a normal level of 25-
hydroxyvitamin D [25(OH) D], no change in intervention will be made. If the subject has a low 
level of vitamin D, which is defined as < 30 ng/ml, then the dose that they are currently enrolled 
in will be increased by 1000 IU (e.g. 5000 IU increase to 6000 IU; 1000 IU increase to 2000 IU). 
There will be a maximum dose of 10000 IU daily. If a subject has an elevated level of vitamin D, 
which is defined as > 100 ng/ml, then the dose will be held for one month and the level will be 
rechecked. If the level returns < 100 mg/ml, the dose will be cut in half and re-tested in two 
months. PFS and OS will be assessed at the end of study (3 years). 

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"Watch and Wait" patients or 
Newly diagnosed 
Non-Hodgkin’s Lymphoma and 
Chronic Lymphocytic Leukemia 
All Subtypes 
Schema:  
 
A Pilot Study of Vitamin D Replacement in Patients with 
Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia 
With Low Vitamin D Levels 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal Level 
>30ng/ml 
CONTROL GROUP* 
Low Levels 
<30 ng/ml 
RANDOMIZE GROUP 
Randomization will be performed on a 1:1 basis and 
stratified by disease group (aggressive NHL or indolent 
NHL/CLL). 
Dose Modifications at 6 mo, 12 mo, and year 2 and 3: 
 
Low level of 25(OH) D < 30 ng/ml the dose that they are 
currently enrolled in will be increased 1000 IU (e.g. 5000 
IU increase to 6000 IU; 1000 IU increase to 2000 IU). 
There will be a maximum dose of 10000 IU daily 
 
Elevated level of 25(OH) D > 100 ng/ml then the dose 
will be held for one month and a level will be rechecked. 
If the repeat level is < 100 mg/ml, the dose will be cut in 
half and re-tested in two months. 
Analysis 
 
a. Baseline 
b. 6 months 
c.
12 months 
d. year 2 and 3 
Evaluate serum 25 (OH) D 
*Control group will not have any 
further lab testing done after 
baseline. 
Lower Dose 
Cohort 
Vitamin D 
1000 IU 
(1 tablet) 
Daily 
Higher Dose 
Cohort 
Vitamin D 
5000 IU 
(5 tablets) 
Daily 

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Table of Contents 
 
Abstract 
Page 2 
Schema 
Page 3 
Section 1.0 Objectives 
Page 5 
Section 2.0 Background 
Page 5 
Section 3.0 Eligibility Criteria 
Page 11 
Section 4.0 Registration/Randomization Procedures 
Page 11 
Section 5.0 Treatment Plan 
Page 13 
Section 6.0 Measurement of Effect 
Page 15 
Section 7.0 Study Parameters 
Page 17 
Section 8.0 Drug Formulation and Procurement 
Page 18 
Section 9.0 Toxicity Reporting Guidelines 
Page 28 
Section 10.0 Statistical Considerations 
Page 31 
Section 11.0 Records to Be Kept 
Page 34 
Section 12.0 Patient Consent Form Statement 
Page 34 
Section 13.0 References 
Page 36 
Section 14.0 Data Forms 
Page 38 
Appendix A Eligibility checklist 
Page 39 
Appendix B NCI Common Toxicity Criteria Version 4.0 (CTCAE) 
Page 41 
Appendix C FDA MEDWATCH form 
Page 41 
Appendix D Oral, Sublingual, and/or Buccal Route Medication 
Adherence Standard Procedure (V 1.0 11-25-2013) 
Page 42 

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Section 1.0 Objectives: 
1.1  Primary Objectives 
1.1.1 To evaluate the Primary End Point, the 3 year progression-free survival (PFS), 
defined as time from the time of study entry of "watch and wait" or newly diagnosed 
NHL or CLL until relapse, progression, starting new therapies or death from any 
cause. Response will be determined by the principal investigator or the lead site 
investigators. The 3 year PFS of the low dose and high dose groups will each be 
compared to a historical fixed expected 3-year PFS of 45%. 
 
1.2  Secondary Objectives 
1.2.1 To evaluate changes in the levels of serum vitamin D levels during therapy with daily 
oral Vitamin D supplementation 
1.2.2 To evaluate the Secondary End Point, the overall survival (OS), defined as defined 
as time from the time of study entry of "watch and wait" patients or newly diagnosed 
NHL or CLL until death from any cause. For subjects who are still alive at the time of 
the study analysis at 3 years or are lost to follow-up, survival will be censored at the 
last recorded date that the subject was known to be alive. 
 
Section 2.0 Background: 
Vitamin D deficiency is a common problem in the Unites States.1 Multiple studies have 
demonstrated that 25% to 50% of patients evaluated in the clinical setting have insufficient 
levels of vitamin D.2,3,4 Vitamin D has long been recognized as essential for the efficient 
absorption and utilization of dietary calcium as well as for bone and muscle health. Intestinal 
calcium absorption is significantly enhanced by the presence of adequate vitamin D and is 
conversely reduced in deficiency of this micronutrient.3 There are some studies that have shown 
that lower vitamin D levels have been reported to increase risk for fractures, falls, functional 
limitations, some types of cancer, diabetes, cardiovascular disease, depression, and death.1,2,3 
There are limited studies that have evaluated vitamin D deficiency in lymphoma but even fewer 
that have looked at the effects of vitamin D in the clinical setting and the impact it has on event 
free survival and overall survival.2 
Lymphomas are types of cancer derived from lymphocytes that often develop into lymphatic 
tissues. Non-Hodgkin lymphomas (NHLs) is the sixth most common type of cancer in U.S. 
adults.5 Non-Hodgkin lymphomas are heterogeneous group of hematological malignancies that 
vary significantly in their severity, from indolent to very aggressive types. Symptoms may 
include enlarged lymph nodes that are not generally painless, fevers, night sweats, weight loss, 
and fatigue. Non-Hodgkin lymphomas are treated by combinations of chemotherapy, 
immunotherapy, radiation, and hematopoietic stem cell transplantation. Risk factors for NHL 
include autoimmune diseases, HIV/AIDS, infections with human T-lymphotrophic virus, eating a 
large amount of meat and fat, immunosuppressant medications, and some pesticides. 

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2.1  Sources of Vitamin D 
There are three ways in which humans obtain vitamin D; two are obtained naturally (food and 
sun), and one is artificial (supplements which includes fortificants). The partition of intake across 
the three sources depends on dietary habits, and exposure of skin to solar ultraviolet (UV)-B 
radiation.6 A combination of dietary intake of foods rich in vitamin D in addition to regular periods 
of skin exposure to the sun can provide the body with an adequate supply of this micronutrient. 
However, the average person’s lifestyle allows little time to be spent outdoors along with the risk 
of melanoma, and diets are usually replete with highly processed foods; thus, vitamin D intake 
and synthesis is seldom adequate to avoid deficiency.6 Fatty fish and vitamin-D enriched dairy 
products can supply a small amount of the estimated 3000-5000 IU of vitamin D that is needed 
daily.6 However, the average dietary intake nationwide is typically less than 5% of the body’s 
vitamin D requirement.6 
2.2  Definition 
Total serum 25-hydroxyvitamin D [25(OH) D] is the major form of vitamin D that circulates in the 
body and is used to assess inadequacy or deficiency. 25(OH) D is converted to 1,25-
dihydroxyvitamin D [1,25 (OH)2D] considered the physiologically active form of vitamin D, via the 
action of 1-α-hydroxylase. While much of the conversion occurs in the kidney, multiple other 
tissues (including lymphoma cells) also have 1-α-hydroxylase activity, and can thus regulate 
1,25 (OH)2D levels at the local tissue level. Once formed, 1,25 (OH)2D exerts its effects 
through binding to the vitamin D nuclear transcription factor receptor, where it may regulate the 
expression of nearly 200 genes.7 
Vitamin D insufficiency is defined as serum 25(OH) D <30 ng/mL although consensus 
guidelines for the diagnosis of vitamin D insufficiency have not been established because 
opinions differ on what constitutes as a deficiency. The Institute of Medicine (IOM) has 
concluded that persons are at risk for: vitamin D deficiency at serum 25(OH) D concentrations: 
<30 nmol/L (<12 ng/mL); risk of inadequacy deficiency if levels range from 30 to 50 nmol/L (12-
20 ng/mL); and sufficient if level > 50 nmol/L (>20 ng/mL).6 
2.3  Detection 
Many testing methods are available that measure total serum 25-(OH) D levels. However, the 
accuracy of these tests to detect vitamin D deficiency is difficult to determine because of the 
lack of studies that use an internationally recognized reference standard and the lack of 
consensus on the laboratory values that define vitamin D deficiency. The preferred test for 
assessment of vitamin D is serum 25-hydroxyvitamin D (25(OH) D). The results of this test are 
minimally influenced by recent dietary intake or recent sun exposure, and it is considered the 
most accurate functional indicator of vitamin D stores.6 
2.4  Risk Factors 
A number of factors influence the body’s ability to synthesize vitamin D from sun exposure to 
the skin, including the skin’s melanin pigmentation. A person with a darker skin tone will 

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synthesize less vitamin D with sun exposure compared with a person who has a lighter skin 
tone. The use of sunscreen, while helpful minimizing the risk of certain skin cancers and other 
solar damage, likely increases the risk of vitamin D deficiency, as application of sunscreen with 
a sun protection factor of 8 reduces the capacity of the skin to produce vitamin D by as much as 
95%. Obviously, individuals who spend little time outdoors have a significant risk for vitamin D 
deficiency.6 
The time of year and place of residence also influence sun-induced vitamin synthesis, with 
winter sun and northern latitudes providing the weakest effect. Even people who are regularly 
involved in outdoor activities that facilitate exposure to sunshine can have vitamin D deficiency if 
little skin is left sun exposed. General guidelines about the amount of sun exposure needed to 
maintain adequate vitamin D levels are difficult to provide. However, it has been suggested by 
some researchers that approximately 5 to 30 minutes of sun exposure between 10 AM and 3 
PM at least twice a week to the face, arms, legs, or back without sunscreen usually lead to 
sufficient vitamin D synthesis. This level of sun exposure is unlikely to induce sunburn or 
increase skin cancer risk.6 
The use of certain prescription medications and supplements, including phenytoin (Dilantin), 
phenobarbital, and St. John’s Wort, is potentially vitamin D depleting. As a result, patients taking 
these medications and supplements require two to five times the recommended daily amount of 
vitamin D.6 
Vitamin D deficiency is also common in the presence of hepatic or renal disease as well as after 
gastric bypass. Body mass index > 30 kg/m2 is associated with lower serum 25 (OH) D levels 
compared with non-obese individuals. Additional risk factors for vitamin D deficiency include 
obesity, > 65 years or < 25 years, and fat malabsorption due to conditions such as inflammatory 
bowel disease and celiac disease.6 
2.5  Vitamin D Supplements 
Vitamin D3 is the preferred form of micronutrient for the treatment of vitamin D deficiency and 
maintenance of vitamin levels. Serum 25(OH) D can be expected to rise by 1 ng/ml (2.5 nmol/L) 
for every 100 IU of additional vitamin D each day. Recent data indicates that cholecalciferol 
(vitamin D3) is substantially more potent than ergocalciferol (vitamin D2) and that safe upper 
intake level for vitamin D3 is 10,000 IU/day.8 ,9,10 The two seem to be absorbed from the 
intestine and to be 25-hydroxylated in the liver with equal efficiency; however, vitamin D2 seems 
to upregulate several 24-hydroxylases, leading to increased metabolic degradation of both the 
administered D2 and endogenous D3.10 Thus, although it is certainly possible to treat patients 
satisfactorily with vitamin D2, ergocalciferol seems to have no advantage over vitamin D3 
(cholecalciferol), which, as noted, is the natural form of the vitamin and which is, today, less 
expensive.11 It should be noted that, in this brief review, all of the evidence brought forth with 
respect to the relationship of vitamin D status to health and disease has been developed mainly 
for cholecalciferol (vitamin D3). 
Most commercial vitamin D supplements carry vitamin D either as a crystalline powder in a 
tablet that consists of otherwise inert excipients or in an oily vehicle (as in drops or gel caps). 

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Whether the vehicle affects absorption of D3 is unclear. The literature on this topic is extremely 
limited, and studies in which the vehicle was the primary variable are even more limited. 
Further, the outcome variable in all published studies was not serum D3 but serum 25(OH) D. 
Maalouf et al. (2008) compared 14,000 IU D3 in ethanol and in a medium-chain fatty acid 
vehicle. They found a statistically significant, higher increase in 25(OH) D from baseline in the 
oil group than in the ethanol group.12 Holvik et al. (2007) examined the effect of 400 IU D3 
administered in a multivitamin tablet containing cellulose and other vitamins and fillers versus 
400 IU D3 administered in a fish oil capsule and found no significant differences in 25(OH) D 
response between the two groups.13 The Grassroots Health project collects data on supplement 
type and has found no difference in the 25(OH) D concentration achieved with either 5,000 or 
10,000 IU daily doses, irrespective of whether the D3 was delivered via a gel cap in oil or as dry 
powder in a tablet.14 
Vitamin D, being fat soluble, is often presumed to require co-ingested fat for optimal absorption. 
However, it should be recognized that for the quantities consumed (in the microgram range), 
usual solubility considerations may not be pertinent.15, 16 However, fat malabsorption syndromes 
are known to lead to vitamin D deficiency, and the mechanism is generally considered to be a 
specific impairment in the absorption of the fat-soluble vitamin D. 15, 16 Dawson-Hughes et al. 
(2013) using pharmacokinetic methods in individuals with normal absorptive function, reported 
equal absorbability for D3 under fasting and high-fat meal conditions, with slightly better 
absorption from a low-fat meal.17 Mulligan and Licata (2010), in an observational study of 17 
poor responders to oral D preparations, reported greater absorption from a large meal 
containing fat than from intake on an empty stomach.18 Too few studies of this issue have been 
reported to permit a reliable estimate of how much absorption of vitamin D may vary and what 
factors may influence that absorption. 
2.6  Vitamin D Toxicity 
Vitamin D, particularly its active hormonal form, calcitriol, is a highly potent molecule, capable of 
producing serious toxic effects, including death, at milligram intake levels.25 Nevertheless, 
despite these appropriate concerns, there is, in fact, a comfortable margin of safety between the 
intakes required for optimization of vitamin D status and those associated with toxicity.25 It is 
worth noting, for example, that a single minimum erythema dosage of ultraviolet radiation (e.g., 
15 min in the sun in a bathing suit in July) produces, in a light-skinned individual, 10,000 to 
20,000 IU of vitamin D.25 Repeated day after day, this can add up to substantial vitamin D 
inputs. Nevertheless, there has never been a reported case of vitamin D intoxication from sun 
exposure.25 Controlled metabolic studies, necessarily limited in scope (although extending into 
the 100s of individuals), showed that dosages up to 50,000 IU/day for 1 to 5 months produce 
neither hypercalcemia nor hypercalciuria.25 A recent publication, reviewing the totality of the 
toxicity data, concluded that there were no cases of intoxication reported for daily intakes of 
<30,000 IU/d for extended periods and no cases of vitamin D intoxication for serum 25(OH)D 
levels <200 ng/ml (500 nmol/L).25 Thus, it was concluded that a daily intake of 10,000 IU should 
be considered the tolerable upper intake level. There is no known medical reason for dosages 
approaching that level; hence, there is a comfortable margin of safety between therapeutic and 
toxic intakes.25 

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2.7  Vitamin D in Cancer 
Although the central role of vitamin D is maintaining serum calcium and skeletal homeostasis 
has been long understood, more recent research has demonstrated that vitamin D may have a 
multiple effects on cellular differentiation by inhibiting abnormal cellular growth, thereby by 
minimizing abnormal proliferation, apoptosis and angiogenesis.4,27 Several studies have 
suggested that low levels of serum 25 (OH) D levels may be associated with an increase 
incidence of developing colorectal, breast and other cancers.28,28,30,31 And low levels of serum 25 
(OH) D levels at diagnosis may be associated with poorer prognosis in colorectal, melanoma, 
breast and lung cancer.32,33,34,35,36 Despite growing evidence for relationship between vitamin D 
levels and solid tumor risk, far less is known about vitamin D and the risk of hematologic 
malignancy. 
In in vitro and in vivo animal models, calcitriol has been shown to have anti-proliferative, pro-
differentiate and pro-apoptotic actions in cancer cells. In this manner, vitamin D could limit 
cancer progression or prevent it. A large number of observational studies have shown that low 
circulating levels of cholecalciferol, which are related to geographical location, diet and activity, 
are associated with a higher risk of cancer and cancer-specific worse prognostic. However, data 
regarding the role of vitamin D in cancer risk, incidence and mortality is still controversial. Some 
studies suggest a positive correlation between circulating 25(OH) D concentrations in patients 
with a diagnostic of cancer, although several epidemiologic studies including colorectal, breast, 
and hepatocellular carcinoma have demonstrated an inverse association between serum 
25(OH) D levels and the risk to develop these pathologies. It has not yet been clearly elucidated 
if low serum 25 (OH) D levels are causative of associative parameters of cancer. Some 
evidences are described below.37, 38, 39 
2.8  Vitamin D in Non-Hodgkin’s Lymphoma 
A pooled analysis of 10 studies found that higher levels of recreational sun exposure, which 
would be anticipated to increase vitamin D levels was associated with a lower risk for non-
Hodgkin’s lymphoma.40 Furthermore, data from 2 prospective cohort studies provide suggestive 
evidence that low serum 25 (OH) D levels are associated with increased incidence of NHL.41,42 
There are only a few studies that have evaluated the relationship of vitamin D and non-
Hodgkin’s lymphoma.32 A study performed by Shanafelt et colleagues (2011) evaluated 390 
newly diagnosed CLL patients. The time to treatment (TTT) was HR=1.47; P=.008 and overall 
survival (OS) was not significant in both cohorts (HR=1.47; P=.07) in the multivariate analysis of 
the patients adjusting for variables but in the individual cohorts there was a shorter TTT and OS 
in patients with CLL that were 25 (OH) D insufficient at time of diagnosis.43 
Another trial performed by Drake et colleagues (2010) evaluated vitamin D insufficiency and 
prognosis in non-hodgkin’s lymphoma.2 Circulating 25-hydroxyvitamin D [25(OH) D] levels were 
predictive of event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 
newly diagnosed patients with NHL. 25(OH) D and 1, 25-dihydroxyvitamin D [1, 25(OH) 2D] 
Median follow-up was 34.8 months; 404 events and 193 deaths of which 168 from lymphoma. 
For DLBCL, 52% of the patients were 25(OH) D insufficient. After adjusting for known 
prognostic factors and treatment, 25(OH) D insufficient patients with diffuse large B-cell 

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lymphoma (DLBCL) had inferior (hazard ratio [HR], 1.41; 95% CI, 0.98 to 2.04) and OS (HR, 
1.99; 95% CI, 1.27 to 3.13). The association of 25(OH) D levels with EFS and OS was mainly 
observed over the range of 15 to 25ng/mL, and was relatively flat above 30 ng/mL.2 
T-cell lymphoma (which included PTCL and CTCL), 57% of the patients were 25(OH) D 
insufficient, and after adjustment for known prognostic factors insufficient patients continued to 
have an inferior EFS (HR, 1.94; 95% CI, 1.04 to 3.61) and OS (HR, 2.38; 95% CI, 1.04 to 5.41). 
Inferior EFS and OS were observed among TCL patients in both the insufficient (<25 ng/mL) 
and the lower end of the optimal range (25 to 80 ng/mL) of 25 (OH) D levels. Vitamin D 
deficiency in mycosis fungoides and Sézary syndrome patients is similar to other cancer 
patients.2 
The prevalence of 25 (OH) D insufficiency for the remaining subtypes ranged from 27% to 39%, 
and there were no associations of 25 (OH) D insufficiency with EFS. There were no association 
with EFS for the other NHL subtypes. Among patients with DLBCL and T-cell lymphoma, higher 
1.25 1, 25 (OH) 2D levels were associated with better EFS and OS, suggesting that any 
putative tumor 1-α-hydroxylase activity did not explain the 25(OH) D associations. 25 (OH) D 
insufficiency was associated with inferior EFS and OS in DLBCL and T-cell lymphoma. One 
potential interpretation of the association of low 25 (OH)D levels with inferior DLBCL and TCL 
prognosis is that patients with larger tumor burden might have increased conversion of 25 (OH) 
D to 1,25 (OH)2D due to increased 1- α-hydroxylase activity from the tumor, leading to artificially 
low serum 25(OH)D levels. This study did not support the hypothesis that the association of 
lower 25 (OH) D levels were poor prognosis in DLBCL and TCL is confounded by tumor 
production of 1- α-hydroxylase. Further, these data also indicate that there appears to be a 
direct association of lower 1, 25 (OH) 2D levels with inferior outcome.2 
Another study that looked at newly diagnosed follicular lymphoma (FL) was SWOG participants 
that were previously untreated patients with FL enrolled on a clinical trials involving CHOP 
chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab) between 1998 
and 2008 or participants also previously untreated patients with FL enrolled onto the Lymphoma 
Study Association (LYSA) PRIMA trial of rituximab plus chemotherapy (randomly assigned to 
rituximab maintenance versus observation) between 2004 and 2007 had 25-hydroxyvitamin D 
measured at baseline. The primary end point was progression-free survival (PFS). After a 
median follow-up of 5.4 years, the adjusted PFS and overall survival hazard ratios for the 
SWOG cohort were 1.97 (95% CI, 1.10 to 3.53) and 4.16 (95% CI, 1.66 to 10.44), respectively, 
for those who were vitamin D deficient (< 20 ng/mL; 15% of cohort). After a median follow-up of 
6.6 years, the adjusted PFS and overall survival hazard ratios for the LYSA cohort were 1.50 
(95% CI, 0.93 to 2.42) and 1.92 (95% CI, 0.72 to 5.13), respectively, for those who were vitamin 
D deficient (< 10 ng/mL; 25% of cohort). Conclusion of this study demonstrated that although 
statistical significance was not reached in the LYSA cohort, the consistent estimates of 
association between low vitamin D levels and FL outcomes in two independent cohorts 
suggests that serum vitamin D might be the first potentially modifiable factor to be associated 
with FL survival.44 

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We propose to conduct a Pilot study evaluating the effects of vitamin D supplementation on the 
3-year PFS and OS of patients with newly diagnosed or previously untreated (patients may be 
under no treatment “wait and watch” or have received two cycles of chemotherapy before 
informed consent) Non-Hodgkin’s Lymphoma or CLL. 
Section 3.0: Eligibility Criteria: 
3.1  Inclusion 
1. Patients must have histologically confirmed newly diagnosed or previously untreated 
(patients may be under no treatment “wait and watch” or have received two cycles of 
chemotherapy or localized radiation therapy before informed consent) Non-Hodgkin’s 
Lymphoma or CLL. 
2. Patients must be 18 years of age or older (19 years or older in Nebraska). 
3. Patients must have serum 25-hydroxyvitamin D [25(OH) D] drawn at time of enrollment. 
(NOTE: subjects currently taking Vitamin D supplements are eligible for screening. See 
Exclusion 2.) 
4. Simultaneous participation in other therapeutic clinical trials will be allowed. 
5. Patients must be aware of the neoplastic nature of his/her disease and willingly provide 
written, informed consent after being informed of the procedure to be followed, the 
nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. 
3.2  Exclusion 
1. History of uncontrollable allergic reactions to vitamin D 
2. Currently taking vitamin D supplement ≥ 1000 IU/day 
3. History of Paget’s disease. 
4. Hypercalcemia 
5. Any other clinically significant medical disease or condition laboratory abnormality or 
psychiatric illness that, in the Investigator’s opinion, may interfere with protocol 
adherence or a subject’s ability to give informed consent. 
6. Inability to cooperate with the requirements of the protocol. 
 
Section 4.0: Registration and Randomization Procedures: 
4.1  Recruitment 
Patients with newly diagnosed or previously untreated (patients may be under no treatment 
“wait and watch” OR have received two cycles of chemotherapy before informed consent) Non-
Hodgkin’s Lymphoma or CLL may be eligible for this trial. 
Screening eligibility based on standard clinical care will be performed by the treating physician 
at the time of encounter. On initial presentation, a history and physical examination are 
performed, laboratory data obtained, radiologic/imaging, or bone marrow evaluations for staging 
will be performed per standard practice and as clinically indicated and is at the discretion of the 
treating physician. 

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The patient’s primary oncologist will make the decision as to screened eligibility of the candidate 
based on the eligibility criteria listed in Section 3.0 prior to offering consent. 
If the patient is screened as potentially eligible, he/she will then be offered the option to 
participate. An informed consent will be signed by the patient after thorough review of the study 
is completed by the physician and his/her designee. 
Some insurance carriers may decline to cover the costs of usual medical care if the patient is 
participating in a clinical trial. The patient will be provided assistance by the research nurse 
coordinator or designated staff in determining if the insurance carrier will decline coverage. 
Insurance carriers may or may not pay for study related expenses. The patient can then decide 
if they wish to participate. 
4.2  Eligibility Verification/Registration: 
Before subjects are registered to the study, the Eligibility Checklist (Appendix A) must be 
completed to verify the subject meets the eligibility criteria. This will be used as source 
documentation once it has been reviewed, signed, and dated, which should be done prior to 
registration by the treating physician. 
Date of Enrollment: The date of consent will be considered the date of enrollment. 
Subjects will be registered through the sponsor site (UNMC) by contacting the UNMC Project 
Coordinator. Study personnel from UNMC, affiliate and IRB approved non-UNMC sites will 
contact the UNMC Project Coordinator if a potential subject appears to meet the eligibility 
criteria. 
The site will email the following information: 
• 
Registration request (which includes the subject's demographics) 
• 
Completed Eligibility Checklist (Appendix A), and 
• 
Signed consent form. 
Once the UNMC Research Project Coordinator confirms that all documents have been received, 
approval for the patient will be given with an assigned study subject number. The UNMC IIT 
Project Coordinator will send a confirmation of registration email to the site. (Please note: A 
Study Subject ID number can be assigned prior to final confirmation, if needed.) 
Each subject consented to the protocol is loaded into the UNMC Clinical Trial Management 
System (CTMS) within one week of consent. CTMS registration includes entering the required 
demographic information (included on the registration request form) as stated in the SRC 
policies and procedures. For external sites, this is completed by the UNMC Research Project 
Coordinator. 
Section 5.0 Treatment Plan: 
This is a Pilot study evaluating the effects of vitamin D supplementation on the outcomes of 
patients with newly diagnosed or previously untreated (patients may be under no treatment “wait 

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and watch” OR have received two cycles of chemotherapy or localized radiation therapy before 
informed consent) Non-Hodgkin’s Lymphoma or CLL. 
5.1  Randomization plan 
This is a randomized study. All subjects will have a serum 25-hydroxyvitamin D [25(OH) D] 
drawn at time of enrollment. (NOTE: Only subjects currently taking < 1000 IU Vitamin D 
supplements are eligible for screening.) Subjects found to have low levels of serum 25-
hydroxyvitamin D [25(OH) D] <30 ng/ml will be randomized on a 1:1 basis to vitamin D 5000 IU 
daily (Higher Dose Cohort) or vitamin D 1000 IU daily (Lower Dose Cohort) and stratified by 
disease group (aggressive NHL or indolent NHL/CLL). 
The randomization schedule is generated by the study statistician. The randomization schedule 
is then provided to the UNMC research pharmacist. 
Site study personnel will complete the Subject Randomization Request for those subjects 
meeting criteria for randomization and submit this along with the registration request documents 
outlined in Section 4.2 to the UNMC project coordinator. The UNMC research pharmacist will 
assign a randomization number and cohort. When finalizing the registration procedures, the 
randomization assignment is sent to study personnel by the UNMC project coordinator. 
5.2  Evaluations 
Pre-treatment Evaluations Within One Month (30 Days) of Consent: 
• 
History and physical 
• 
Calcium level 
• 
Serum 25-hydroxyvitamin D [25(OH) D] 
• 
Height and weight 
• 
Vital signs, including blood pressure 
If subjects have a normal level of serum 25-hydroxyvitamin D [25(OH) D] ≥ 30 ng/ml at time of 
enrollment, the subject will automatically be enrolled in the controlled group and will be followed 
only for long-term progression free survival and outcome. No further evaluation of serum 25-
hydroxyvitamin D [25(OH) D] will be obtained. (NOTE: Subjects currently taking Vitamin D 
supplements will be encouraged to continue their supplementation.) 
If subjects are found to have low levels of serum 25-hydroxyvitamin D [25(OH) D] <30 ng/ml at 
time of enrollment, the subjects will be randomized to receive either vitamin D 5000 IU (5 
tablets) daily (Higher Dose Cohort) or vitamin D 1000 IU (one tablet) daily (Lower Dose Cohort) 
for three years. To provide a means of ensuring oral routes of medication adherence of patients 
while participating in a clinical trial, Appendix D “Oral, Sublingual, and/or Buccal Route 
Medication Adherence Standard Procedure (V 1.0 11-25-2013)” will be followed. (NOTE: 
Subjects who were currently taking Vitamin D supplements at the time of screening will be 
asked to discontinue the use of their Vitamin D supplementation and use only the Vitamin D 
dosing and supply instructed by the study.) 

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UNMC subjects will take oral over the counter supply through UNMC pharmacy. 
Subjects at affiliate and Non-UNMC IRB approved sites will take oral over the counter Vitamin D 
1000 IU (vitamin D-3, (cholecalciferol)) tablets. Investigators will need to prescribe the 
appropriate dose in which the subject is randomized. 
Follow-up Evaluations 
Subjects randomized to the Vitamin D cohorts: at 6 months, 12 months, and year 2 and 3 (Day 
1095) (+/- 30 days) from registration confirmation: 
• 
Serum 25-hydroxyvitamin D [25(OH) D] (Levels will be measured at a location 
convenient for the patient, for example, at their local primary care provider office.) 
After year 3 (1095 days), the investigator will discuss continuation of Vitamin D supplementation 
recommendations with the subject. The supply of any recommendations for continued Vitamin D 
will be at the subjects cost. 
Control group subjects: disease status must be assessed at the end of 3 years. Three years is 
defined as from the time of registration confirmation to day 1095 (+/- 180 days). For subjects no 
longer being followed by the study site, an attempt should be made by contacting the referring 
physician or reaching out to the subject at the 3-year time point to assess survival or 
progression free survival status. Contact and subject status should be documented in the 
medical record. 
Covid Visit Exceptions: 
If a subject visit is cancelled due to Covid concerns, then the study staff will confirm with the 
subject that they have an adequate supply of the study vitamin D supplement to continue daily 
dosing as prescribed. 
The lab work required for the study will be collected at their next visit. 
The Vitamin D administration diary may be collected at their next visit or via US Mail. 
The visit will be documented as delayed due to Covid. The visit schedule will otherwise be 
maintained so that subject is on study for 3 years per protocol. The above will be fully 
documented in the medical record. 
 
 
Dose Modifications based on vitamin D levels at 6 month, 12 month and year 2 and 3. 
If subject is at a normal level (30-100 ng/ml) of 25-hydroxyvitamin D [25(OH) D], no change in 
intervention will be made. 
If the subject has a low level of 25-hydroxyvitamin D [25(OH) D], which is defined as [OH] D< 
30 ng/ml, then the dose that they are currently enrolled in will be increased 1000 IU (e.g. 5000 

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IU increase to 6000 IU; 1000 IU increase to 2000 IU). There will be a maximum dose of 10000 
IU daily. 
If a subject has an elevated level of 25-hydroxyvitamin D [25(OH) D], which is defined as [OH] 
D> 100 ng/ml, then the dose will be held for one month and a level will be rechecked. If the 
repeat level is < 100 mg/ml, the dose will be cut in half and re-tested in two months. 
After the 12 month time point, if Vitamin D levels are not within normal limits, the investigator 
may manage subjects as clinically indicated, i.e. levels can be monitored more frequently than 
annually. Dose adjustment will be managed according to guidelines above or as recommended 
by the patient's primary care physician or Endocrinologist. 
5.3  Removal of Patients from Protocol Therapy 
If at any time the constraints of this protocol are detrimental to the patient's well-being, or if the 
patient is unable to comply with the requirements of the protocol, the patient will be removed 
from protocol therapy. 
5.4  Development of intercurrent medical problems that would make continued protocol therapy 
detrimental to the patient’s safety 
If a non-treatment related intercurrent illness is expected to be of limited nature, then treatment 
may be delayed for more than 2 weeks. In this case, the patient would need to be re-evaluated 
before resuming protocol therapy. 
5.5  Patient chooses to discontinue treatment or follow-up 
In this event, the reason(s) for withdrawal will be documented. 
The reason(s) for withdrawing the patient from the treatment portion of the study will be 
documented in the case report form. If available, the following information will be recorded in the 
case report form: date of disease relapse, date of death, cause of death, and autopsy report. 
Section 6.0 Measurement of Effect: 
To avoid assay variability which can confound vitamin D determinations a radioimmunoassay 
method will be used to measure all vitamin D measurements by liquid chromatography-tandem 
mass spectrometry (LC-MS/MS) (this is the Nebraska Medicine’s standard). Calibration used a 
6-point standard curve over a concentration range 0-100 ng/mL. This is the preferred test for 
assessment of vitamin D is serum 25-hydroxyvitamin D (25(OH) D). The reason for this test is 
because it is minimally influenced by recent dietary intake or recent sun exposure, and it is 
considered the most accurate functional indicator of vitamin D stores. However, if this method 
is not available, the method used by the local lab will be acceptable. 
Study ranges used: 
• 
<30 is considered inadequate 
• 
30-80 Adequate 

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• 
>150 Potentially toxic vitamin D level 
6.1  Toxicity criteria 
This trial will assess only the grade 3 and 4 toxicities related to the Vitamin D administration. 
The NCI Common Toxicity Criteria Adverse Events (CTCAE) Version 4 (Appendix B) will be 
used to grade toxicity. It is available at the following internet site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
6.2  Survival 
Subjects will be analyzed with respect to overall and progression-free survival. 
Overall survival is defined as time from study entry until death from any cause. For subjects who 
are still alive at the time of the study analysis or are lost to follow-up, survival will be censored at 
the last recorded date that the subject was known to be alive. 
Progression-free survival is defined as time from study entry until the first notation of clinical 
progression, relapse, starting new therapies or death from any cause. For subjects who are still 
progression-free at the time of the study analysis or are lost to follow-up, progression-free will 
be censored at the last recorded date that the subject was known to be progression-free. 
Response will be determined by the Principal Investigator or the lead site investigators. 
Section 7.0 Study Parameters: 
 
Low Levels <30 ng/mL - RANDOMIZED GROUP 
Pre-
Treatment 
(within 30 days 
of Consent) 
First 
Dose 
6 months 
Day 182 
(+/- 30 
Days) 
12 months 
Day 365 
(+/- 30 Days) 
Year 2 
Day 730 
(+/- 30 Days) 
Year 3 
Day 1095 
(+/- 30 Days) 
End of Study 
History & Physical 
X 
Height, Weight, 
Vital Signs 
X 
Monitor for Vitamin 
D related AEs 
X 
X 
X 
X 
Serum Calcium 
X 
Serum 25- 
hydroxyvitamin D 
[25(OH) D] 
X 
X 
X 
X 
X 
Vitamin D 
X - Daily Dosing at Home for 3 years 
Long-term 
progression free 
survival and 
outcome1 
X 

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Normal Level >30ng/ml - CONTROL GROUP* 
Followed only for long-term progression free survival and outcome. No further evaluation of serum 25-hydroxyvitamin D [25(OH) D] 
will be obtained. (NOTE: subjects currently taking Vitamin D supplements will be encouraged to continue their supplementation.) 
Required studies 
Pre-Treatment 
(Within 30 days of 
Consent) 
Year 3 - Day 1095 
(+/- 180 Days) 
End of Study 
History & Physical 
X 
Height, Weight, Vital Signs 
X 
Serum Calcium 
X 
Serum 25-hydroxyvitamin D [25(OH) D] 
X 
Long-term progression free survival and outcome1 
X 
 
1 Progression defined as relapse, progression, or starting new therapies, or death 
 
Section 8.0 Drug Formulation and Procurement (per UNMC Lexicomp Online): 
8.1  Clinical Overview 
Vitamin D (Natural Products Database) 
Common Name(s): Sunshine vitamin; Vitamin D 
8.1.1 Uses 
Vitamin D, long recognized as playing a role in bone and calcium homeostasis, is being 
investigated for use in cardiovascular disease, cancer, diabetes, infections, multiple sclerosis, 
psoriasis, respiratory health, and other conditions. More clinical trials are needed. 
8.1.2 Dosing 
The American Academy of Pediatrics recommends 400 units/day of vitamin D in infants and 
adolescents. Clinical data are not yet sufficiently robust to make definitive recommendations for 
therapeutic dosages of vitamin D; however, in the elderly, 700 to 1,000 units/day have been 
shown to reduce the risk of falls. 
8.1.3 Contraindications 
Contraindications have not been identified. 
8.1.4 Pregnancy/Lactation 
Routine use of supplemental vitamin D during pregnancy is not supported by safety evidence. 
However, adequate maternal intake of vitamin D-containing foods during lactation ensures that 
breast-fed infants receive sufficient vitamin D. 

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8.1.5 Interactions 
The use of statins has been shown to increase serum vitamin D levels. Corticosteroids 
decrease the metabolism of vitamin D and orlistat reduces its absorption; phenobarbital and 
phenytoin increase the hepatic metabolism of vitamin D. 
8.1.6 Adverse Reactions 
High doses of vitamin D have rarely produced adverse events in clinical trials. 
8.1.7 Toxicology 
Toxicity due to vitamin D is considered to manifest at serum levels greater than 150 ng/mL of 
25-hydroxyvitamin D. Symptoms of hypervitaminosis D include fatigue, nausea, vomiting, and 
weakness associated with hypercalcemia. (Page 27 sites more toxicity details) 
8.1.8 Source 
Vitamin D3 (cholecalciferol) is synthesized in the skin by transformation of 7-dehydrocholesterol 
exposed to ultraviolet B rays of the midday sun. Vitamin D binding protein transports D3 to the 
liver, where it is hydroxylated to the inactive 25-hydroxyvitamin D form (calcidiol). In the kidneys, 
it is further hydroxylated by the enzyme 1-alpha-hydroxylase to active 1, 25-dihydroxyvitamin D 
(calcitriol).Ref 
Vitamin D as ergocalciferol (vitamin D2) is found in some plants and in salmon, sardines, 
mackerel, tuna, cod liver oil, shiitake mushrooms, egg yolk, and fortified foods.Ref Deficiency 
may result from decreased absorption (such as in cystic fibrosis, celiac and Crohn diseases, 
and drug interactions), increased catabolism (caused by anticonvulsant and antiretroviral 
therapy and some immunosuppressant drugs), and hepatic and renal failure, as well as from 
inadequate intake.Ref 
8.1.9 Chemistry 
Vitamin D is a hormone precursor and acts to control calcium absorption in the small intestine. It 
affects parathyroid hormone, which in turn affects the metabolism of skeletal mineralization and 
calcium homeostasis in the blood. Additionally, effects on cytokines and immune-modulating 
effects are reported.Ref 
The accepted biomarker is 25-hydroxyvitamin D (or calcidiol). Only in advanced renal disease 
are measurements of 1, 25-dihydroxyvitamin D (calcitriol) relevant.Ref Concern over 
standardization of assays exists.Ref 
8.2  Uses and Pharmacology 
8.2.1 Cancer 
8.2.1.1 Animal data 

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Preclinical studies have shown an effect of vitamin D on a variety of cancer cell lines. Cell cycle 
interruption, apoptosis, and other mechanisms have been demonstrated.Ref 
8.2.1.2 Clinical data 
Meta-analyses of observational studies suggest a lower incidence of cancer with higher vitamin 
D serum levels.Ref Particular attention has focused on breast, colon, and prostate cancer. In the 
Women's Health Initiative study, no association was found between vitamin D and breast 
cancerRef while the Health Professionals Follow-Up Study suggested a decreased risk of cancer 
with increasing 25-hydroxyvitamin D levels.Ref In a meta-analysis evaluating the effects of 
vitamin D supplementation on overall mortality risk, a subgroup analysis (n = 13 in studies) of 
long-term vitamin D supplementation for at least 3 years revealed a significant reduction in 
cancer mortality (relative risk [RR] = 0.88; 95% confidence interval [CI], 0.79 to 0.98).Ref 
The American Society of Clinical Oncology clinical practice guideline adaptation for the 
screening, assessment, and management of fatigue in adult survivors of cancer (2014) notes 
that results from small pilot studies on the effectiveness of supplements, such as vitamin D, for 
managing cancer-related fatigue are equivocal (inconclusive).Ref 
8.2.2 Cardiovascular 
Vitamin D is thought to exert cardiovascular effects by a number of mechanisms, including 
effects on the renin-angiotensin-aldosterone system, homeostasis of calcium, and secondary 
effects on hyperparathyroidism and insulin resistance.Ref 
8.2.2.1 Animal data 
Available data from large clinical trials make animal data largely redundant. 
8.2.2.2 Clinical data 
No clinically important effect on coronary or cerebrovascular risk or outcomes was found with 
vitamin D and calcium supplementation over 7 years in the Women's Health Initiative 
randomized trial.Ref Other systematic reviews of clinical trials have largely found no effect of 
vitamin D supplementation on cardiovascular outcomes and hypertension.Ref Based on limited 
trial data in populations with vitamin D insufficiency, moderate to high doses of vitamin D 
increase the serum vitamin D metabolite status and may reduce cardiovascular risk; however, 
further studies are required before a definitive place in therapy can be established.Ref In a meta-
analysis evaluating the effects of vitamin D supplementation on overall mortality risk, a 
subgroup analysis (n = 13 in studies) of long-term vitamin D supplementation for at least 3 years 
revealed no reduction in cardiovascular mortality.Ref 
8.2.3 Diabetes 
8.2.3.1 Animal data 
Animal studies suggest vitamin D exerts effects on the homeostasis of glucose metabolism, as 
supplementation in animals has led to decreases in plasma glucose.Ref A direct effect on insulin 

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secretion has been suggested, as well as effects on insulin receptor expression, insulin 
sensitivity, and direct action on insulin itself.Ref 
8.2.3.2 Clinical data 
Epidemiological data support a role of vitamin D in reducing the incidence of diabetes. Vitamin 
D supplementation in infants has been associated with a decreased risk of type 1 diabetes, and 
a meta-analysis has demonstrated an association between low vitamin D status and the 
prevalence of type 2 diabetes or metabolic syndrome.Ref However, limited, small studies have 
shown equivocal results on the impact of vitamin D on serum glucose.Ref A 12-month, double-
blind, randomized controlled trial (n = 86) in adults with type 2 diabetes mellitus and vitamin D 
deficiency (median, 11.9 ng/mL), found that vitamin D supplementation (1,904 units/day) for 6 
months did not significantly affect blood glucose, insulin levels, HbA1c, systolic blood pressure, 
or body weight. However, a significant correlation was observed between vitamin D levels and 
HbA1c with the lowest HbA1c occurring at less than 20 ng/mL.Ref Similar results were seen in 
another double-blind randomized clinical trial conducted in 158 Koreans with type 2 diabetes 
and vitamin D deficiency or insufficiency who supplemented their diet with 2,000 units/day of 
vitamin D3 plus calcium for 24 weeks. Neither glycemic control nor HbA1c were significantly 
different in patients treated with vitamin D plus calcium compared with those treated with only 
calcium supplementation.Ref Interestingly, in a meta-analysis evaluating the effects of vitamin D 
supplementation on overall mortality risk, a subgroup analysis (n = 13 in studies) of long-term 
vitamin D supplementation for at least 3 years revealed a reduction in mortality only when 
vitamin D plus calcium was compared with placebo but not when compared with calcium, and 
not when vitamin D alone was compared with placebo. Other long-term subgroup benefits 
appeared in patients younger than 80 years, with a dose of 800 units or less, and in patients 
with a baseline 25-hydroxyvitamin D level less than 50 nmol/L. The meta-analysis primary 
outcome (n = 42 intervention randomized clinial trials; N = 85,466 patients) identified a decrease 
in all-cause mortality when vitamin D supplementation was continued for 3 years or longer (P = 
0.001); heterogeneity was insignificant.Ref 
As a component of medical nutrition therapy for patients with type 1 or type 2 diabetes, the 
American Diabetes Association Standards of Care (2014 and 2015) does not support routine 
supplementation with micronutrients such as vitamin D to improve glycemic control (low-quality 
evidence).Ref 
8.2.4 Infectious disease 
Vitamin D receptors are ubiquitous in the body and are found in immune system-related cells, 
such as B and T lymphocytes, neutrophils, and macrophages. An emerging role is being 
described for vitamin D in immune response.Ref 
The Randomized Evaluation of Calcium or Vitamin D (RECORD) trial investigated the effect of 
vitamin D supplementation (800 units/day) on self-reported infections and antibiotic use but did 
not find a statistically significant association.Ref A single dose of vitamin D demonstrated an 
enhanced immune response in a randomized clinical trial in tuberculosis patientsRef while a 
systematic review of clinical trials evaluating the effect of vitamin D supplementation (largely in 

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tuberculosis, influenza, and other viral infections) concluded that further studies are 
warranted.Ref 
Despite a significant increase in serum 25-hydroxyvitamin D, the recurrence of bacterial 
vaginosis in women being treated at an urban sexually-transmitted disease clinic was not 
significantly reduced by vitamin D supplementation (50,000 units × 9 doses) over 24 weeks. The 
trial was a randomized, placebo-controlled, double-blind study (N = 118).Ref 
8.2.5 Multiple sclerosis 
Theoretical and epidemiological models support a place in therapy for vitamin D in multiple 
sclerosis. An inverse relationship has been demonstrated between vitamin D levels and multiple 
sclerosis, especially in patients younger than 20 years of age, while the development of multiple 
sclerosis in women has been associated with low 25-hydroxyvitamin D levels. Lower serum 
vitamin D and severity of multiple sclerosis, as well as incidence of relapses, has also been 
demonstrated.Ref 
Little prospective data exist; however, a small clinical study (N = 12) showed a decrease in the 
number of lesions with magnetic resonance imaging with administration of 1 mg (40,000 units) 
daily over 28 weeks.Ref No serious adverse events were reported at this dosage, and no 
hypercalcemia or hypercalciuria was reported. 
8.2.6 Renal 
8.2.6.1 Animal data 
Available data from large clinical trials make animal data largely redundant. 
8.2.6.2 Clinical data 
As kidney function is impaired, the inability to maintain adequate phosphorus and calcium levels 
results in compensatory mechanisms involving parathyroid hormone. Resultant increases in 
bone metabolism to release calcium to the system cause bone deformation, pain, and an 
increased risk of fractures. Supplementation of vitamin D suppresses parathyroid hormone, but 
it may also slow the progression of chronic kidney disease via novel pathways. Vitamin D 
analogs, such as paricalcitol, may exert anti-inflammatory effects, as well as affect the renin-
angiotensin systems and decrease morbidity and mortality. However, studies are limited.Ref A 
randomized, double-blind trial in chronic dialysis patients (n = 50) observed no improvement in 
cardiac function as measured by 24-hour blood pressure, arterial stiffness, and cardiac function 
in patients treated for 6 months with 75 mcg (3,000 units) or placebo. Although, left ventricular 
end-diastolic function was increased significantly in the treatment group (P = 0.024).Ref 
8.2.7 Other uses 
8.2.7.1 Alopecia 
The role of vitamin D and its receptors is not well understood, but the potential for topical 
calcitriol to upregulate the receptors has been evaluated in animal models of chemotherapy- 

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induced alopecia. Hair loss is not prevented; however, hair regrowth over the entire animal has 
been demonstrated.Ref Limited clinical studies have produced varying results, possibly 
dependent on the chemotherapeutic agent.Ref 
8.2.7.2 Atopic eczema/dermatitis 
A 2012 Cochrane review identified 2 randomized clinical trials evaluating vitamin D for atopic 
eczema/dermatitis that met criteria for analysis. Vitamin D supplementation alone did not 
provide significant benefit over placebo in any of the primary, secondary, or tertiary outcomes. 
However, vitamin D (cholecalciferol 1,600 units) and E (600 units alpha-tocopherol) combination 
therapy resulted in a significant difference in severity scores at the end of 60-day treatment, as 
well as improvement in dryness, pruritis, and erythema compared with placebo in 52 adults and 
children older than 13 years of age.Ref 
8.2.7.3 Dementia/Depression 
Observational studies and animal models suggest a role for vitamin D in treating dementia. 
Vitamin D exerts antioxidant effects, and receptors are found in the human cortex and 
hippocampus. Correlations between the Mini-Mental State Examination scores and vitamin D 
serum levels, as well as global cognitive function, have been shown.Ref One clinical trial 
demonstrated an improvement in mild depression with vitamin D supplementation.Ref 
8.2.7.4 Falls in the elderly 
Systematic reviews have been conducted on the effects of supplemental vitamin D and the risk 
of falls in the elderly.Ref Low doses (200 to 600 units/day) showed no effect, while higher doses 
(700 to 1,000 units/day) reduced the risk of falling in the elderly by 19% to 22%.Ref 
8.2.7.5 Mortality 
A meta-analysis of 32 studies published and indexed between 1966 and 2013 evaluated the 
relationship between vitamin D (25-hydroxyvitamin D) and all-cause mortality in healthy 
participants as well as patients in clinic cohorts. The age-adjusted death rate in individuals with 
vitamin D levels in the lowest quantile (0 to 9 ng/mL) was almost twice that of those in the 
highest quantile (more than 35 ng/mL). The pooled dose-response curve declined steeply 
between 0 and 30 to 39 ng/mL and flattened at greater than 50 ng/mL, with all-cause mortality 
being significantly higher when levels were up to 30 ng/mL (P < 0.01).Ref 
8.2.7.6 Psoriasis 
Topical synthetic vitamin D (eg, tacalcitol) may be an alternative to topical steroids and may 
inhibit keratinocyte proliferation, as well as influence immune modulation.Ref 
8.2.7.7 Respiratory health 
Vitamin D appears to be capable of inhibiting the pulmonary inflammatory response and 
enhancing pulmonary defense against pathogens. Population-based studies support an 
association between circulating vitamin D levels and lung function.Ref The use of vitamin D in 

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cystic fibrosis is based on knowledge of vitamin insufficiency due to pancreatic insufficiency; 
however, evidence of benefit is lacking for vitamin D supplementation despite routine use.Ref 
Addition of high-dose vitamin D3 (100,000 units for 1 dose, then 4,000 units/day x 28 weeks) to 
inhaled corticosteroid therapy (ciclesonide 320 mcg/day) in adults with symptomatic asthma and 
low vitamin D3 levels who failed previous treatment, did not significantly alter the rate of first 
treatment failure or overall treatment failure.Ref 
8.2.7.8 Dosing 
Clinical response to vitamin D does not always correspond with serum levels of the markers.Ref 
Generally, a serum level of less than 20 ng/mL of 25-hydroxyvitamin D constitutes a deficiency 
in adults and children.Ref 
The American Academy of Pediatrics recommends 400 units/day vitamin of D in infants and 
adolescents.Ref 
To maintain a serum 25-hydroxyvitamin D level of 25 ng/mL, independently living elderly adults 
required vitamin D 7.9 to 42.8 mcg daily in a clinical studyRef (20 mcg is equivalent to 800 
units).Ref Data from clinical studies are not yet sufficiently robust to make definitive 
recommendations for therapeutic dosages of vitamin D; however, in the elderly, 700 to 1,000 
units/day have been shown to reduce the risk of falls.Ref 
8.2.7.9 Pregnancy/Lactation 
The safety and efficacy of vitamin D in pregnancy has not been confirmed. Clinical trials have 
evaluated the excretion of vitamin D in breast milk by mothers given supplementation. Adequate 
levels of vitamin D are achieved in breast-fed infants from mothers with a vitamin D intake of 
400 units/day. All milk formulas sold in the United States contain at least 400 units/L of vitamin 
D.Ref 
8.3  Interactions 
The use of statins has been shown to increase serum vitamin D levels.Ref Corticosteriods 
decrease the metabolism and orlistat reduces absorption of vitamin D, while phenobarbital and 
phenytoin increase the hepatic metabolism of vitamin D.Ref 
8.4  Adverse Reactions 
High doses of vitamin D have rarely produced adverse events in clinical trials.Ref 
Apart from the obvious hazards, prolonged sun exposure alone cannot cause vitamin D 
overdose because sunlight destroys excess vitamin D3.Ref 
8.5  Toxicology 
Toxicity due to vitamin D is considered to manifest at levels greater than 150 ng/mL of serum 
25-hydroxyvitamin D. Symptoms of hypervitaminosis D include fatigue, nausea, vomiting, and 
weakness associated with hypercalcemia.Ref Reports of toxicity exist for children administered 

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high-dose vitamin D after World War II in Europe. Hypercalcemia, nephrocalcinosis, adverse 
cardiovascular effects, early aging, and premature death were reported.Ref 
Hypervitaminosis D in 2 young brothers was reported subsequent to an overdose of an OTC 
vitamin D supplement that resulted from 2 simultaneous dosing errors; the OTC product 
(Merluzzovis cod liver oil-based capsules) contained approximately 1,000 times the labeled 
vitamin D content per capsule, and the mother administered twice the dose as recommended on 
the label. After 1 month of supplementation, the 12-year-old had received a total of 7,632,000 
units (254,490 units/day instead of the recommended 400 units/day) and was hospitalized for 
abdominal pain, constipation, vomiting, hypercalcemia, suppressed parathyroid, and acute renal 
failure. The 15-year-old brother had received a total of 3,180,000 units over the previous 2 
weeks, was asymptomatic, normocalcemic, and had normal renal function. Their vitamin D 
levels were well over the toxic lower limit (150 ng/mL) and were 535 ng/mL and 484.9 ng/mL, 
respectively. The 12-year-old was normocalcemic and had normal renal function within 1 month 
of discharge.Ref 
8.6  References for Section 8.0 
1. Kulie T, Groff A, Redmer J, Hounshell J, Schrager S. Vitamin D: an evidence-based review. J 
Am Board Fam Med. 2009;22(6):698-706.[PubMed 19897699] 
2. Office of Dietary Supplements. Vitamin D Fact Sheet. National Institutes of Health, Bethesda, 
USA. http://ods.od.nih.gov. 
3. Sage RJ, Lim HW. Therapeutic Hotline: Recommendations on photoprotection and vitamin D. 
Dermatol Ther. 2010;23(1):82-85.[PubMed 20136911] 
4. Collins N, Spaulding-Albright N. Vitamin D deficiency: shining new light on the sun nutrient. 
Ostomy Wound Manage. 2009;55(4):14, 16-17.[PubMed 19603572] 
5. Trump DL, Deeb KK, Johnson CS. Vitamin D: considerations in the continued development 
as an agent for cancer prevention and therapy. Cancer J. 2010;16(1):1-9.[PubMed 20164683] 
6. Chiang KC, Chen TC. Vitamin D for the prevention and treatment of pancreatic cancer. World 
J Gastroenterol. 2009;15(27):3349-3354.[PubMed 19610135] 
7. Bischoff-Ferrari H. Health effects of vitamin D. Dermatol Ther. 2010;23(1):23-30.[PubMed 
20136906] 
8. Gupta D, Lammersfeld CA, Trukova K, Lis CG. Vitamin D and prostate cancer risk: a review 
of the epidemiological literature. Prostate Cancer Prostatic Dis. 2009;12(3):215-226.[PubMed 
19350051] 
9. Chlebowski RT, Johnson KC, Kooperberg C, et al; Women's Health Initiative Investigators. 
Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst. 
2008;100(22):1581-1591.[PubMed 19001601] 
10. Pilz S, Tomaschitz A, Ritz E, Pieber TR; Medscape. Vitamin D status and arterial 
hypertension: a systematic review. Nat Rev Cardiol. 2009;6(10):621-630.[PubMed 19687790] 
11. Hsia J, Heiss G, Ren H, et al; Women's Health Initiative Investigators. Calcium/vitamin D 
supplementation and cardiovascular events. Circulation. 2007;115(7):846-854.[PubMed 
17309935] 
12. Margolis KL, Ray RM, Van Horn L, et al; Women's Health Initiative Investigators. Effect of 
calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative 
Randomized Trial. Hypertension. 2008;52(5):847-855.[PubMed 18824662] 
13. Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic 
review and meta-analysis. J Hypertens. 2009;27(10):1948-1954.[PubMed 19587609] 

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14. Pittas AG, Chung M, Trikalinos T, et al. Systematic review: Vitamin D and cardiometabolic 
outcomes. Ann Intern Med. 2010;152(5):307-314.[PubMed 20194237] 
15. Zittermann A, Frisch S, Berthold HK, et al. Vitamin D supplementation enhances the 
beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr. 
2009;89(5):1321-1327.[PubMed 19321573] 
16. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium 
supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152(5):315-
323.[PubMed 20194238] 
17. Ozfirat Z, Chowdhury TA. Vitamin D deficiency and type 2 diabetes. Postgrad Med J. 
2010;86(1011):18-25.[PubMed 20065337] 
18. Teegarden D, Donkin SS. Vitamin D: emerging new roles in insulin sensitivity. Nutr Res Rev. 
2009;22(1):82-92.[PubMed 19555519] 
19. Baz-Hecht M, Goldfine AB. The impact of vitamin D deficiency on diabetes and 
cardiovascular risk. Curr Opin Endocrinol Diabetes Obes. 2010;17(2):113-119.[PubMed 
20150805] 
20. Chesney RW. Vitamin D and The Magic Mountain: the anti-infectious role of the vitamin. J 
Pediatr. 2010;156(5):698-703.[PubMed 20385316] 
21. Walker VP, Modlin RL. The vitamin D connection to pediatric infections and immune 
function. Pediatr Res. 2009;65(5, pt 2):106R-113R.[PubMed 19190532] 
22. Avenell A, Cook JA, Maclennan GS, Macpherson GC. Vitamin D supplementation to prevent 
infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, 
ISRCTN 51647438). Age Ageing. 2007;36(5):574-577.[PubMed 17702768] 
23. Martineau AR, Wilkinson RJ, Wilkinson KA, et al. A single dose of vitamin D enhances 
immunity to mycobacteria. Am J Respir Crit Care Med. 2007;176(2):208-213.[PubMed 17463418] 
24. Yamshchikov AV, Desai NS, Blumberg HM, Ziegler TR, Tangpricha V. Vitamin D for 
treatment and prevention of infectious diseases: a systematic review of randomized controlled 
trials. Endocr Pract. 2009;15(5):438-449.[PubMed 19491064] 
25. Myhr KM. Vitamin D treatment in multiple sclerosis. J Neurol Sci. 2009;286(1-2):104-
108.[PubMed 19549608] 
26. Sioka C, Kyritsis AP, Fotopoulos A. Multiple sclerosis, osteoporosis, and vitamin D. J Neurol 
Sci. 2009;287(1-2):1-6.[PubMed 19800081] 
27. Pierrot-Deseilligny C. Clinical implications of a possible role of vitamin D in multiple sclerosis. 
J Neurol. 2009;256(9):1468-1479.[PubMed 19399382] 
28. Palmer SC, McGregor DO, Craig JC, Elder G, Macaskill P, Strippoli GF. Vitamin D 
compounds for people with chronic kidney disease requiring dialysis. Cochrane Database Syst 
Rev. 2009;(4):CD005633.[PubMed 19821349] 
29. Li M, Batuman V. Vitamin D: a new hope for chronic kidney disease? Kidney Int. 
2009;76(12):1219-1221.[PubMed 19946310] 
30. Williams S, Malatesta K, Norris K. Vitamin D and chronic kidney disease. Ethn Dis. 
2009;19(4)(suppl 5):S5-8-11.[PubMed 20077598] 
31. Amor KT, Rashid RM, Mirmirani P. Does D matter? The role of vitamin D in hair disorders 
and hair follicle cycling. Dermatol Online J. 2010;16(2):3.[PubMed 20178699] 
32. Grant WB. Does vitamin D reduce the risk of dementia? J Alzheimers Dis. 2009;17(1):151-
159.[PubMed 19494440] 
33. Annweiler C, Allali G, Allain P, et al. Vitamin D and cognitive performance in adults: a 
systematic review. Eur J Neurol. 2009;16(10):1083-1089.[PubMed 19659751] 
34. Bertone-Johnson ER. Vitamin D and the occurrence of depression: causal association or 
circumstantial evidence? Nutr Rev. 2009;67(8):481-492.[PubMed 19674344] 
35. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with 
supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. 
BMJ. 2009;339:b3692.[PubMed 19797342]10.1136/bmj.b3692 

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36. Bikle DD. Vitamin D and the skin. J Bone Miner Metab. 2010;28(2):117-130.[PubMed 
20107849] 
37. Miller J, Gallo RL. Vitamin D and innate immunity. Dermatol Ther. 2010;23(1):13-22.[PubMed 
20136905] 
38. Tanghetti EA. The role of topical vitamin D modulators in psoriasis therapy. J Drugs 
Dermatol. 2009;8(8)(suppl):s4-s8.[PubMed 19702030] 
39. Hughes DA, Norton R. Vitamin D and respiratory health. Clin Exp Immunol. 2009;158(1):20-
25.[PubMed 19737226] 
40. Ferguson JH, Chang AB. Vitamin D supplementation for cystic fibrosis. Cochrane Database 
Syst Rev. 2009;(4):CD007298.[PubMed 19821402] 
41. Bordelon P, Ghetu MV, Langan RC. Recognition and management of vitamin D deficiency. 
Am Fam Physician. 2009;80(8):841-846.[PubMed 19835345] 
42. Bischoff-Ferrari H. Vitamin D: what is an adequate vitamin D level and how much 
supplementation is necessary? Best Pract Res Clin Rheumatol. 2009;23(6):789-795.[PubMed 
19945690] 
43. Cashman KD, Wallace JM, Horigan G, et al. Estimation of the dietary requirement for vitamin 
D in free-living adults ≥ 64 y of age. Am J Clin Nutr. 2009;89(5):1366-1374.[PubMed 19297462] 
44. Aloia JF, Li-Ng M, Pollack S. Statins and vitamin D. Am J Cardiol. 
2007;100(8):1329.[PubMed 17920383] 
45. Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A. Vitamin D, nervous system and 
aging. Psychoneuroendocrinology. 2009;34(suppl 1):S278-S286.[PubMed 19660871] 
46. Bath-Hextall FJ, Jenkinson C, Humphreys R, Williams HC. Dietary supplemenets for 
established atopic eczema (review). Cochrane Database Syst Rev. 2012;2:CD005205.[PubMed 
22336810] 
47. Castro M, King TS, Kunselman SJ, et al; National Heart, Lung, and Blood Institute’s 
AsthmaNet. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic 
asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA. 
2014;311(20):2083-2091.[PubMed 24838406] 
48. Salehpour A, Shidfar F, Hosseinpanah F, Vafa M, Razaghi M, Amiri F. Does vitamin D3 
supplementation improve glucose homeostasis in overweight or obese women? A double-blind, 
randomized, placebo-controlled clinical trial. Diabet Med. 2013;30:1477-1481.[PubMed 23822797] 
49. Bower JE, Bak K, Berger A, et al. Screening, Assessment, and Management of Fatigue in 
Adult Survivors of Cancer: An American Society of Clinical Oncology Clinical Practice Guideline 
Adaptation. J Clin Oncol. 2014 Apr 21. [Epub ahead of print] [PubMed 24733803] 
50. American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes 
Care. 2014;37(suppl 1):S14-S80.[PubMed 24357209] 
51. Strobel F, Reusch J, Penna-Martinez M, et al. Effect of a randomised controlled vitamin D 
trial on insulin resistance and glucose metabolism in patients with type 2 diabetes mellitus. 
Horm Metab Res. 2014;46:54-58.[PubMed 24198221] 
52. Mose FH, Vase H, Larsen T, et al. Cardiovascular effects of cholecalciferol treatment in 
dialysis patients – a randomized controlled trial. BMC Nephrol. 2014;15:50.[PubMed 24661355] 
53. Garland CF, Kim JJ, Mohr SB, et al. Meta-analysis of all-cause mortality according to serum 
25-hydroxyvitamin D. Am J Public Health. 2014;104:e43-e50.[PubMed 24922127] 
54. Ryu OH, Lee S, Yu J, Choi MG, Yoo HJ, Mantero F. A prospective randomized controlled 
trial of the effects of vitamin D supplementation on long-term glycemic control in type 2 diabetes 
mellitus of Korea. Endocrine J. 2014;61(2):167-176.[PubMed 24240575] 
55. Zheng Y, Zhu J, Zhou M, Cui L, Yao W, Liu Y. Meta-analysis of long-term vitamin D 
supplementation on overall mortality. PLoS ONE. 2013.8(12):e82109.[PubMed 24349197] 
56. Conti G, Chirico V, Lacquaniti A, et al. Vitamin D intoxication in two brothers: be careful with 
dietary supplements. J Pediatr Endocr Met. 2014;27(7-8):763-767.[PubMed 24670344] 

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57. Turner AN, Reese PC, Fields KS,et al. A blinded, randomized controlled trial of high-dose 
vitamin D supplementation to reduce recurrence of bacterial vaginosis. Am J Obstet Gynecol. 
2014;211(5):479.e1-479.e13.[PubMed 24949544] 
58. Beveridge LA, Struthers AD, Khan F, et al; D-PRESSURE Collaboration. Effect of vitamin D 
supplementation on blood pressure: a systematic review and meta-analysis incorporating 
individual patient data. JAMA Intern Med. 2015 Mar 16.[PubMed 25775274] 
59. Standards of medical care in diabetes-2015: summary of revisions. Diabetes Care. 
2015;(suppl 38):S4.[PubMed 25537706] 
 
Disclaimer 
This information relates to an herbal, vitamin, mineral or other dietary supplement. This product 
has not been reviewed by the FDA to determine whether it is safe or effective and is not subject 
to the quality standards and safety information collection standards that are applicable to most 
prescription drugs. This information should not be used to decide whether or not to take this 
product. This information does not endorse this product as safe, effective, or approved for 
treating any patient or health condition. This is only a brief summary of general information 
about this product. It does NOT include all information about the possible uses, directions, 
warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This 
information is not specific medical advice and does not replace information you receive from 
your health care provider. You should talk with your health care provider for complete 
information about the risks and benefits of using this product. 
This product may adversely interact with certain health and medical conditions, other 
prescription and over-the-counter drugs, foods, or other dietary supplements. This product may 
be unsafe when used before surgery or other medical procedures. It is important to fully inform 
your doctor about the herbal, vitamins, mineral or any other supplements you are taking before 
any kind of surgery or medical procedure. With the exception of certain products that are 
generally recognized as safe in normal quantities, including use of folic acid and prenatal 
vitamins during pregnancy, this product has not been sufficiently studied to determine whether it 
is safe to use during pregnancy or nursing or by persons younger than 2 years of age. 
Section 9.0 Toxicity Reporting Guidelines: 
This protocol will comply with monitoring and adverse event reporting requirements of the 
UNMC/Fred & Pamela Buffett Cancer Center Data Monitoring plan. The protocol will adhere to 
the institutional and FDA guidelines for the toxicity reporting. 
Grade 3 and 4 adverse events (AEs) related to the Vitamin D administration will be graded 
according to the National Cancer Institute Common Terminology, Criteria for Adverse Events 
(NCI-CTCAE), version 4.0, which can be accessed at the following URL. 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
The over the counter agent used in the protocol is commercially available with a well-
characterized toxicity profile. 

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All subjects will be closely followed for grade 3 and 4 toxicity/adverse events related to the 
Vitamin D administration from the time that the first dose of study drug is administered and 
ending 30 days following the final therapy. Adverse events will be assessed by reports from 
subjects of Vitamin D related grade 3 or higher adverse events to their physician-investigators, 
standard laboratory results and by physical examinations. Vitamin D related Only prescription 
medication taken to relieve symptoms of the Vitamin D related AE will be recorded in addition to 
the outcome. All other/routine concomitant medications WILL NOT be recorded. Deaths 
occurring within 30 days of study treatment regardless of relationship will be reported to the 
UNMC DSMC. Only fatal AEs will be reported to the UNMC IRB per the IRB's policy and 
procedures. 
In addition to complying with all applicable regulatory reporting laws and regulations, vitamin D 
related serious adverse events and toxicities for all subjects will be reported to the University of 
Nebraska Medical Center, Institutional Review Board (IRB) and Fred & Pamela Buffett Cancer 
Center Data and Safety Monitoring Committee (DSMC) and the FDA (if applicable). 
9.1  Adverse Experiences Definitions: 
9.1.1 Adverse Event 
A Vitamin D related adverse event (AE) is defined as any untoward medical occurrence in a 
subject or clinical investigation subject administered a pharmaceutical product and which 
possibly has a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product. 
A Vitamin D related adverse event can result from use of the drug as stipulated in the protocol 
or labeling, as well as from accidental or intentional overdose, drug abuse, or drug withdrawal. 
Any worsening of a pre-existing condition or illness is considered an adverse event if related to 
Vitamin D. Laboratory abnormalities and changes in vital signs are considered to be adverse 
events if they result in discontinuation from the study, necessitate therapeutic medical 
intervention, meet protocol specific criteria and/or if the investigator considers them to be 
adverse events related to Vitamin D. In general, if a laboratory abnormality or change in vital 
sign is associated with a specific diagnosis that is being reported concurrently as an adverse 
event (e.g. elevated creatinine with renal failure) the findings that support the diagnosis do not 
need to be reported as separate adverse events unless the investigator feels it is appropriate. 
9.1.1.1 Treatment-emergent Adverse Event 
Treatment-emergent Vitamin D related adverse event is defined as any adverse event with 
onset or worsening from the time that the first dose of study drug is administered until 30 days 
after the final dose of study drug is administered. 
9.1.1.2 Unexpected Adverse Event 
An unexpected Vitamin D related adverse event is any adverse drug event that is not listed in 
the current labeling/Investigator’s Brochure. This includes events that may be symptomatically 

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and pathophysiologically related to an event listed in the labeling, but differ from the labeled 
event because of greater severity or specificity. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral 
vascular accidents. “Unexpected,” as used in this definition, refers to an adverse drug 
experience that has not been previously observed (i.e., included in the labeling) rather than from 
the perspective of such experience not being anticipated from the pharmacological properties of 
the pharmaceutical product. 
9.1.2 Serious Adverse Event 
A Vitamin D related serious adverse event is one that at any dose (including overdose) that: 
• 
Results in death 
• 
Is life-threatening1 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity2 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event3 
 
 
1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse event; it does not refer to 
a serious adverse event that hypothetically might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability to carry out normal 
life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in situations where 
none of the outcomes listed above occurred. 
 
 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above should also usually be considered serious. 
Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in subject 
hospitalization, or the development of drug dependency or drug abuse. A new diagnosis of 
cancer during the course of a treatment should be considered as medically important. 
9.2  Adverse Event Reporting Per University of Nebraska Medical Center, IRB and Fred & 
Pamela Buffett Cancer Center Data and Safety Monitoring Committee (DSMC): 
This protocol will adhere to all institutional guidelines for adverse event reporting. 
9.2.1 IRB Reporting 
All Vitamin D related internal serious adverse events (SAEs) must be reported to the local IRB 
promptly per institutional human research protection program policies. 

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9.2.2 Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee (DSMC) 
Reporting 
All Vitamin D related adverse events grade 3 or higher (expected or unexpected) will be 
reported to the University of Nebraska Medical Center, Fred & Pamela Buffett Cancer Center 
Data and Safety Monitoring Committee (DSMC) in accordance with DSMC guidelines. 
In its initial review, the DSMC will make a recommendation for the frequency of DSMC 
monitoring based on an assessment of risk associated with study-associated therapy, per the 
DSMC policy. 
Detailed policy and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html 
Attribution of AE: The likelihood of relationship of the AE to the study drugs will be determined 
by the investigator based on the following definitions: 
• 
Not Related: The subject was not exposed to the study treatment or another cause is 
obvious. 
• 
Probably Not Related: The AE is most likely explained by another cause, and the time of 
occurrence of the AE is not reasonably related to the study treatment. 
• 
Possibly Related: Study treatment administration and AE occurrence reasonably related 
in time, and the AE is explained equally well by causes other than study treatment, or 
treatment administration and AE occurrence are not reasonably related in time, but the AE 
is not obviously a result of other causes. 
• 
Probably Related: Study treatment administration and AE occurrence are reasonably 
related in time, and the AE is more likely explained by study treatment than by other 
mechanisms. 
• 
Definitely Related: There occurrence and timing of the AE are clearly attributable to the 
study treatment. 
Severity Grade of AE. The severity of events reported on the AE case report form will be 
determined by the principal investigator according the NCI Common Toxicity Criteria (CTC 
version 4.0). Copies of the AE report will be submitted to the IRB as indicated in Section 9.1.1. 
9.3  Auditing 
The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee (SRC) will 
review this protocol on at least an annual basis. 
This study will undergo audit on at least a semi-annual basis by the UNMC Fred & Pamela 
Buffett Cancer Center Audit Committee. 
Detailed policy and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html 

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Section 10.0 Statistical Considerations: 
Primary Objective 
To evaluate the Primary End Point, the 3 year progression-free survival (PFS), defined as time 
from the time of study entry of the "watch and wait" or newly diagnosed NHL or CLL until 
relapse, progression, starting new therapies or death from any cause. Response will be 
determined by the principal investigator or the lead site investigators. The 3 year PFS of the low 
dose and high dose groups will each be compared to a historical fixed expected 3-year PFS of 
45%. 
Secondary Objectives 
To evaluate changes in the levels of serum vitamin D levels during therapy with daily oral 
Vitamin D supplementation. 
To evaluate the Secondary End Point, the overall survival (OS), defined as defined as time of 
study entry of "watch and wait" or newly diagnosed NHL or CLL until death from any cause. For 
subjects who are still alive at the time of the study analysis at 3 years or are lost to follow-up, 
survival will be censored at the last recorded date that the subject was known to be alive. 
Study Endpoints 
The primary end point is 3 year progression-free survival (PFS), defined as time of study entry 
of "watch and wait" or diagnosed NHL or CLL until relapse, progression, starting new therapies 
or death from any cause. Response will be determined by the principal investigator or the lead 
site investigators. 
The secondary end point is 3 year overall survival (OS), defined as defined as time of study 
entry of "watch and wait" or newly diagnosed NHL or CLL administered on trial until death from 
any cause. 
 
10.1  Patient Accrual 
Subjects found to have low levels of serum Vitamin D <30 ng/ml at time of enrollment will be 
randomized on a 1:1 basis to receive vitamin D 5000 IU daily (Higher Dose Cohort) or vitamin D 
1000 IU daily (Lower Dose Cohort) stratified by disease group aggressive NHL (fast-growing 
tumors) or indolent NHL/CLL (slow-growing tumors). 
The sample size calculations are based on the primary endpoint of 3-year PFS. The expected 
PFS for patients with low levels of serum Vitamin D is 45%.44 The 3 year PFS of the low dose 
and high dose groups will each be compared to a historical fixed expected 3-year PFS of 45%.44 
The sample size calculations are based on a single arm survival calculation based on an 
assumption of exponentially distributed PFS times using a 3-year PFS of 60% for each of the 
randomized arms (low dose or high dose). Therefore, the sample size calcuations are based on 
detecting a 15% difference in 3-year PFS for each randomized arm (low dose or high dose) vs. 

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a historical fixed expected PFS of 45%. Since such single arm studies are typically conducted 
as a one-sided test, we use alpha =0.025, however, no other adjustments will be made for 
multiplicity. Sample size calculations were conducted using the SWOG statistical calculator 
found at https://www.swogstat.org/stat/public/one_survival.htm. 
Using a one sided test with accrual time of 2 years, follow-up time of 3 years, alpha=0.025, a 
null PFS of 45% and an alternative PFS of 60% a total of 230eligible patients will be enrolled in 
the normal serum Vitamin D group based on current accrual rate and until 70 eligible patients in 
each randomized arm (low or high dose) to provide 80% power. These results assume that two 
sequential tests are made (1 interim analysis and the final analysis) using the O’Brien-Fleming 
spending function to determine the test boundaries. Our final enrollment is projected to be 370 
patients expecting a ~10% loss to follow-up/inevaluability rate. 
10.2  Statistical Methods 
10.2.1 Intention-to-Treat 
The intention-to-treat (ITT) population will include all subjects who were randomized to study 
treatment in the randomized part of the study. In analyses based on the ITT population, 
subjects will be assigned to the treatment group they were randomized to. Subjects in the non-
randomized group will be analyzed in the “Normal Level” group. 
10.2.2 General Considerations 
All efficacy analyses will be performed using the ITT population. For this Pilot study, no 
adjustments for multiplicity will be carried out. All statistical tests will be performed using two-
sided tests with a 0.025 level of significance unless otherwise specified. 
Continuous variables will be summarized using descriptive statistics, i.e. number of subjects (N), 
mean, median, standard deviation, 25th percentile, 75th percentile, minimum and maximum. 
Categorical variables will be summarized using frequencies and percentages. 
10.2.3 Analysis for the Primary Endpoint 
The primary endpoint of 3-year PFS will be presented using Kaplan-Meier curves and will be 
presented for the normal serum Vitamin D control group and the low and high dose randomized 
groups. Each randomized group (low and high dose) will be compared to a historical fixed 
expected 3-year PFS of 45% using a one-sample logrank test following the method of Woolson 
(1981) 45. 
10.2.4 Analysis for the Secondary Endpoint 
The secondary endpoint of 3-year OS will be analyzed as described for the primary endpoint, 
using a historical fixed outcome of 80%. 45 
10.2.5 Safety 

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The incidence of adverse events (AEs) and serious adverse events (SAEs) will be described for 
the low dose and high dose groups and compared between groups using a Chi-square. The 
frequency of occurrence of overall toxicity, categorized by toxicity grades, will be described for 
the low dose and high dose groups and compared between groups using a Chi-square. 
10.3  Evaluable Patient 
Histologically confirmed disease. 
No premature discontinuation before completion of vitamin D cycles for reasons other than 
disease progression, starting new therapies, death, or study drug related unacceptable toxicity. 
10.4  Stopping Rules 
10.4.1 Interim Analyses 
One interim monitoring analysis for efficacy will be conducted after n=35 patients in each 
randomized arm (35 patients in the low dose group and 35 patients in the high dose group) 
have enrolled. Two separate tests will be conducted to compare 1- the PFS in the low dose arm 
to the fixed expected value of 45% and 2- the PFS in the high dose arm to the fixed expected 
value of 45%. We will use an O’Brien-Fleming-type spending function to assess whether the 
interim results are sufficient to conclude that vitamin D supplementation in either the low dose or 
high dose arm is effective in increasing the PFS to 60%. The monitoring boundary p-values 
associated with the 1 interim look using the O’Brien-Fleming spending function will be 0.001525 
with the final analysis being done with p=0.024501. The type I error associated with this 
monitoring plan is approximately 0.025. If >10% of patients in either Vitamin D arm has severe 
adverse events that are felt to be directly related to the Vitamin D supplement, the study will be 
stopped. 
Section 11.0 Records to Be Kept: 
11.1  Quality Assurance 
Complete records must be maintained in a research chart on each patient treated on the 
protocol. These records should include primary documentation (e.g., lab report slips, X-ray 
reports, scan reports, pathology reports, physician notes, etc.) which confirm that: 
- 
The patient met the eligibility criteria. 
- 
Signed informed consent was obtained prior to treatment. 
- 
Treatment was given according to protocol (dated notes about doses given and reasons 
for any dose modifications). 
- 
Toxicity was assessed according to protocol (laboratory report slips, etc.). 
- 
Response was assessed according to protocol (x-ray, scan, lab reports, dated notes on 
measurements & clinical assessment, as appropriate). 

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11.2  Electronic Data Capturing (EDC) System 
Data will be stored electronically for this study in the Advarra EDC system contained on the 
company’s secure server. Data forms will not differ from the paper versions with the exception 
of an electronic format containing the UNMC Fred & Pamela Buffett Cancer Center and Advarra 
logo. 
Advarra EDC provides for remote data collection that meets FDA 21 CFR Part 11 requirements 
as well as HIPAA and other regulatory requirements designed to enhance data security and 
protect patient confidentiality. Authorized users log into Advarra through a secure connection 
and must provide a valid username, password, and database ID. This data may be made 
available to the public at large. 
Section 12.0 Patient Consent Form Statement: 
12.1  Human Subjects Research Protection Training 
All personnel involved in this research project will have completed the OHRP-approved 
computer based training course on the Protection of Human Research Subjects. All clinical and 
correlative research included in this application will have approval by the institutional review 
board. 
12.2  Study Population 
Subjects are from all socio-economic groups and will be entered into the study without bias with 
respect to gender or race. Attempts will be made to recruit minorities. No vulnerable subjects 
will be included in the study. 
12.3  Recruitment and Informed Consent 
Subjects with an initial diagnosis of cancer seen and evaluated at IRB approved sites will be 
available for recruitment. These subjects will be informed of the nature of this study, and will be 
asked to participate on a voluntary basis after informing them of the possible risks and benefits 
of the study. A number of public registries may be accessible to health care providers and 
prospective subjects as listed below. 
National Library of Medicine – NCT02553447; http://clinicaltrials.gov () 
National Cancer Institute – NCI-2015-01502; http://www.cancer.gov () 
12.4  Subject Competency 
Subjects will be eligible to participate in the study only if they are competent to give informed 
consent. A subject that the investigator judges to be incompetent will not be enrolled. 
12.5  Process of Informed Consent 
If the patient chooses to be participate in this study, informed consent will be obtained by the 
investigators. The study and procedures involved, including the risks, will be explained in detail 

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to each subject. It will be clearly explained to the subject that this is a research study and that 
participation is entirely on a voluntary basis. Subjects will be given the option to discuss the 
study with a family member, friend, counselor or, another physician. The participating 
investigators will be available to discuss the study with them. 
12.6  Subject/Representative Comprehension 
When the process of informed consent is completed, the subject will be asked to state in his/her 
own words, the purpose of the study, the procedures that will be carried out, potential risks, 
potential benefits to the subject, the alternatives and the right to withdraw from the study. If 
there is any indication that a given subject's comprehension is anything less than accurate, the 
points of confusion will be discussed and clarified. 
12.7  Information Purposely Withheld 
The results of the tests done solely for research purposes will not be disclosed to the subject. 
No other information will be purposely withheld from the subject. 
12.8  Potential Benefits of the Proposed Research to the Subjects 
Normal Vitamin D levels are associated with improved bone health and possibly improved 
progression-free and overall survival in patients with NHL and CLL. 
12.9  Potential Benefits to Society. 
Information obtained from this study may help other patients by contributing to the knowledge of 
the biology of cancers, and to understand the potential clinical benefit of this regimen. 
12.10  Potential Risks 
A rare but potential harm of treatment with oral vitamin D is toxicity, which may lead to 
hypercalcemia, hyperphosphatemia, suppressed parathyroid hormone, and hypercalciuria. 
However, the 25-(OH) D level associated with toxicity (often defined as >500 nmol/L [>200 
ng/mL]) is well above the level considered to be sufficient. Treatment with vitamin D plus 
calcium may also be associated with increased risk for kidney stones; vitamin D alone does not 
seem to increase this risk. It is believed the treatment option outlined in the study will not pose 
significant additional risks compared to conventional treatment. 
12.11  Therapeutic Alternatives 
If subjects choose not to participate in this study, they may elect to receive standard therapy as 
per their primary oncologist, which may include no evaluation of vitamin level in the oncology 
setting and/or treatment recommendations that may or may not be similar to treatment as 
described in this protocol per individual practitioner. 

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12.12  Risk/Benefit Relationship 
The risks involved with the use of Vitamin D supplementation at standard doses are minimal. 
The potential benefits might be improved bone health and improved PFS and OS. 
Section 13.0 References 
1. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to 
treat. Mayo Clin Proc 2010:85:752-758. 
2. Drake, MT., Maurer, MJ, Link, BK, Habermann, TM, Ansell, SM, Micallef, IN, Kelly, JL, 
Macon, WR, Nowakowski, GS, Inwards, DJ, Johnston, PB, Singh, RJ, Allmer, C, Slager, SL, 
Weiner, GJ, Witzig, TE, & Cerhan, JE. Vitamin D Insufficiency and prognosis in non-
hodgkin’s lymphoma. J Clin Oncol 28:4191-4198, 2010. 
3. Holick MF. Vitamin D deficiency. N Engl J Med 2007:357:266–281. 
4. Holick, MF (2006) High prevalence of vitamin D inadequacy and implications for health. 
Mayo Clin Proc 81:353-373. 
5. Siegel, R., Ma, J., Zou, Z. and Jemal, A. (2014), cancer statistics, 2015.CA: A cancer journal 
for clinicians, 64: 9–29. doi: 10.3322/caac.21208. 
6. LeFevre ML. Screening for Vitamin D Deficiency in Adults: U.S. Preventive ServicesTask 
Force Recommendation Statement. Annals of Internal Medicine 2015: 162(2):133-141. 
7. Carlberg, C. Current understanding of the function of the nuclear vitamin D receptor in 
response to its natural and synthetic ligands. Recent Results Cancer Res 2003:164:29-42. 
8. Heaney, RP Clin J Am Soc Nephrol 3: 1535-1541, 2008. Doi:10.2215/CJN.01160308. 
9. Trang HM, Cole DE, Rubin LA, Pierratos A, Siu S, Vieth R: Evidence that vitamin D3 
increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr 
68: 854– 858, 1998. 
10. Armas LAG, Hollis BW, Heaney RP: Vitamin D2 is much less effective than vitamin D3 in 
humans. J Clin Endocrinol Metab 89:5387– 5391,2004. 
11. Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, 
Ameri A, Tannenbaum AD: Vitamin D2 is as effective as vitamin D3 in maintaining 
circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab 93 :677–
681,2008. 
12. Maalouf J, Nabulsi M, Vieth R, et al. Short- and long-term safety of weekly high-dose vitamin 
D3 supplementation in school children. J Clin Endocrinol Metab2008; 93(7):2693-2701. 
13. Holvik K, Madar AA, Meyer HE, et al. A randomized comparison of increase in serum 25-
hydroxyvitamin D concentration after 4 weeks of daily oral intake of 10 mg cholecalciferol 
from multivitamin tablets or fish oil capsules in healthy young adults. Br J Nutr 2007; 
98(3):620-625. 
14. Heaney RP & Armas LAG. Quantifying the vitamin D economy. Nutrition Reviews 
2015:73(1):51–67. 
15. Biancuzzo RM, Young A, Bibuld D, et al. Fortification of orange juice with vitamin D (2) or 
vitamin D(3) is as effective as an oral supplement in maintaining vitamin D status in adults. 
AmJ Clin Nutr 2010; 91(6):1621—1626. 
16. Tangpricha V, Koutkia P, Rieke SM, et al. Fortification of orange juice with vitamin D: A 
novel approach for enhancing vitamin D nutritional health. Am J Clin Nutr 2003; 77(6):1478-
1483. 
17. Dawson-Hughes B, Harris SS, Palermo NJ, et al. Meal conditions affect the absorption of 
supplemental vitamin D3 but not the plasma 25-hydroxyvitamin D response to 
supplementation. J Bone Miner Res 2013;28(8):1778-1783. 

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18. Mulligan GB, Licata A.Taking vitamin Dwiththe largest meal improves absorption and results 
in higher serum levels of 25-hydroxyvitamin D. J Bone Miner Res 2010;25(4):928-930. 
19. Holick M. Sunlight, ultraviolet-radiation, vitamin D and skin cancer. How much sunlight do 
we need? In: J Reichrather, ed. Sunlight, Vitamin D and Skin Cancer. 2nd ed. New York, 
NY, Landes Bioscience and Springer Science; 2014:1—16. 
20. Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in 
humans.J Clin Endocrinol Metab 004; 89(11):5387—5391. 
21. Tripkovic L, Lambert H, Hart K, et al. Comparison of vitamin D2 and vitamin D3 
supplementation in raising serum 25-hydroxyvitamin D status: A systematic review and 
meta-analysis. AmJClin Nutr.2012; 95:1357-1364. 
22. Heaney RP, Recker RR, Grote J, et al. Vitamin D3 is more potent than vitamin D2 in 
humans. J Clin Endocrinol Metab 2011;96(3):E447—452. doi:10.1210/ jc.2010-2230. 
23. Tjellesen L, Hummer L, Christiansen C, et al. Serum concentration of vitamin D metabolites 
during treatment with vitamin D2 and D3 in normal premenopausal women. Bone Miner 
1986; 1(5):407—413. 
24. Binkley N, Gemar D, Engelke J, et al. Evaluation of ergocalciferol or cholecalciferol dosing, 
1,600 IU daily or 50,000 IU monthly in older adults. J Clin Endocrinol Metab 
2011;96(4):981—988. 
25. Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihen GE-H, Seely 
EW: Hypervitaminosis D associated with drinking milk. N Engl J Med 326:1173– 1177, 1992. 
26. Hathcock JN, Shao A, Vieth R, Heaney RP: Risk assessment for vitamin D. Am J Clin Nutr 
85:6– 18, 2007. 
27. Bikle, D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94:26-34, 2009. 
28. Gorham ED, Garland CF, et al. (2005) Vitamin D and prevention of colorectal cancer. J 
Steroid Biochem Mol Biol 97:179–19. 
29. Yin L, Grandi N, Raum E, et al. (2009) Meta-analysis: Longitudinal studies of serum vitamin 
D and colorectal cancer risk. Aliment Pharmacol Ther 30:113–125. 
30. Crew KD, Shane E, Cremers S, et al. (2009) High prevalence of vitamin D deficiency despite 
supplementation in premenopausal women with breast cancer undergoing adjuvant 
chemotherapy. J Clin Oncol 27:2151–2156. 
31. Chen P, Hu P, Xie D, et al. (2010) Meta-analysis of vitamin D, calcium and the prevention of 
breast cancer. Breast Cancer Res Treat 121:469–477. 
32. Mian,L, Chen, P, Jingquan, L, Chu, R, dong, X & Wang, H. Review: The impacts of 
circulating 5-hydroxyvitamin D levels on cancer patient outcomes: a systematic review and 
meta-analysis. J of Clin Endocinolo Metab 2014. 
33. Ng K, Meyerhardt JA, Wu K, et al. Circulating 25-hydroxyvitamin d levels and survival in 
patients with colorectal cancer. J Clin Oncol 2008; 26 (18):2984-2991. 
34. Goodwin PJ, Ennis M, Pritchard KI, Koo J, Hood N. Prognostic effects of 25-hydroxyvitamin 
D levels in early breast cancer. J Clin Oncol 2009; 27 (23):3757-3763. 
35. Newton-Bishop JA, Beswick S, Randerson-Moor J, et al. Serum 25-hydroxyvitamin D3 
levels are associated with breslow thickness at presentation and survival from melanoma. J 
Clin Oncol 2009; 27(32):5439-5444. 
36. Zhou W, Heist RS, Liu G, et al. Circulating 25-hydroxyvitamin D levels predict survival in 
early-stage non-small-cell lung cancer patients. J Clin Oncol 2007; 25(5):479-485. 
37. Lee, J.E.; Li, H.; Chan, A.T.; Hollis, B.W.; Lee, I.M.; Stampfer, M.J.; Wu, K.; Giovannucci, E.; 
Ma, J. Circulating levels of vitamin D and colon and rectal cancer: The Physicians’ Health 
Study and a meta-analysis of prospective studies. Cancer Prev. Res. (Phila) 2011, 4, 735–
743. 
38. Villasenor, A.; Ballard-Barbash, R.; Ambs, A.; Bernstein, L.; Baumgartner, K.; Baumgartner, 
R.; Ulrich, C.M.; Hollis, B.W.; McTiernan, A.; Neuhouser, M.L. Associations of serum 25- 

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hydroxyvitamin D with overall and breast cancer-specific mortality in a multiethnic cohort of 
breast cancer survivors. Cancer Causes Control CCC 2013, 24, 759–767. 
39. Bosetti, C.; Turati, F.; La Vecchia, C. Hepatocellular carcinoma epidemiology. Best Pract. 
Res. Clin. Gastroenterol. 2014, 28, 753–770. 
40. Kricker A, Armstrong BK, Hughes AM, et al. (2008) Personal sun exposure and risk of non-
Hodgkin lymphoma: A pooled analysis from the Interlymph Consortium. Int J Cancer 
122:144–154. 
41. Giovannucci E, Liu Y, Rimm EB, et al. (2006) Prospective study of predictors of vitamin D 
status and cancer incidence and mortality in men. J Natl Cancer Inst 98:451–459. 
42. Lim U, Freedman DM, Hollis BW, et al. (2009) A prospective investigation of serum 25-
hydroxyvitamin D and risk of lymphoid cancers. Int J Cancer 124:979–986. 
43. Shanafelt, TD, Drake, MT, Maurer,MJ, Allmer, C, Rae, KG, Slager, Sl, Weiner, GJ, Call, TG, 
Link, bK, Zent, CS, Kay, NE, Hanson, CA, Witzig, TE, & Cerhan, JR. Vitamin D insufficiency 
and prognosis in chronic lymphocytic leukemia. Blood 117:5: 1492-1498, 2011. 
44. Kelly JL, Salles G, Goldman B, Fisher RI, Brice P, Press O, Casasnovas O, Maloney DG, 
Soubeyran P, et al. Low Serum Vitamin D Levels Are Associated With Inferior Survival in 
Follicular Lymphoma: A Prospective Evaluation in SWOG and LYSA Studies. J Clin Oncol 
2015:57: 5092 
45.  
Woolson RF: Rank tests and a one-sample logrank test for comparing observed survival 
data to a standard population. Biometrics 37:687-696, 1981 
 
 
Section 14.0 Data Forms 
Please refer to the Study Site Manual for the forms. 

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Appendix A: Eligibility checklist 
 
Date Completed: 
IRB# 556-15 
Title: A Pilot Study of Vitamin D Replacement in 
Patients with Non-Hodgkin’s Lymphoma or 
Chronic Lymphocytic Leukemia with Low 
Vitamin D Levels 
PI: Julie Vose, MD 
Checklist Version # 6.X 
Dated: XXMmmYYYY 
Site: 
Subject ID#: 
Subject Initials: 
Waiver #: 
Inclusion Criteria: Response should be YES 
Yes 
No 
NA 
1. Histologically confirmed newly diagnosed or previously untreated Non- 
Hodgkin’s Lymphoma or CLL 
(Subjects may be under no treatment “wait and watch” OR have received 
two cycles of chemotherapy or localized radiation therapy before 
informed consent.) 
☐ 
☐ 
☐ 
2. 18 years of age or older (19 years or older in Nebraska). 
☐ 
☐ 
☐ 
3. Serum 25-hydroxyvitamin D [25(OH) D] drawn at time of enrollment 
(NOTE: Subjects currently taking < 1000 IU/day Vitamin D supplements 
are eligible for screening.) 
☐ 
☐ 
☐ 
Record 25(OH) D: 
4. Simultaneous participation in other therapeutic clinical trials will be 
allowed. 
☐ 
☐ 
☐ 
5. Subject must be aware of the neoplastic nature of his/her disease and 
willingly provide written, informed consent after being informed of the 
procedure to be followed, the nature of the therapy, alternatives, 
potential benefits, side-effects, risks, and discomforts. 
☐ 
☐ 
☐ 
Exclusion Criteria: Response should be NO 
Yes 
No 
NA 
1. History of uncontrollable allergic reactions to vitamin D. 
☐ 
☐ 
☐ 
2. Currently taking vitamin D supplement ≥ 1000 IU/day. 
☐ 
☐ 
☐ 
3. History of Paget’s disease. 
☐ 
☐ 
☐ 
4. Hypercalcemia 
☐ 
☐ 
☐ 
5. Any other clinically significant medical disease or condition, laboratory 
abnormality, or psychiatric illness that, in the Investigator’s opinion, may 
interfere with protocol adherence or a subject’s ability to give informed 
consent. 
☐ 
☐ 
☐ 
6. Inability to cooperate with the requirements of the protocol. 
☐ 
☐ 
☐ 
All questions regarding eligibility for potential subjects should be directed to the UNMC IIT 
Office at IITOffice@unmc.edu. 

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Subject satisfies all criteria. 
Eligibility: 
Printed Name of Reviewer: 
Date 
 
ELIGIBILITY reviewed and confirmed. 
(Reviewer - Study Nurse Coordinator(s) or PI designee) 
 
Reviewer Signature  
 
Subject not formally eligible, but admitted to this study because (state reason): 

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Appendix B: NCI Common Toxicity Criteria Version 4.0 (CTCAE) 
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse event reporting. A 
copy of the NCI CTC Version 4.0 can be downloaded from the CTEP homepage: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
All appropriate treatment areas have access to a copy of the CTC Version 4.0. 
Minor editorial updates have been made to CTCAE v4.0, which are represented in v4.03. These 
edits do not change the meaning of v4.0 content and all previous versions (CTCAE v4.0, v4.01, 
v4.02) are still valid and referred to as CTCAE v4.0. Version 4.03 includes clarifications for a 
select few grading scales and adverse event term definitions. Most of the revisions are 
associated with grading scales that include a quantitative component. A list of changes is 
located at http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
An updated version (4.03) is now in use as of June 14, 2010. 
 
 
 
 
Appendix C: FDA MEDWATCH form 
 
 
Available on-line at 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 

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Appendix D: Oral, Sublingual, and/or Buccal Route 
Medication Adherence Standard Procedure - V 1.0 11-25-2013 
PURPOSE 
To provide a means of ensuring oral, sublingual and/or buccal routes of medication adherence 
to patients while participating in a clinical trial. 
1. A physician’s order will be completed by study patients or representative for oral, 
sublingual and/or buccal administration per IRB approved protocol. 
2. To ensure the consistent and safe administration of medications not given under the 
direct supervision of study staff (at home), there will be a “Medication Information Sheet” 
and a calendar to document times of drug administration. 
3. To record medication adherence Study staff will document results of medication 
reconciliation and or medication return in the patient’s chart. 
4. Maintain documentation of medications returned or sent to investigational pharmacy for 
destruction (if applicable). 
PROCEDURE 
1. Protocol specific information regarding the individual medication(s) should be listed on 
the form “Medication Information Sheet” and given to the patient at the start of the study 
and throughout treatment if necessary to help ensure adherence. 
2. Name, dose and route of each medication should be listed under ‘How to take your 
Medication’ on the “Medication Information Sheet”. 
3. Patients will be given a monthly “Medication Calendar”. The calendar will have a place 
for the patient to record the time that the medication(s) were taken. 
4. The research nurse will review the patient’s “Medication Calendar” for adherence to the 
study regimen for oral medication administration. Adherence will be noted in the patient’s 
chart. For UNMC subjects, medication reconciliation will be done. If there is medication 
to be returned/destroyed, it will be sent to the Nebraska Medical Center Investigational 
Pharmacist for return/destruction in accordance to the Nebraska Medical Center 
Destruction of Investigational product, Policy #4.860. 

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Medication Information Sheet 
Subject Initials: 
Study ID #: 
Title: A Pilot Study of Vitamin D Replacement in Patients with Non-Hodgkin’s Lymphoma or 
Chronic Lymphocytic Leukemia with Low Vitamin D Levels 
 
IRB# 556-15 
Date: 
 
Medication: Vitamin D is a pill. 
How to take your medication: Enter information regarding Vitamin D dosing This should be 
taken by mouth once a day until your treating physician tells you to stop (this could be up to 3 
years or 1095 days). Follow your Medication Calendar that is provided to you by the research 
nurse. 
Things to know about your medication: 
1. IF you are currently taking Vitamin D supplements/medication at the time of 
screening, you will need to discontinue the use of your home supply of Vitamin D 
and use only the Vitamin D medication/dosing and supply instructed by the study.) 
2. You should take your medication at the same time each day. 
3. If you miss a dose of your medication, it should be taken as soon as possible on the 
same day. 
4. If it is missed for the entire day, it should not be made up. 
5. If a dose is missed, make sure to mark it on your Medication Calendar. 
 
NOTE: After year 3 (1095 days), the investigator will discuss continuation of Vitamin D 
supplementation recommendations with you. The supply of any recommendations for continued 
Vitamin D will be at your cost. 
Your research nurse is:  
 
 
Contact information: phone  
 pager _ 
***We will re-check your Vitamin D level in insert time point for Vitamin D level check. 
Call if you need anything in the meantime. 
 
After hours, nights, weekends and holidays please call 402-559-5600 and ask for the Oncologist 
on call. 
UNMC Subjects only: *** PLEASE CALL YOUR RESEARCH NURSE ABOVE TO LET THEM 
KNOW THAT YOU RECEIVED YOUR VITAMIN D SUPPLEMENT. *** 

Vitamin D Administration Diary → Your prescribed dose is 
 If you missed a dose please add the comment “missed dose” on the corresponding date. 
 If your Study Doctor has asked you to change your dose, please add the new dosage 
on the corresponding date. 
 All completed diaries must be returned to the Study Coordinators at the study site. 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Date: 
 
Time of dose: 
 
AM / PM 
Date: 
 
Time of dose: 
 
AM / PM 
Date: 
 
Time of dose: 
 
AM / PM 
Date: 
 
Time of dose: 
 
AM / PM 
Date: 
 
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AM / PM 
Date: 
 
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AM / PM 
 
 
 
 
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Enter Dose. 
Name: 
MR: 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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