Treatment of Vitamin D Deficiency With Large Bolus Cholecalciferol in the Outpatient Setting
Phase: PHASE1
Conditions: Vitamin D Deficiency
Sponsor: Parkview Medical Center

 
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Parkview Institutional Review Board 
400 West 16th Street 
Pueblo, Colorado 81003 
Office:  (719) 584-4855 or (719)584-4769 
 
 
TITLE:   Treatment of Vitamin D deficiency with large bolus cholecalciferol in the outpatient setting      
 
PROTOCOL VERSION DATE:  1/2/19      
VERSION:  3 
 
PRINCIPAL INVESTIGATOR (PI):  
Name: Stephanie Franquemont, DO       
Address:  311 W 14th St, Pueblo, CO 81003      
Telephone:  303/519-3588      
 
KEY PERSONNEL: 
Name:   Kourtney Aylor, DO     
Role in project: co-investigator 
 
Name:  Vincent Vaughn, DO      
Role in project: co-investigator 
 
Name:  Stephanie Murphy, DO; Stanley Sicher, MD     
Role in project: faculty advisor/study coordinator 
 
I. 
OBJECTIVES 
The primary purpose of our study will be to evaluate the efficacy of large, single bolus vitamin D 
supplementation for the treatment of vitamin D deficiency when compared to standard treatment 
regimens. The null hypothesis will be that large single bolus administration of vitamin D will be non-
inferior in efficacy of the standard vitamin D replacement. Secondary objectives will include evaluation 
of the duration of sufficient serum levels after the large bolus of cholecalciferol and evaluation of 
compliance with single dose regimens compared with standard daily regimens. We hypothesize that 
large bolus vitamin D replacement will have a duration of sufficient serum levels of at least one year.  
II. 
BACKGROUND AND SIGNIFICANCE 
Vitamin D deficiency has been recognized as a worldwide health concern for many years. 
Vitamin D is a fat-soluble steroid hormone with known effects on the absorption of calcium, magnesium 
and phosphorus from bone and the gastrointestinal tract, as well as other, less well understood effects 
on multiple body systems. Vitamin D deficiency is seen more in elderly patients, patients with 
autoimmune disorders (2), chronic kidney disease (3), chronic liver disease (4), hypertension (5), and 
malabsorptive conditions such as inflammatory bowel disease (6). Vitamin D deficiency is more common 
at far north and south latitudes and in climates with decreased sun exposure.  
Vitamin D deficiency is associated with increased calcium resorption from bone leading to 
osteomalacia and increased risks of osteoporosis (7,8). Treatment of vitamin D deficiency has been 

 
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shown to slow progression of osteoporosis in elderly women. In recent years, vitamin D deficiency has 
been shown to be associated with other health conditions including cardiovascular disease (9), 
hypertension, type 2 diabetes mellitus (10), thyroid dysfunction, colon cancer, and neuropsychiatric 
disorders such as depression and dementia. These conditions are simply associated with vitamin D 
deficiency and there is a paucity of data regarding the effect of treatment of vitamin D deficiency on the 
overall disease state. Interestingly, vitamin D supplementation had been associated with a decrease in 
overall mortality (11) 
In humans, vitamin D is predominantly obtained via exposure to sunlight. Solar ultraviolet B 
(UVB) radiation penetrates into the skin and starts the synthesis of vitamin D3 from pre-vitamin D. This 
is then hydroxylated to 25-hydroxyvitamin D in the liver. Serum 25-hydroxyvitamin D is the vitamin D 
level that is checked on routine laboratory testing because it is the best measure for total body stores. 
The 25-hydroxyvitamin D is hydroxylated again in the kidney to the biologically active form, 1,25-
dihydroxyvitamin D (2). The biologically active form has a short half-life in plasma. 
Pharmacologic preparations of vitamin D are available as both enteral and parenteral depot 
formulations. Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are the two calciferols 
available in the United States. Vitamin D2 is a plant-derived form while vitamin D3 is the form naturally 
produced in humans. When administered, both forms enter the metabolism cascade at the first 
hydroxylation step. Large bolus doses of ergocalciferol have been available in the United States for 
decades while large dose cholecalciferol became readily available in the last 15 years. There is limited 
data but some small studies have shown Vitamin D3 to be more effective for treatment in humans (12). 
High dose Vitamin D therapy in children and adolescents, also known as Stoss therapy, was 
initiated in late 1930’s Germany in the study of treatment and prevention of rickets (13). Since that time 
several studies have been performed to investigate Vitamin D supplementation in many different areas, 
patient populations and disease states. Current Endocrine Society guidelines define vitamin D deficiency 
at levels <20 ng/mL and insufficiency of Vitamin D at levels <30 ng/ml. Those guidelines recommend 
daily supplementation equivalent to 5,000-6,000 IU to achieve levels above this range (2). There are not 
guidelines regarding the frequency of checking Vitamin D levels while on treatment. 
The significance of this research will aim to help guide treatment guidelines in terms of routine 
laboratory testing for follow-up, which will then potentially aid in guidance of when repeat dosing will 
occur. Upon review of the literature, many articles looked at serum levels immediately after large dose 
administration and with follow up as far as 9 months, but in the longer follow up studies laboratory 
testing from initial dose to last check was sparse. While many studies had short term follow up after 
initial dose, whether this was due to initial serum Vitamin D levels or dosage administered was not 
clearly defined. This study will aim to provide closer follow-up after a researched dose of 300,000IU that 
has been shown to have minimal adverse effects and multiple benefits beyond serum Vitamin D levels. 
 
III. 
PRELIMINARY STUDIES 
The pharmacodynamics of cholecalciferol allow for the potential of infrequent, large bolus 
administration. Once absorbed, cholecalciferol is either metabolized into 25(OH)-D or can be 
redistributed into fat. 25(OH)-D has a prolonged circulating half-life of approximately 2-3 weeks prior to 
being further hydroxylated in the kidney to the active metabolite (14).  Cholecalciferol that is 
redistributed into fat is released slowly overtime to sustain circulating levels of 25(OH)-D for prolonged 
periods of time between dosing (13, 15, 16). 
To this point, there has been inconclusive research on the efficacy of high dose vitamin D 
supplementation for vitamin D deficiency. Studies have shown that doses of 300,000IU are typically 
most efficacious for normalizing vitamin D levels while minimizing adverse effects (16). Dosage of 
250,000IU or less have been ineffective for long-term improvement of vitamin D status (17, 18, 16). 

 
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Doses greater than 300,000IU have shown similar efficacy in raising serum vitamin D levels but increase 
the risk of adverse effects (19). No studies have identified a standard duration of efficacy for large bolus 
vitamin D supplementation.  
Of the studies that were reviewed, none showed significant adverse effects related to 
hypervitaminosis D. This was even with cholecalciferol doses greater than 300,000IU (13, 15, 16). Two 
case series that evaluated patients with vitamin D toxicity in India showed toxicity resulting from 
repeated cholecalciferol administration totaling greater than 1,000,000IU over a minimum of three 
months. All case reports of hypervitaminosis D reviewed had a significantly higher dose of 
cholecalciferol than our proposed dose. 
IV. 
RESEARCH STUDY DESIGN 
 
Study will be a prospective, unblinded, randomized controlled study. 
 
There will be two study arms: 
○ Large-bolus group that will get one-time, 300,000IU cholecalciferol. 
○ Standard treatment group that will take 5,000IU cholecalciferol daily. 
 
Participants will be randomized based on the order they join the study. Randomizer.org 
was used to create at randomly organized set of 20 including 10 ones (large bolus) and 10 
twos (standard treatment).  
 
 
 
1. 
Bolus   
11.  
Standard 
 
2. 
Standard 
12. 
Bolus 
 
 
3. 
Bolus 
 
13. 
Standard 
 
4. 
Bolus 
 
14. 
Standard 
 
5. 
Standard 
15. 
Bolus 
 
6. 
Standard 
16. 
Standard 
7. 
Bolus 
 
17. 
Bolus 
 
 
8. 
Bolus 
 
18. 
Standard 
9. 
Bolus 
 
19. 
Bolus 
10. 
Standard 
20. 
Standard 
 
We will repeat this organization for subsequent sets 
of 20 participants to maintain relatively equal groups 
as participants are added. 
 
  
 
We plan to enroll a total of 100 participants. We should be able to meet the goals of the 
study with 86 participants. Please see Appendix A for calculation of study size. 
 
We expect the study to last a total of 20 months:  
○ 6 months for initial enrollment 
○ 12 months for data gathering 
○ 2 months for analysis and write up 
 

 
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V. 
ABOUT THE SUBJECTS 
 
We plan to enroll a total of 100 participants. 
 
We anticipate 86 participants will complete the study. 
 
The subject’s population will include residents of southeastern Colorado. We will include 
men and women, age 18-75. All ethnic groups will be included. All participants will be seen 
at Parkview Adult Medicine for primary care.  
 
Inclusion criteria will include: 
1. 
18-75 years old 
2. 
Serum 25(OH)D level <20ng/mL 
3. 
Patient of Parkview Adult Medicine Clinic 
4. 
Not currently on vitamin D supplementation >5,000IU daily. 
5. 
No ergocalciferol administration within the last week. 
 
Exclusion criteria will include: 
1. 
History of hypercalcemia or hyperparathyroidism due to risk of elevation of 
calcium levels with administration of vitamin D. 
2. 
History of chronic kidney disease with a baseline creatinine >1.1mg/dL as this can 
alter the metabolism of vitamin D. 
3. 
History of gastric absorptions abnormalities such as previous intestinal surgery, 
Celiac disease, or inflammatory bowel disease as this can alter the absorption of 
vitamin D. 
4. 
History of bone diseases such as Paget’s disease or osteoporosis (on treatment)or 
granulomatous conditions as these can alter vitamin D metabolism and calcium 
levels. 
5. 
History of thyrotoxicosis as this can alter vitamin D metabolism. 
6. 
Subjects on anticonvulsants, barbiturates, steroids, or calcium supplementation 
>1200mg/day as these can increase risk of elevated calcium levels. 
7. 
Subjects with known malignancy as metabolism could be affected by both the 
malignancy and chemotherapy. 
8. 
Subjects who are pregnant or breastfeeding as vitamin D metabolism and needs 
are known to be altered during pregnancy. 
9. 
Patients who do not speak English at a conversational level as all communication 
with the investigators and the study paperwork will be in English. 
10. 
Inpatient hospitalization at the initiation of the study dosing as this study is 
specifically focusing on outpatient treatment. Participants found to have Vitamin 
D deficiency while hospitalized will be considered for inclusion after they are 
stabilized and discharged from the hospital.  
 
VI. 
VULNERABLE POPULATIONS 
 
Educationally disadvantaged individuals will be considered for the study. The forms and 
questionnaires will be written in language to attempt to make them understandable to 
everyone, including educationally disadvantaged individuals. 
 
Economically disadvantaged individuals will be considered for the study. No monetary 
incentives will be provided for participation in the study to avoid coercion to participate. 
 

 
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VII. 
RECRUITMENT METHODS 
 
The study population will be recruited from patients of the Parkview Adult Medicine Clinic 
(PAMC) after routine Vitamin D testing. 
 
Pre-screening will be done by the providers caring for patients both outpatient at PAMC 
and inpatient at Parkview Medical Center. These providers are the ones ordering/initially 
getting the results of routine Vitamin D level testing. They will be the first to inquire about 
the patients participating in the study. If patients do express interest, their contact 
information will be shared with the investigators for formal enrollment and consent. 
 
Recruitment flyers will be hung in exam rooms at PAMC for participants in read and 
express interest to their providers. Recruitment flyer can be found in Appendix B. 
 
Participants will not be forced to check their vitamin D level for sole purpose of screening 
for study participation. Investigators will be honest regarding potential benefits and risks 
of participating in the study and will be forthcoming with answers to all questions from 
the participants.  
 
List recruitment methods/materials and attach a copy of each: 
1. Flyer to be hung in the Parkview Adult Medicine Clinic (Appendix B) 
 
VIII.       COMPENSATION 
 
The participants will not be compensated monetarily for participation in this study.  
 
IX.          CONSENT PROCESS 
 
All participants will be patients at the Parkview Adult Medicine Clinic. Providers will be 
notified of study and inclusion/exclusion criteria. When, through routine testing, patients 
are found to have vitamin D deficiency the provider ordering the test will initially inquire if 
their patients are interested in participation. Once participants indicate their interest, the 
clinic providers will provide the investigators with the name of the interested party. 
Investigators will then meet with the participant at the Parkview Adult Medicine Clinic to 
go through the formal consent. 
 
No change to the informed consent will be needed. 
 
All providers and investigators will be forthcoming with goals of the study and the idea 
that participation is entirely voluntary. Investigators will not approach patients that are 
not under their care in clinic without first being notified by the appropriate provider. No 
benefits will be provided to the providers for referring their patients to the study. 
 
Participants who do not speak English and would require a consent form translator will 
not be included in the study.  
 
X.          PROCESS TO DOCUMENT CONSENT IN WRITING 
 
After participants are pre-screened by and express interest in participation to their PCP, 
study investigators will reach out to schedule the initial study meeting. At this meeting, 
the participant will meet with one of the investigators to go through the written consent 
and sign. A copy of the signed consent will be given to the participant. 
 

 
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XI.          PROCEDURES 
 
Initial, pre-study encounter: 
○ 
Participants will have their 25(OH)-D level drawn for routine screening purposes 
outpatient or inpatient. The ordering provider/team will recognize level <20ng/dL as 
potential candidate for the study and inquire regarding interest for participation. 
○ 
If individual expresses interest in participation, their provider will provide the 
investigators with the measured vitamin D level and the prospect’s contact 
information. 
 Phone call #1: 
○ 
Investigator will contact prospective participant to schedule initial screening 
encounter. 
○ 
Phone call should take no more than 2-5 minutes. 
 Encounter #1: 
○ 
Participant will meet with one (or more) investigator to go through consent. The 
participant will be given a signed copy of the consent.  
○ 
The participant and investigator will go through the screening questionnaire 
(Appendix C) and collect routine vital signs ( Appendix D). 
○ 
 The participant will go to the Parkview outpatient lab to have complete metabolic 
panel for screening of renal function and calcium levels.  
○ 
Visit should take approximately 45 minutes total. 
 
IF PARTICIPANT MEETS ALL INCLUSION CRITERIA AND NONE OF THE EXCLUSION CRITERIA, THEY WILL 
PROCEED TO THE NEXT STEPS: 
 
 
Randomization: 
○ 
As noted above, participants will be randomized into either Group 1 (large-bolus 
cholecalciferol) or Group 2 (standard treatment) based on their enrollment position.  
 
Study meds: 
○ 
Based on the randomization group, participants will have a prescription for the 
assigned therapy sent to the Pharmacy at Parkview. They will be instructed to pick up 
the medications and start the medications the next non-weekend morning (pick-up 
meds on Friday-Sunday then start on Monday. Other days, start on the following 
day). 
■ 
Group 1 will take six 50,000IU cholecalciferol tablets one time. 
■ 
Group 2 will take one 5,000IU cholecalciferol capsule daily. 
 
 
 
 Phone call #2: 
○ 
Participants will be called and instructed to pick up the medications and start the 
medications the next non-weekend morning (pick-up meds on Friday-Sunday then 
start on Monday. Other days, start on the following day). 
■ 
Group 1 will take six 50,000IU cholecalciferol tablets one time. 
■ 
Group 2 will take one 5,000IU cholecalciferol capsule daily. 
○ 
Phone call should take no more than 2-5 minutes. 

 
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 
Encounter #2: 
○ 
One week after starting the study medications, participants will return to clinic and 
go through the follow-up questionnaire (Appendix E) with one of the investigators.  
○ 
Participant will go to the Parkview outpatient lab to have their BMP and Vitamin D 
level drawn.  
○ 
Visit should take approximately 30 minutes total. 
 Encounters #3, #4, #5, #6: 
○ 
Three, six, nine, and twelve months after starting the study medications, participants 
will return to clinic to go through the same follow-up questionnaire as Encounter #2.  
○ 
At all visits, participants will once again have BMP and vitamin D levels drawn at the 
Parkview outpatient lab. 
○ 
Each visit should take approximately 30 minutes total. 
○ 
Participants in the standard treatment group will get new prescriptions for 2000IU 
Vitamin D at encounters 3, 4, and 5.   
 
XII.        SPECIMEN MANAGEMENT 
 Blood samples from the participants will be labeled with their name and sent through the 
Parkview outpatient laboratory. 
 Specimens will be drawn in the lab and not transported by the investigators or not 
laboratory staff.  
 
XIII.      DATA MANAGEMENT 
 Hard copy data (consent, questionnaires) will be kept in a locked file box in clinic. 
Researchers and faculty-supervisor will be the only ones with access to the locked files. Files 
will be de-identified by using the patients first and last initial as well as an assigned number 
(starting with 001 and going up numerically by enrollment place). Hard copies of all data will 
be destroyed by shredding at the end of the study. 
 Data will be transcribed to electronic files. These files will be password-protected and stored 
on the secure Parkview Medical Center server. 
 
XIV.      WITHDRAWAL OF PARTICIPANTS 
 Circumstances that would require the patient to be withdrawn would include: not starting 
the study medication, not returning for scheduled follow-up, or becoming pregnant. 
Participants will also be withdrawn if they become seriously ill and require hospitalization 
for an extended period of time for non-study related illness (>10 days).  
 Participants that require hospitalization due to effect of study drugs will continued to be 
monitored for safety but the data will not be included in the final analysis. The study 
enrollment will stop prematurely if two or more participants require hospitalization.  
 Participants in the standard of care arm will be withdrawn if they develop severe adverse 
reactions from the study medication that prevent continued compliance. If participants in 
the standard treatment arm have 25(OH)D levels >100ng/mL they will be reduced to taking 
2,000IU daily but will not automatically be removed from the study.  
 We will recommend that participants who withdraw from the study get a BMP and Vitamin 
D level drawn within 3 months of withdrawing to ensure no negative effects on their renal 
function or calcium level and to ensure that they are being treated for vitamin D deficiency. 

 
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XV.       RISKS TO PARTICIPANTS 
 The major risk to human subjects is related to symptomatic hypercalcemia from vitamin D 
toxicity.  
○ 
These symptoms typically occur at serum 25(OH)D levels >150ng/mL 
○ 
The risk is greater with prolonged high dose vitamin D administration (Kaur).  
○ 
Symptoms of vitamin D toxicity include fatigue, muscle weakness, anorexia, 
dehydration leading to acute kidney injury, polyuria and polydipsia, confusion, and 
gastrointestinal effects such as constipation, nausea/vomiting.  
○ 
The risk of vitamin D toxicity is greatest 1 week after administration of the high-dose 
bolus but the overall risk remains low (Kearns). 
○ 
Large bolus vitamin D administration has been incompletely studies so there are 
possible unforeseen risks associated with this. 
 Participants will undergo blood draws at the initial visit and every three months. When done 
but persons trained in phlebotomy there is minimal risk. The risks are unlikely but do include 
unintentional bleeding, bruising, hematoma, or infection. There is also risk of vasovagal 
events.  
 
XVI.       MANAGEMENT OF RISKS 
 Overall, the risk of vitamin D toxicity remains very low (Kearns). We will monitor vitamin D 
and calcium levels one week after starting the study medications. We will also monitor 
calcium levels every three months. 
o 
If participants do develop symptoms listed above, treatment of the hypercalcemia 
will be managed outpatient by the investigators or other provider at PAMC. If 
symptoms become so severe that they require hospitalization, they will be admitted 
to Parkview Medical Center and managed by the inpatient IM residents. 
 Blood draws will all be done by phlebotomy trained individuals with standard precautions. 
The site will be clean prior to the blood draw. Direct pressure and bandage will be used after 
the blood draw. Participants will be asked prior to the blood draw if they have had vasovagal 
episodes before and if they would like to lay down while having their blood drawn. 
 
XVII.      POTENTIAL BENEFITS 
 
Vitamin D deficiency has historically been associated with bone disorders but research in 
recent years has shown to play a role in disease states of multiple body systems. 
Treatment of vitamin D deficiency has been shown to resolve symptoms related to 
deficiency as well as reduce risk of developing certain health conditions.  
 
Single, large-bolus treatment also reduces the daily burden of traditional 
supplementation. 
 
Results from this study could potentially influence clinical practices for the treatment of 
vitamin D deficiency.  
 
XVIII.     PROVISIONS TO MONITOR THE DATA FOR SAFETY OF PARTICIPANTS 
 
Data will be evaluated at a minimum of once every month to ensure safety of all 
participants. It will likely be review more frequently than this and on an individual basis for 
each participant as they have their routine blood draws. 

 
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 
The investigators or study coordinator will identify, document, and report any adverse 
events. 
 
The summarized safety data will be reviewed every three months by the primary 
investigator.  
 
XIX.        PROVISIONS TO PROTECT THE PRIVACY INTEREST OF PARTICIPANTS 
 
We do not anticipate any impact of the study or study procedures on the participants’ 
privacy interests. All study meetings and lab draws will take part at facilities frequented by 
all patients of the Parkview Adult Medicine Clinic. 
 
XX.        MEDICAL CARE AND COMPENSATION FOR INJURY 
 
The risk of injury due to participation in this study is exceedingly low. If injury dose occur, 
participants will be cared for at the Parkview Adult Medicine Clinic. If hospitalization is 
necessary, participants will be admitted to the Parkview Internal Medicine Residency 
inpatient teams.   
 
Participants requiring medical attention due to the study medications will not be 
compensated monetarily but will also not have to pay for the medical care they receive 
that is specifically tied to the study.  
 
The administration at Parkview Medical Center as agreed to cover the cost for patients 
that require hospital admission due to study participation. Please see Appendix F for 
approval letter from administration.  
 
XXI.       COSTS TO PARTICIPANTS 
 
Participants will be responsible for travel costs to get to clinic. They will not have to pay 
for clinic visits, labs, or medication.  
 
XXII.     DRUG ADMINISTRATION 
 
300,000IU dose 
○ 
Decalcitrol brand 
○ 
50,000IU tablet preparation 
○ 
Manufactured by Pharmin USA, LLC 
○ 
Packaged and labeled per pharmacy distribution 
○ 
Prescriptions will be sent to The Pharmacy at Parkview for the participants to pick up  
○ 
Recommend storage temperatures 59-86F 
○ 
One-time PO administration of 6 tablets 
○ 
Participants will be walked to the pharmacy to pick up the study medication 
 
5,000IU dose 
○ 
Rugby, Vitamin D3 
○ 
Manufactured by Nutri-force 
○ 
Packaging: white bottle with tamper resistant lid, 100 capsules per bottle  
○ 
 

 
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○ 
Daily PO administration of one capsule 
○ 
Participants will be walked to The Pharmacy at Parkview to buy OTC 5,000IU 
capsules. They will be asked to bring bottle to follow-up every three months to count 
capsules remaining. They will get a new bottle every three months. Participants will 
be allowed to keep leftover capsules.  
 
XXIII.     INVESTIGATIONAL DEVICES 
 
Investigational devices will not be used during this study. 
 
XXIV.     MULTI-SITE STUDIES 
 
Study will be performed only at the Parkview Adult Medicine Clinic.  
 
XXV.      SHARING OF RESULTS WITH PARTICIPANTS 
 
All personal results will be shared with the individual participants at the end of the trial.  
 
 
 
References: 
1. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of 
vitamin D deficiency: An Endocrine Society clinical practice guideline.  J Clin Endocrinol Metab. 
2011, 96(7): 1911-1930. 
2. Holick MF, Chen TC.  Vitamin D deficiency: a worldwide problem with health consequences. Am J 
Clin Nutr. 2008;87 supp:1080s-1086s. 
3. Williams S, Malatesta K, Norris K. Vitamin D and chronic kidney disease. Ethn Dis. 2009; 19(5): 
8-11. 
4. Stokes CS, Volmer DA, Grunhage F, Lammert F. Vitamin D in chronic liver disease. Liver 
International: Official Journal of the International Association for the Study of the Liver. 2013; 
33(3): 338-352. 
5. Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of 
incident hypertension. Hypertension. 2007;49:1063–1069 
6. Anathakrishnan AN. Vitamin D and inflammatory bowel disease. Gastroenterol Hepatol. 2016; 
12(8): 513-515. 
7. Reid IR. Vitamin D effect on bone mineral density and fractures. Endocrinol Metab Clin N Am. 
2017; 46: 935-945. 
8. Boonen S, Vanderschueren D, Haentjens P, Lips P. Calcium and vitamin D in the prevention and 
treatment of osteoporosis - a clinical update. J Intern Med. 2006;259:539–552. 
9. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. 
Circulation. 2008;117:503–511. 
10. Witham MD, Dove FJ, Dryburgh M, et al. The effect of different doses of vitamin D(3) on markers 
of vascular health in patients with type 2 diabetes: a randomised controlled trial. Diabetologia. 
2010;53:2112–2119 
11. Autier P, Gandini S. Vitamin D supplementation and total mortality: A meta-analysis of 
randomized controlled trials. Arch Intern Med. 2007; 167(16): 1730-1737. 
12. Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J 
Clin Endocrinol Metab. 2004, 89: 5387-5391.  
13. Smith EM, Tangpricha V. Driving up the dose: Implications for high-dose vitamin D therapy. 
Endocr Pract. 2015; 21(10): 1178-1180. 

 
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14. Ilahi M, Armas LA, Heaney RP. Pharmacokinetics of a single, large dose of cholecalciferol. Am J 
Nutr. 2008; 87(3): 688-691. 
15. Kearns MD, Binongo JNG, Watson D, et al. The effect of a single, large bolus of vitamin D in 
healthy adults over the winter and following year: a randomize, double-blinded, placebo-
controlled trial. Euro J of Clin Nutr. 2015; 69: 193-197. 
16. Kearns MD, Alvarez JA, Tangpricha V. Large, single-dose, oral vitamin D supplementation in 
adult populations: A systemic review.  Endocrin Pract. 2014; 20(4): 341-351. 
17. Premaor MO, Scalco R, da Silva MJ, et al. The effect of a single dose versusa daily dose of 
cholecalciferol on the serum 25-hydroxycholecalciferol and parathyroid hormone levels in the 
ederly with secondary hyperparathyroidism living in a low-income housing unit. J Bone Miner 
Metab. 2008;26:603-608. 
18. Stricker H, Tosi Bianda F, Guidicellli-Nicolosi S, et al. Effect of a single, oral, high-dose vitamin D 
supplementation on endothelial function in patients with peripheral arterial diseas: a 
randomised controlled pilot study. Eur J Vasc Endovasc Surg. 2012;44:307-312. 
19. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose vitamin D3 and mental well-
being: Randomised controlled trial. Brit J of Psych. 2011; 198: 357-364. 
20. Kaur P, Mishra SK, Mithal A. Vitamin D toxicity resulting from overzealous correction of vitamin 
D deficiency. Clin Endocrinol. 2015; 83: 327-331. 
21. Koul PA, Ahmad SH, Ahmad F, et al. Vitamin D toxicity in adults: A case series from an area with 
endemic hypovitaminosis D. Oman Med J. 2011; 26(3): 201-204 
22. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: When to test and how to treat. 
Mayo Clin Proc. 2010; 85(8): 752-758. 
23. Rode A, Fourlanos S, Nicoll A. Oral vitamin D replacement is effective in chronic liver disease. 
Gastroenterol Clin Biol. 2010; 34: 618-620.  
 

 
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Appendix A: Confidence interval and sample size calculations 
 
For Confidence interval of 95% 
- 
85 participants (rounded to nearest integer)  
For Power of 90%  
- 
58 participants 
 
Assumptions: 
- 
Acceptable error rate of 3 units 
- 
Significant data meaning > 6 unit change from baseline 
- 
Standard deviation on 6.7 
- 
The latter 2 were taken from Premaor et al.  
 
Calculation for Confidence interval:  
  
 
N = sample size  
Z = constant for desired confidence interval = 1.96 
σ is the standard deviation of the outcome of interest = 6.7 
E = acceptable margin of error = 3 
This was then multiplied by 2 (for the treatment group vs control group) and then divided by .9 
(assuming a 90% retention rate)  
 
Calculation for Power:  
 
N = sample size  
Z 1-α /2  = constant for standard normal distribution of 1-alpha/2= 1.96 
Z 1-  = constant for standard normal distribution of 1-beta= 1.282 (if power of 90%) 
ES = Effect Size = 
 
Numerator is the expected difference between popultions (taken from 9 month difference of Premoar 
et al) 
σ is the standard deviation of the outcome of interest = 6.7 
 
This was then multiplied by 2 (for the treatment group vs control group) and then divided by .9 
(assuming a 90% retention rate)  

 
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Template Protocol January 9, 2017 
 
Appendix B: Recruitment Flyer 
 
 

 
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Template Protocol January 9, 2017 
 
Appendix C: Screening Questionnaire 
 
 

 
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Template Protocol January 9, 2017 
 
Appendix D: Data collection sheet for initial visit 
 
 

 
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Template Protocol January 9, 2017 
 
Appendix E: Follow-up Questionnaire 
 
 
 
 

 
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Template Protocol January 9, 2017 
Appendix F: Letter from Michael Baxter, CEO of Parkview Medical Center