The Pittsburgh Vitamin D Study: Vitamin D Supplementation in Vitamin D-deficient Subjects at Risk of Lung Cancer

Smoking avoidance or cessation are essential to the prevention of lung cancer. However, not
all smokers are able to quit smoking and, importantly, former smokers remain at increased
risk of lung cancer compared to never smokers. Despite smoking prevention/cessation programs
and treatment advances, lung cancer is still the leading cause of cancer-related mortality in
the United States with more than 158,000 individuals expected to die from this disease in
2015. Effective and safe prevention strategies are expected to be more successful in reducing
lung cancer deaths than treatment of established disease.

NF-kappaB (NF-kB) pathway activation underlies smoking-related inflammation and lung
carcinogenesis, and those agents which suppress NF-κB signaling may have the potential to
prevent lung cancer. Recent preclinical data from our group and others indicate that the
active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has lung cancer
chemopreventive activity. Because systemic 1,25(OH)2D3 administration is complicated by its
hypercalcemia-inducing properties, the investigators propose to use oral supplementation with
vitamin D3 (cholecalciferol) to safely achieve chemopreventive 1,25(OH)2D3 levels within the
lung.

This randomized, placebo-controlled Phase IIb study aims to evaluate the ability of 4,000 IU
oral vitamin D3/day (in combination with a daily multivitamin) to safely convert vitamin
D3-deficient subjects at risk of lung cancer to a vitamin D3-sufficient state.

Study participants will be recruited from among Pittsburgh Lung Screening Study Extension
(PLuSS-X) and PLuSS-XX participants not diagnosed with lung cancer, and from among the
patient population seen by the PI of this protocol. The study consists of two stages, a
screening and an intervention stage, with their own consent forms. In Stage 1 (the screening
stage), the vitamin D3 status of subjects potentially eligible for participation in the
intervention will be determined; in Stage 2 (the intervention stage), supplementation with
oral vitamin D3 will be evaluated.

Participants who fulfill the eligibility criteria and provided signed consent for Stage 2
will be randomized in a 2:1 ratio to receive: (A) 4,000 IU vitamin D3 plus a multivitamin
(containing 400 IU vitamin D3) daily for one year, or (B) a placebo vitamin D3 pill plus a
multivitamin daily for one year. Both groups will contain equal numbers of current and
ex-smokers; in total 120 subjects will be randomized. To evaluate whether supplementation
safely corrects vitamin D3 deficiency in this population, blood samples will be obtained at
baseline, 3, 6, and 12 months of intervention for evaluation of 25(OH)D3 and serum calcium.
The collected blood will also be used to facilitate biomarker assessment. Pulmonary function
tests (PFTs) will be obtained at baseline and repeated after 12 months to determine whether
supplementation has an effect on lung function. Sputum and nasal epithelium will be collected
at baseline, 6 months and 12 months to facilitate biomarker assessment.

- Study Objectives Primary Objective: To establish the 12-month conversion rate (i.e.,
proportion of subjects whose baseline vitamin D3 deficiency is corrected after 12 months of
supplementation).

Secondary Objectives: To determine the 3-month and 6-month conversion rates and examine the
effect of vitamin D3 supplementation in current and former smokers. Additionally, to examine
the effects of vitamin D3 supplementation on biomarkers of lung cancer risk, inflammation,
and pulmonary function.

Inclusion Criteria:

1. Age ≥ 50 years old.

2. Current or ex-smoker with at least 10 pack-year history

3. COPD, GOLD II or greater (defined as FEV1/FVC <70% and FEV1 % predicted <80%)

4. 25(OH)D3 level ≤25 ng/mL

5. Willingness to comply with study guidelines.

6. Willingness to avoid alternative/additional vitamin D3 supplementation for the
duration of the trial

7. Participant must understand the investigational nature of this study and sign an
Independent Ethics Committee/Institutional Review Board approved written informed
consent form prior to receiving any study related procedure.

Exclusion Criteria:

1. Personal history of lung cancer or head and neck cancer

2. History of malabsorption syndrome (e.g., pancreatic insufficiency, celiac disease, or
tropical sprue).

3. History of known thyroid disease

4. History of known sarcoid disease

5. History of known abnormalities in calcium metabolism

6. Hypercalcemia (serum calcium in excess of laboratory ULN)

7. Self-reported consumption of more than 4 alcoholic drinks per day

8. Use of anti-seizure medications phenobarbital or phenytoin, which can disrupt vitamin
D metabolism

9. History of known renal dysfunction

10. History of known nephrolithiasis (kidney stones)

11. Current participation in another cancer chemoprevention study

12. Any condition which in the Investigator's opinion deems the subject an unsuitable
candidate to receive study drug.

13. Inability to swallow pills.

14. Vitamin D supplementation > 2,000 IU/day of vitamin D within 30 days prior to
enrollment.

15. Being pregnant