Vitamin D and Type 2 Diabetes (Phoenix Site)

Objectives:

People with low levels of vitamin D are at increased risk of developing type 2 diabetes.
Supplementation with vitamin D may improve insulin sensitivity and insulin secretion,
especially in those with prediabetes. However, no large clinical trial has demonstrated the
ability of vitamin D supplementation to prevent or delay the onset of diabetes. The
objective of the Vitamin D and type 2 diabetes study (D2d) is to determine whether vitamin
D3 supplementation will decrease the risk of type 2 diabetes. D2d will evaluate, in 2382
people study-wide (150 at the Phoenix site), whether supplementation with vitamin D3 will
prevent progression to type 2 diabetes in a high-risk population, compared with placebo.

Study Population:

American Indians are at a disproportionate risk for developing type 2 diabetes and carry a
disproportionate burden of disease as a result. The Phoenix site of D2d will recruit
American Indian participants exclusively, to ensure representation by this population.
Potential participants will be eligible if they do not have diabetes, have a BMI at least 25
kg/m2, and meet at least two out of three criteria for pre-diabetes (fasting plasma glucose
100-125 mg/dl, 2-hour plasma glucose 140-199 mg/dl, and HbA1c 5.7-6.4%). Exclusion criteria
include any condition that would increase the risk of complications due to vitamin D3
supplementation (e.g., history of kidney stones, hypercalcemia, or intolerance to vitamin D3
supplements).

Design:

Participants eligible for D2d will be randomly assigned to either vitamin D3 supplementation
(4,000 international units daily by mouth) or placebo. Participants and staff will be
blinded to treatment assignment. Both intervention groups will be offered education on
lifestyle changes to prevent diabetes.

Participants will be followed every 6 months at a formal clinic visit at which blood will be
drawn for fasting glucose and HbA1c. At annual visits a 75-gm 2-hour oral glucose tolerance
test will also be done.

Outcome Parameters:

The primary outcome of the study will be time to onset of type 2 diabetes. Secondary
outcomes will include variability in response to vitamin D3 supplementation by baseline
characteristics and by adherence to the intervention.

- INCLUSION CRITERIA:

1. -Pre-diabetes (at increased risk for diabetes) defined by meeting 2-out-of-3 of
the following glycemic criteria, established by the ADA in the 2010 clinical
practice guidelines, at the baseline visit:

--FPG 100-125 mg/dL, inclusive

- 2hPG 140-199 mg/dL, inclusive

- HbA1c 5.7-6.4%, inclusive

2. -Age greater than or equal to 30 years. Age is a major risk factor for type 2
diabetes; avoid contamination with type 1 Diabetes or Latent Autoimmune Diabetes
of Adults, conditions that have a different pathophysiology; minimize loss to
follow-up due to social mobility; facilitate recruitment and increase
applicability of findings

3. -BMI greater than or equal to 25.0 (23.0 for Asians) and less than or equal to
40.0 kg/m(2). Overweight/obesity is a major risk factor for type 2 diabetes;
those with severe obesity require higher doses of vitamin D

4. -Provision of signed and dated written informed consent prior to any study
procedures.

EXCLUSION CRITERIA:

Exclusion Criteria were selected to: (1) ensure participants safety; (2)
avoid conditions that would affect the outcomes (i.e. minimize competing risk);
(3) make recruitment targets realistic; (4) amplify generalizability of study
results; (5) maximize participants adherence with study procedures.

5. -Diabetes based on either of the following criteria:

- History (past 1 year) of hypoglycemic pharmacotherapy (oral or injectable
medication approved by the FDA for type 2 diabetes) used for any condition
(e.g. pre-diabetes, diabetes, polycystic ovarian syndrome).

- Meeting glycemic criteria for diabetes, as defined by the ADA guidelines
(FPG greater than or equal to 126 mg/dL, 2hPG greater than or equal to 200
mg/dL or HbA1c greater than or equal to 6.5%).

6. -History (past 3 years) of hyperparathyroidism, nephrolithiasis or
hypercalcemia.

7. -Any medical condition (past 3 years) that in the opinion of the site
investigator may increase risk for nephrolithiasis or hypercalcemia during the
trial (e.g. sarcoidosis).

8. -Use of tanning devices within 12 weeks of the baseline visit and unwilling to
stop using tanning devices for the duration of the study interference with
intervention

Medications and Supplements:

9. -Use of supplements containing vitamin D at total doses higher than 1000 IU/day
within 12 weeks of the baseline visit initiating the protocol and unwillingness
to limit vitamin D supplementation dosage to no higher than 1000 IU/day for the
duration of the study.

10. -Use of supplements containing calcium at total doses higher than 600 mg/day
within 1 week of the baseline visit initiating the protocol and unwillingness to
limit calcium supplementation dosage to no more than 600 mg/day for the duration
of the study.

11. -Current use of medications or conditions (e.g. untreated celiac disease) that
would interfere with absorption or metabolism of vitamin D.

12. -Current use of medications approved by the FDA for weight management.

13. -Use of thiazide diuretics at a total dose greater than 37.5 mg/day.

14. Use of anticonvulsant drug started within 6 months of screening. Stable regimen
of anticonvulsants is allowed.

15. -History of intolerance to vitamin D supplements.

Other Medical History:

16. -Severe symptomatic cardiovascular disease based on history and physical
examination (unstable angina, dyspnea on exertion, paroxysmal nocturnal dyspnea,
arrhythmia, congestive heart failure NYHA class II or higher, claudication).

17. -History (past 1 year) of myocardial infarction, percutaneous coronary
intervention or coronary artery bypass graft.

18. -History (past 1 year) of cerebrovascular disease (stroke, transient ischemic
attack). 19-.-Any type of cancer (past 5 years) except for basal cell skin
cancer. Participants with prostate cancer (for men over age 55) or
well-differentiated thyroid cancer that are not expected to require treatment
(except for suppression with thyroid hormone) over the next 4 years are not
excluded.

20.-History (past 6 months) of treatment with oral (for > 7 days) or intravenous
glucocorticoids or disease likely to require oral or intravenous glucocorticoid
therapy during the study (inhaled glucocorticoids are not excluded). Interference
with outcome assessment

21.-History (past 1 year) of substance abuse or unstable psychiatric disorder that in
the opinion of the site investigator would impede competence or adherence with study
procedures or hinder completion of the study or increase risk. Use of marijuana with
a medical prescription is permitted.

22.-History of bariatric surgery or planned bariatric surgery in the next 4 years.
Participants with gastric banding more than 2 years ago with self-reported weight
stability (defined as weight change no greater than 3 kg during the prior 6 months)
are not excluded. Interfere with vitamin D absorption.

23.-A life-threatening event within 30 days of screening or currently planned major
surgery.

24.-Any other unstable active medical condition (including but not limited to liver
disease, wasting illness, AIDS, tuberculosis, oxygen-dependent chronic obstructive
pulmonary disease, organ transplant, Cushing s syndrome) that in the opinion of the
site investigators would impede competence or adherence with study procedures or
increase risk.Aadherence, plasma 25OHD may decrease as an acute-phase response. Such
conditions will be assessed based on self-report and/or review of medical records (if
available).

25.-Uncontrolled hypertension (systolic blood pressure > 160 mm Hg or diastolic
blood pressure > 100 mm Hg).

26.-Poor venous access.

Laboratory Evaluation:

27.-Serum liver transaminase (ALT or AST) higher than 3 times the normal range for the
clinical site s laboratory

28.-Anemia (hematocrit < 32 for women, < 36 for men), whole blood transfusion (within 6
months of screening) or chronic requirement, whole blood donation (within 3 months of
screening) or other condition (hemolysis, hemoglobinopathy) rendering HbA1c results
unreliable as indicator of chronic glycemia. Interference with outcome assessment.
Participants who donate platelets are not excluded. Whole blood transfusion or donation
does not exclude participant, but screening and study visits need to be timed
appropriately.

29.-Low platelet count (< 50,000). Safety for blood draws

30.-Chronic kidney disease, defined as estimated glomerular filtration rate GFR < 50
mL/min, from creatinine measured at the clinical site s laboratory and GFR calculated
centrally. Vitamin D homeostasis changes as GFR declines. These changes start when GFR
falls around 40-60 mL/min per 1.73 m(2). The planning committee selected 50 mL/min as the
exclusion cutoff to ensure that participants maintain GFR > 40 mL/min during the study.
Please note: to prevent potential confusion, GFR units will be denoted as mL/min
throughout the protocol and associated documents.

31.-Hypercalcemia, defined as serum calcium concentration greater than or equal to the
upper limit of normal, measured at the clinical site s laboratory.

Hypercalciuria, defined as spot urine (morning void) calcium-creatinine ratio > 0.275.

Other

33.-Participation (within 30 days of screening) in another interventional research study.

34.-Previous randomization in the D2d study. Participants who did not qualify after
screening may be screened again if the prior reason for exclusion has been addressed (e.g.
high blood pressure is treated).

35.-Any other reason that in the opinion of the site investigator would impede adherence
with study procedures or hinder completion of the study or increase risk (e.g. use of
non-approved or experimental drugs, inability to follow instructions or understand the
informed consent, dementia, unable to remain in the program for the duration of the study,
inability to comply with the study protocol for any reason).

Women only

36.-Pregnancy (past 1 year by report or positive pregnancy test at screening), intent to
become pregnant in the next 4 years or unprotected intercourse. History of gestational
diabetes is not an exclusion criterion.

37.-Currently breastfeeding.

38.-Use of oral contraceptives or menopausal hormone therapy started within 3 months of
baseline. Stable regimen of oral contraceptives or any other hormonal method of
contraception (e.g. implantable) is allowed.