Study To Understand Fall Reduction and Vitamin D in You

The public health burden of falls in older persons is substantial. Several lines of evidence
suggest that vitamin D supplements might reduce the risk of falls, potentially by 25% or more
in persons with low serum 25-hydroxyvitamin D [25(OH)D] levels. However, existing evidence is
inconsistent and insufficient to guide policy. The trial is a seamless two-stage, Bayesian
response-adaptive, randomized dose-finding trial designed to select the best dose of vitamin
D supplementation and to potentially confirm the efficacy of that dose for fall prevention
and other related outcomes. Participants will be community-dwelling adults, aged 70+ (goal of
~40% black, ~60% women), with a baseline serum 25(OH)D level of 10-29 ng/ml, who are at high
risk for falling.

In Stage 1 of the adaptive design, participants will be randomly assigned to one of four
vitamin D3 (cholecalciferol) doses: 200 IU/d, 1000 IU/d, 2000 IU/d, or 4000 IU/d, with
assignment probabilities that will vary as falls are reported. Participants will take their
assigned pills for two years, or until the study ends, whichever comes first. This stage of
the design will select the best dose of vitamin D for prevention of falls, or confirm the
futility of distinguishing any differences among the doses for fall prevention. If a best
dose is selected, subsequent participants will be randomized in Stage 2 of the trial into the
comparison (200 IU/d) or best dose group, and all participants (Stage 1 and Stage 2) will
continue to be followed to potentially confirm efficacy. The investigators anticipate
enrolling approximately 1,200 participants over the entire length of the project.

The primary outcome is time to first fall (or death) over two years of therapy. Next in
importance is the outcome of gait speed. Other outcomes include fall rates, types of falls,
balance, muscle strength, frailty, Short Physical Performance Battery (SPPB) score, 6-minute
walk time, and physical activity assessed by accelerometry. Falls will be ascertained from
fall calendars completed daily by participants and from self-report by phone. In-person
follow-up visits will occur at 3, 12, and 24 months, with telephone visits occurring at 1, 6,
9, 15, 18, and 21 months after randomization. Subgroups with potential for greater benefit
from vitamin D supplementation are blacks, those with baseline 25(OH)D of 10-19 ng/ml, and
those with objective evidence of low physical function.

Inclusion Criteria:

- Age 70 and older

- Non-institutionalized

- High risk for falling, defined by a 'yes' response to at least one of the following:

- 1. Have you fallen and hurt yourself in the past year?

- 2. Have you fallen 2 or more times in the past year?

- 3. Are you afraid that you might fall because of balance or walking problems?

- 4. Do you have difficulty maintaining your balance when bathing, dressing, or getting
in and out of a chair?

- 5. Do you use a cane, walker, or other device when walking inside or outside your
home?

- Serum vitamin D [25(OH)D] level of 10-29 ng/ml

- Able to provide informed consent

- Willing to accept randomization to each vitamin D dose

- One of the following:

- 1. No vitamin D supplementation at baseline

- 2. Average daily vitamin D supplementation judged by study staff as being consistent
with the goal of 1000 IU/day or less at screening and willing to continue the dose
unchanged throughout the trial

- One of the following:

- 1. No calcium supplementation at baseline

- 2. Average daily calcium supplementation judged by study staff as being consistent
with the goal of 1200 mg/day or less at screening and willing to continue the dose
unchanged throughout the trial

Exclusion Criteria:

- Cognitive impairment, defined by Mini-Mental State Exam (MMSE) score <24

- Hypercalcemia, serum Ca++ 11.0 mg/dl or higher or >10.5 mg/dl (confirmed)

- Hypocalcemia, serum Ca++ <8.5 mg/dl

- Kidney, ureteral, or bladder stones made of calcium compounds (2 or more in lifetime,
or 1 in the last 2 years); in the absence of information on the type of stone, stones
will be assumed to be made of calcium compounds

- Planning to move out of area within 2 years, where plans would prevent compliance with
the study protocol

- Disease or condition expected to cause death or to prevent compliance with the study
protocol in the next 2 years

- Participation in another trial of vitamin D or falls, or any trial that might affect
the risk of falls

- Lactose allergy (lactose intolerance is okay)

- Use of any form of oral or injected calcitriol (brand names: Rocaltrol (R), Calcijex
(R), and Zemplar (R); generic names: calcitriol, paricalcitol, doxycalcitriol,
22-oxacalcitriol)