Falls, Vitamin D Deficiency
Conditions
Keywords
vitamin D, falls, high risk of falling, insufficient or deficient serum vitamin D levels, 10-29 ng/ml
Brief summary
Vitamin D supplements might substantially reduce the risk of falls, potentially by more than 25%. The proposed study is a clinical trial that will determine the effects of 4 doses of vitamin D (200 International Units \[IU\]/day, 1000 IU/day, 2000 IU/d and 4000 IU/d) as a means to prevent falls in high-risk adults, ages 70 and older. Results of this trial will be directly relevant to public health and clinical guidelines, and will immediately influence policy.
Detailed description
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 (control), 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 non control dose of vitamin D for prevention of falls, or confirm the futility of distinguishing any differences among the non control 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.
Interventions
DIETARY_SUPPLEMENT200 IU/d cholecalciferol
DIETARY_SUPPLEMENT1000 IU/d cholecalciferol
DIETARY_SUPPLEMENT2000 IU/d cholecalciferol
DIETARY_SUPPLEMENT4000 IU/d cholecalciferol
Sponsors
National Institute on Aging (NIA)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of First Fall or Death (Whichever Comes First) | Randomization to 24 months or end of trial, whichever came first | Falls were ascertained by a monthly fall calendar completed by each participant, scheduled interviews at 1 month and 3 months after randomization and every 3 months thereafter up to 24 months or trial end. Death was ascertained primarily by reports from family or friends. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Gait Speed | Baseline, 3 months, 12 months and 24 months | Gait speed in meters per second (m/s) was obtained from the timed 4-meter, usual-paced walk component of the Short Physical Performance Battery. The change in gait speed was obtained as follow-up measure minus baseline measure. |
Countries
United States
Participant flow
Recruitment details
From October 2015 to March 2018, new participants were randomized in the trial's Stage 1 and began their individual 2-year period of trial participation. Stage 1 ended on March 23, 2018 and Stage 2 began; randomization continued but to the 200 and 1000 groups only. Some participants completed their 2 years of participation during Stage 1, some participants had follow-up time during both Stage 1 and Stage 2, and some participants began their 2 years of participation during Stage 2.
Participants by arm
| Arm | Count |
|---|---|
| 200 IU/d The 200 IU/d group is the control group. | 339 |
| 1000 IU/d During dose-finding, the 1000 IU/d dose was identified as the best of the non-control doses for fall prevention. | 212 |
| 2000 IU/d Randomization to the 2000 IU/d group was stopped in February 2018 as part of planned dose-finding. | 68 |
| 4000 IU/d Randomization to the 4000 IU/d group was stopped in March 2018 as part of planned dose-finding. | 69 |
| Total | 688 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Stage 1 | Death | 4 | 0 | 2 | 0 | 3 | 2 |
| Stage 1 | Finished the trial (did the 2 year visit) during Stage 1 and did not advance to Stage 2 | 4 | 0 | 0 | 0 | 3 | 1 |
| Stage 1 | Lost to Follow-up | 12 | 0 | 6 | 0 | 3 | 3 |
| Stage 2 | Death | 4 | 2 | 1 | 0 | 0 | 1 |
| Stage 2 | Finished the trial (did the 2 year visit) prior to or during trial closeout | 180 | 0 | 63 | 0 | 54 | 52 |
| Stage 2 | Lost to Follow-up | 23 | 4 | 11 | 9 | 3 | 6 |
Baseline characteristics
| Characteristic | Total | 200 IU/d | 1000 IU/d | 2000 IU/d | 4000 IU/d |
|---|---|---|---|---|---|
| Afraid of falling due to balance or walking problem | 601 Participants | 290 Participants | 190 Participants | 65 Participants | 56 Participants |
| Age, Continuous | 77.2 years STANDARD_DEVIATION 5.4 | 77.2 years STANDARD_DEVIATION 5.4 | 76.5 years STANDARD_DEVIATION 5.3 | 77.3 years STANDARD_DEVIATION 4.6 | 79.1 years STANDARD_DEVIATION 5.9 |
| BMI | 30.5 kg/m^2 STANDARD_DEVIATION 6 | 30.4 kg/m^2 STANDARD_DEVIATION 6.3 | 30.7 kg/m^2 STANDARD_DEVIATION 5.2 | 30.7 kg/m^2 STANDARD_DEVIATION 6.4 | 30.3 kg/m^2 STANDARD_DEVIATION 6.2 |
| Difficulty maintaining balance | 343 Participants | 173 Participants | 99 Participants | 33 Participants | 38 Participants |
| Fell and hurt self in prior year | 262 Participants | 130 Participants | 81 Participants | 21 Participants | 30 Participants |
| Fell at least once in prior year | 450 Participants | 221 Participants | 139 Participants | 43 Participants | 47 Participants |
| Fell at least twice in prior year | 259 Participants | 120 Participants | 83 Participants | 26 Participants | 30 Participants |
| Frailty status Frail | 81 Participants | 30 Participants | 33 Participants | 7 Participants | 11 Participants |
| Frailty status Pre-frail | 408 Participants | 205 Participants | 127 Participants | 36 Participants | 40 Participants |
| Frailty status Robust | 198 Participants | 104 Participants | 51 Participants | 25 Participants | 18 Participants |
| Gait speed (m/sec) | 0.86 meters per second STANDARD_DEVIATION 0.24 | 0.89 meters per second STANDARD_DEVIATION 0.23 | 0.85 meters per second STANDARD_DEVIATION 0.23 | 0.80 meters per second STANDARD_DEVIATION 0.23 | 0.85 meters per second STANDARD_DEVIATION 0.23 |
| Race/Ethnicity, Customized Black | 124 Participants | 55 Participants | 44 Participants | 15 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic, Latino or Spanish ethnicity | 8 Participants | 3 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 23 Participants | 7 Participants | 12 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 543 Participants | 276 Participants | 159 Participants | 51 Participants | 57 Participants |
| Region of Enrollment United States | 688 Participants | 339 Participants | 212 Participants | 68 Participants | 69 Participants |
| Serum vitamin D (nmol/L) 25 to 49 nmol/L | 200 Participants | 100 Participants | 53 Participants | 25 Participants | 22 Participants |
| Serum vitamin D (nmol/L) 50 to 72.5 nmol/L | 488 Participants | 239 Participants | 159 Participants | 43 Participants | 47 Participants |
| Sex: Female, Male Female | 300 Participants | 141 Participants | 102 Participants | 29 Participants | 28 Participants |
| Sex: Female, Male Male | 388 Participants | 198 Participants | 110 Participants | 39 Participants | 41 Participants |
| SF-12 mental health component score | 55.0 units on a scale STANDARD_DEVIATION 7.9 | 55.1 units on a scale STANDARD_DEVIATION 7.7 | 55.4 units on a scale STANDARD_DEVIATION 7.6 | 54.5 units on a scale STANDARD_DEVIATION 8.4 | 54.3 units on a scale STANDARD_DEVIATION 9.4 |
| SF-12 physical health component score | 43.8 units on a scale STANDARD_DEVIATION 10.5 | 44.5 units on a scale STANDARD_DEVIATION 10.3 | 42.9 units on a scale STANDARD_DEVIATION 11 | 42.9 units on a scale STANDARD_DEVIATION 10.2 | 44.0 units on a scale STANDARD_DEVIATION 9.9 |
| Short Physical Performance Battery score 0 to 3 | 30 Participants | 12 Participants | 12 Participants | 3 Participants | 3 Participants |
| Short Physical Performance Battery score 10 to 12 | 306 Participants | 162 Participants | 90 Participants | 23 Participants | 31 Participants |
| Short Physical Performance Battery score 4 to 6 | 75 Participants | 34 Participants | 18 Participants | 12 Participants | 11 Participants |
| Short Physical Performance Battery score 7 to 9 | 277 Participants | 131 Participants | 92 Participants | 30 Participants | 24 Participants |
| Taking a vitamin D supplement | 256 Participants | 124 Participants | 82 Participants | 27 Participants | 23 Participants |
| Total vitamin D intake (IU/day) < 200 | 253 Participants | 125 Participants | 77 Participants | 21 Participants | 30 Participants |
| Total vitamin D intake (IU/day) 200-399 | 138 Participants | 68 Participants | 40 Participants | 16 Participants | 14 Participants |
| Total vitamin D intake (IU/day) 400-799 | 125 Participants | 63 Participants | 39 Participants | 10 Participants | 13 Participants |
| Total vitamin D intake (IU/day) >= 800 | 172 Participants | 83 Participants | 56 Participants | 21 Participants | 12 Participants |
| Uses cane, walker or other assistive device to walk | 204 Participants | 91 Participants | 64 Participants | 24 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 349 | 10 / 339 | 4 / 308 | 3 / 68 | 2 / 69 |
| other Total, other adverse events | 311 / 349 | 299 / 339 | 250 / 308 | 60 / 68 | 63 / 69 |
| serious Total, serious adverse events | 82 / 349 | 68 / 339 | 49 / 308 | 17 / 68 | 17 / 69 |
Outcome results
Primary
Incidence of First Fall or Death (Whichever Comes First)
Falls were ascertained by a monthly fall calendar completed by each participant, scheduled interviews at 1 month and 3 months after randomization and every 3 months thereafter up to 24 months or trial end. Death was ascertained primarily by reports from family or friends.
Time frame: Randomization to 24 months or end of trial, whichever came first
Population: The primary efficacy analysis compares the Experience on Best Dose group versus the 200 IU/d group. The Experience on Best Dose group includes all participants assigned or switched to best dose, with their data limited to data while on best dose. This group excludes 41 participants randomized to 2000 or 4000 IU/d who were never issued a bottle of 1000 IU/d because they completed the trial, died, dropped out, or stopped using study pills without ever being switched to 1000 IU/d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experience on Best Dose | Incidence of First Fall or Death (Whichever Comes First) | 76.9 First fall or death per 100 person-years |
| 200 IU/d | Incidence of First Fall or Death (Whichever Comes First) | 76.0 First fall or death per 100 person-years |
| Pooled Higher Doses | Incidence of First Fall or Death (Whichever Comes First) | 78.0 First fall or death per 100 person-years |
Comparison: The Experience on Best Dose group includes all participants assigned or switched to best dose (1000 IU/day) and excludes 41 participants randomized to 2000 or 4000 IU/day who were never issued a bottle of best dose. For those randomized to 2000 or 4000 IU/day, at-risk time and events are measured from the date of their switch to best dose. 150 Experience on Best Dose participants (median follow-up, 10.2 mos) and 125 200 IU/day participants (median follow-up, 20.3 mos) were censored.p-value: 0.5495% CI: [0.76, 1.15]Log Rank
95% CI: [0.86, 1.25]
Secondary
Change in Gait Speed
Gait speed in meters per second (m/s) was obtained from the timed 4-meter, usual-paced walk component of the Short Physical Performance Battery. The change in gait speed was obtained as follow-up measure minus baseline measure.
Time frame: Baseline, 3 months, 12 months and 24 months
Population: Change in gait speed since randomization was evaluated in the Pooled Higher Doses group versus the 200 IU/d group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experience on Best Dose | Change in Gait Speed | Change at 3 months | -0.01 m/s | Standard Deviation 0.17 |
| Experience on Best Dose | Change in Gait Speed | Change at 12 months | -0.04 m/s | Standard Deviation 0.17 |
| Experience on Best Dose | Change in Gait Speed | Change at 24 months | -0.03 m/s | Standard Deviation 0.16 |
| 200 IU/d | Change in Gait Speed | Change at 3 months | -0.01 m/s | Standard Deviation 0.18 |
| 200 IU/d | Change in Gait Speed | Change at 12 months | -0.04 m/s | Standard Deviation 0.2 |
| 200 IU/d | Change in Gait Speed | Change at 24 months | -0.09 m/s | Standard Deviation 0.21 |
Comparison: The two groups were assessed for differential change over time in change from baseline using a longitudinal mixed effects regression model with gait speed as the outcome and fixed effects including a single treatment term, 3 time point terms and 3 treatment-by-time interaction terms and a random intercept for participant.p-value: 0.15Regression, Linear