STURDY: Study To Understand Fall Reduction and Vitamin D in You

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02166333
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 688
• Locations: 2
• Arms: 4
• Actual Duration (Months): 47.2
• Patients Per Site: 344
• Patients Per Site Per Month: 7.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Vitamin D Deficiency; Falls	Dietary Supplement: 200 IU/d cholecalciferol; Dietary Supplement: 1000 IU/d cholecalciferol; Dietary Supplement: 2000 IU/d cholecalciferol; Dietary Supplement: 4000 IU/d cholecalciferol	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 688 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Vitamin D Supplements to Prevent Falls in Older Adults: A Dose-Response Trial
• Actual Study Start Date: Jun 30, 2015
• Actual Primary Completion Date: May 31, 2019
• Actual Study Completion Date: Jun 7, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 200 IU/d 200 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually	Dietary Supplement: 200 IU/d cholecalciferol; Other Names: vitamin D3
Active Comparator: 1000 IU/d 1000 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually	Dietary Supplement: 1000 IU/d cholecalciferol; Other Names: vitamin D3
Active Comparator: 2000 IU/d 2000 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually	Dietary Supplement: 2000 IU/d cholecalciferol; Other Names: vitamin D3
Active Comparator: 4000 IU/d 4000 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually	Dietary Supplement: 4000 IU/d cholecalciferol; Other Names: vitamin D3

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 70 Years and Older
• Sexes Eligible for Study: All
• Accepts 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?
• 1. Have you fallen 2 or more times in the past year?
• 1. Are you afraid that you might fall because of balance or walking problems?
• 1. Do you have difficulty maintaining your balance when bathing, dressing, or getting in and out of a chair?
• 1. 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
• 1. 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
• 1. 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ProHealth Clinical Research Unit	Baltimore	Maryland	United States	21207
2	Comstock Center for Public Health Research and Prevention	Hagerstown	Maryland	United States	21740

Sponsors and Collaborators

• Johns Hopkins University
• National Institute on Aging (NIA)

Investigators

• Study Chair: Lawrence J Appel, MD, MPH, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol - May 5, 2017
• Statistical Analysis Plan - May 26, 2017

More Information

Additional Information:

• STURDY study website

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT02166333
• Other Study ID Numbers: IRB00063914; U01AG047837
• First Posted: Jun 18, 2014
• Last Update Posted: May 14, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Johns Hopkins University: vitamin D; falls; high risk of falling; insufficient or deficient serum vitamin D levels; 10-29 ng/ml
• Additional relevant MeSH terms: Vitamin D Deficiency; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins

Study Results

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.

Arm/Group Title	Randomized to 200 IU/d in Stage 1	Additional Participants Randomized to 200 IU/d in Stage 2	Randomized to 1000 IU/d in Stage 1	Additional Participants Randomized to 1000 IU/d in Stage 2	Randomized to 2000 IU/d in Stage 1 and Switched to 1000 IU/d in Stage 2	Randomized to 4000 IU/d in Stage 1 and Switched to 1000 IU/d in Stage 2
Arm/Group Description	These participants received 200 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually throughout their trial participation; those who continued to Stage 2 (neither completed the trial [completed the 2-year visit], nor died, nor dropped out during Stage 1) continued to receive 200 IU/d cholecalciferol during Stage 2.	These participants began their study participation in Stage 2 and received 200 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually throughout their participation.	These participants received 1000 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually throughout their trial participation; those who continued to Stage 2 (neither completed the trial [completed the 2-year visit], nor died, nor dropped out during Stage 1) continued to receive 1000 IU/d cholecalciferol during Stage 2.	These participants began their study participation in Stage 2 and received 1000 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually throughout their participation.	These participants received 2000 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually in Stage 1; those who continued to Stage 2 were switched to 1000 IU/d cholecalciferol (vitamin D3) tablets during Stage 2.	These participants received 4000 IU/d cholecalciferol (vitamin D3) tablets that can be swallowed or consumed sublingually in Stage 1; those who continued to Stage 2 were switched to 1000 IU/d cholecalciferol (vitamin D3) tablets during Stage 2.
Period Title: Stage 1
STARTED	262	0	130	0	68	69
COMPLETED	242	0	122	0	59	63
NOT COMPLETED	20	0	8	0	9	6
Period Title: Stage 1
STARTED	242	77	122	82	59	63
COMPLETED	35	71	47	73	2	4
NOT COMPLETED	207	6	75	9	57	59

Baseline Characteristics

Arm/Group Title	200 IU/d	1000 IU/d	2000 IU/d	4000 IU/d	Total
Arm/Group Description	The 200 IU/d group is the control group.	During dose-finding, the 1000 IU/d dose was identified as the best of the non-control doses for fall prevention.	Randomization to the 2000 IU/d group was stopped in February 2018 as part of planned dose-finding.	Randomization to the 4000 IU/d group was stopped in March 2018 as part of planned dose-finding.	Total of all reporting groups
Overall Participants	339	212	68	69	688
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	77.2 (5.4)	76.5 (5.3)	77.3 (4.6)	79.1 (5.9)	77.2 (5.4)
Sex: Female, Male (Count of Participants)
Female	141 41.6%	102 48.1%	29 42.6%	28 40.6%	300 43.6%
Male	198 58.4%	110 51.9%	39 57.4%	41 59.4%	388 56.4%
Race/Ethnicity, Customized (Count of Participants)
White	276 81.4%	159 75%	51 75%	57 82.6%	543 78.9%
Black	55 16.2%	44 20.8%	15 22.1%	10 14.5%	124 18%
Other	7 2.1%	12 5.7%	2 2.9%	2 2.9%	23 3.3%
Hispanic, Latino or Spanish ethnicity	3 0.9%	3 1.4%	1 1.5%	1 1.4%	8 1.2%
Region of Enrollment (Count of Participants)
United States	339 100%	212 100%	68 100%	69 100%	688 100%
Serum vitamin D (nmol/L) (Count of Participants)
25 to 49 nmol/L	100 29.5%	53 25%	25 36.8%	22 31.9%	200 29.1%
50 to 72.5 nmol/L	239 70.5%	159 75%	43 63.2%	47 68.1%	488 70.9%
Taking a vitamin D supplement (Count of Participants)
Count of Participants [Participants]	124 36.6%	82 38.7%	27 39.7%	23 33.3%	256 37.2%
Total vitamin D intake (IU/day) (Count of Participants)
< 200	125 36.9%	77 36.3%	21 30.9%	30 43.5%	253 36.8%
200-399	68 20.1%	40 18.9%	16 23.5%	14 20.3%	138 20.1%
400-799	63 18.6%	39 18.4%	10 14.7%	13 18.8%	125 18.2%
>= 800	83 24.5%	56 26.4%	21 30.9%	12 17.4%	172 25%
Fell at least once in prior year (Count of Participants)
Count of Participants [Participants]	221 65.2%	139 65.6%	43 63.2%	47 68.1%	450 65.4%
Fell and hurt self in prior year (Count of Participants)
Count of Participants [Participants]	130 38.3%	81 38.2%	21 30.9%	30 43.5%	262 38.1%
Fell at least twice in prior year (Count of Participants)
Count of Participants [Participants]	120 35.4%	83 39.2%	26 38.2%	30 43.5%	259 37.6%
Afraid of falling due to balance or walking problem (Count of Participants)
Count of Participants [Participants]	290 85.5%	190 89.6%	65 95.6%	56 81.2%	601 87.4%
Difficulty maintaining balance (Count of Participants)
Count of Participants [Participants]	173 51%	99 46.7%	33 48.5%	38 55.1%	343 49.9%
Uses cane, walker or other assistive device to walk (Count of Participants)
Count of Participants [Participants]	91 26.8%	64 30.2%	24 35.3%	25 36.2%	204 29.7%
Short Physical Performance Battery score (Count of Participants)
0 to 3	12 3.5%	12 5.7%	3 4.4%	3 4.3%	30 4.4%
4 to 6	34 10%	18 8.5%	12 17.6%	11 15.9%	75 10.9%
7 to 9	131 38.6%	92 43.4%	30 44.1%	24 34.8%	277 40.3%
10 to 12	162 47.8%	90 42.5%	23 33.8%	31 44.9%	306 44.5%
Gait speed (m/sec) (meters per second) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters per second]	0.89 (0.23)	0.85 (0.23)	0.80 (0.23)	0.85 (0.23)	0.86 (0.24)
Frailty status (Count of Participants)
Robust	104 30.7%	51 24.1%	25 36.8%	18 26.1%	198 28.8%
Pre-frail	205 60.5%	127 59.9%	36 52.9%	40 58%	408 59.3%
Frail	30 8.8%	33 15.6%	7 10.3%	11 15.9%	81 11.8%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.4 (6.3)	30.7 (5.2)	30.7 (6.4)	30.3 (6.2)	30.5 (6.0)
SF-12 physical health component score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	44.5 (10.3)	42.9 (11.0)	42.9 (10.2)	44.0 (9.9)	43.8 (10.5)
SF-12 mental health component score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	55.1 (7.7)	55.4 (7.6)	54.5 (8.4)	54.3 (9.4)	55.0 (7.9)

Outcome Measures

1. Primary Outcome

Title	Incidence of First Fall or Death (Whichever Comes First)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Experience on Best Dose	200 IU/d	Pooled Higher Doses
Arm/Group Description	The Experience on Best Dose group includes 121 participants randomized to 1000 IU/d during dose-finding and 96 participants randomized to 2000 or 4000 IU/d during dose-finding who were issued at least one bottle of 1000 IU after dose-finding ended, plus 91 participants randomized to 1000 IU/d after dose-finding ended, for a total of 308 participants who had experience on the dose selected as best of the non-control doses for preventing falls. 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.	The 200 IU/d group is the control group and includes participants randomized to 200 IU/d during Stage 1 and participants randomized to 200 IU/d during Stage 2.	All participants randomized to 1000, 2000, or 4000 IU/d during Stage 1 and all participants randomized to 1000 IU/d during Stage 2.
Measure Participants	308	339	349
Number (95% Confidence Interval) [First fall or death per 100 person-years]	76.9	76.0	78.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experience on Best Dose, 200 IU/d
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments	The P value is nominal and two-sided.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Experience on Best Dose versus 200 IU/day hazard ratio and its 95% confidence interval were derived from a Cox regression model with dose group as the single model variable.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	200 IU/d, Pooled Higher Doses
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	The comparison of the Pooled Higher Doses group versus the 200 IU/d group is a sensitivity analysis.

2. Secondary Outcome

Title	Change in Gait Speed
Description	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

Outcome Measure Data

Analysis Population Description

Change in gait speed since randomization was evaluated in the Pooled Higher Doses group versus the 200 IU/d group.

Arm/Group Title	Pooled Higher Doses	200 IU/Day
Arm/Group Description	The Pooled Higher Doses group includes all participants randomized to 1000, 2000, or 4000 IU/d (n=349).	The 200 IU/d group is the control group.
Measure Participants	349	339
Change at 3 months	-0.01 (0.17)	-0.01 (0.18)
Change at 12 months	-0.04 (0.17)	-0.04 (0.20)
Change at 24 months	-0.03 (0.16)	-0.09 (0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experience on Best Dose, 200 IU/d
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	The overall P tests for difference between groups in differential change from baseline over time and is from a 3 degree of freedom test of the combined 3 treatment-by-time interaction terms from the longitudinal mixed effects model.
Statistical Test of Hypothesis	p-Value	0.15
	Comments	The P value is nominal and not adjusted for multiple comparisons.
	Method	Regression, Linear
	Comments	3 degree of freedom interaction test

Adverse Events

Time Frame	Adverse event information was collected from randomization to last date of participation in the trial, up to 24 months.
Adverse Event Reporting Description	Adverse events are reported for the Pooled Higher Doses group (those randomized to 1000, 2000, or 4000 IU) vs. the control group (those randomized to 200 IU) to be consistent with how the study outcomes are reported, because the Pooled Higher Doses and control groups have comparable numbers and follow-up, and because the 2000 and 4000 IU groups received 1000 IU after 1000 IU was selected as best non control dose. Also shown are counts of adverse event by dose in use when the event occurred.
Arm/Group Title	Pooled Higher Doses		200 IU/d		Those With Experience on 1000 IU		Those With Experience on 2000 IU		Those With Experience on 4000 IU
Arm/Group Description	The Pooled Higher Doses group includes all participants randomized to 1000, 2000, or 4000 IU/d.		The 200 IU/d group is the control group.		This group includes those randomized to 1000 IU and 96 participants randomized to 2000 or 4000 who were issued at least 1 bottle of 1000 IU. Note that participants who switched doses during the trial may have an event while in their original group as well as in the 1000 group if the event recurred after switching to 1000 IU.		Only those randomized to 2000 IU are in this group.		Only those randomized to 4000 IU are in this group.
All Cause Mortality
	Pooled Higher Doses		200 IU/d		Those With Experience on 1000 IU		Those With Experience on 2000 IU		Those With Experience on 4000 IU
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/349 (2.6%)		10/339 (2.9%)		4/308 (1.3%)		3/68 (4.4%)		2/69 (2.9%)
Serious Adverse Events
	Pooled Higher Doses		200 IU/d		Those With Experience on 1000 IU		Those With Experience on 2000 IU		Those With Experience on 4000 IU
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	82/349 (23.5%)		68/339 (20.1%)		49/308 (15.9%)		17/68 (25%)		17/69 (24.6%)
Cardiac disorders
Atrial fibrillation	1/349 (0.3%)		4/339 (1.2%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Atrial flutter	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Cardiac arrest	2/349 (0.6%)		0/339 (0%)		0/308 (0%)		2/68 (2.9%)		0/69 (0%)
Cardiac disorder	1/349 (0.3%)		1/339 (0.3%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Cardiac failure	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Cardiac failure congestive	3/349 (0.9%)		3/339 (0.9%)		1/308 (0.3%)		1/68 (1.5%)		1/69 (1.4%)
Myocardial infarction	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Tachycardia	2/349 (0.6%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		1/69 (1.4%)
Arrhythmia	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Coronary artery occlusion	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Ventricular extrasystoles	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Colitis	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Diarrhea	1/349 (0.3%)		2/339 (0.6%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Gastrointestinal hemorrhage	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Gastrointestinal polyp hemorrhage	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Rectal hemorrhage	3/349 (0.9%)		1/339 (0.3%)		3/308 (1%)		0/68 (0%)		0/69 (0%)
Vomiting	2/349 (0.6%)		1/339 (0.3%)		0/308 (0%)		2/68 (2.9%)		0/69 (0%)
Constipation	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Abdominal pain	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Fecaloma	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Gastric ulcer	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Hiatus hernia	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Nausea	2/349 (0.6%)		1/339 (0.3%)		0/308 (0%)		2/68 (2.9%)		0/69 (0%)
Volvulus	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
General disorders
Abasia	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Asthenia	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Chest pain	2/349 (0.6%)		2/339 (0.6%)		2/308 (0.6%)		0/68 (0%)		0/69 (0%)
Chills	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Fatigue	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Gait disturbance	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Medical device complication	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Peripheral swelling	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Polyp	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Pyrexia	2/349 (0.6%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		1/69 (1.4%)
Unevaluable event	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Device malfunction	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Necrosis	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Ulcer	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Hepatobiliary disorders
Bile duct stone	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Cholecystitis	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Hepatic cirrhosis	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Hepatic failure	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Cholelithiasis	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Immune system disorders
Hypersensitivity	2/349 (0.6%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		1/69 (1.4%)
Infections and infestations
Bronchitis	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Cellulitis	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Influenza	2/349 (0.6%)		3/339 (0.9%)		1/308 (0.3%)		1/68 (1.5%)		0/69 (0%)
Localized infection	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Pneumonia	7/349 (2%)		6/339 (1.8%)		2/308 (0.6%)		4/68 (5.9%)		1/69 (1.4%)
Sepsis	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Urinary tract infection	3/349 (0.9%)		2/339 (0.6%)		1/308 (0.3%)		1/68 (1.5%)		1/69 (1.4%)
Viral infection	0/349 (0%)		2/339 (0.6%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Bacterial infection	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Kidney infection	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Injury, poisoning and procedural complications
Contusion	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Eye injury	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Fall	5/349 (1.4%)		1/339 (0.3%)		4/308 (1.3%)		1/68 (1.5%)		0/69 (0%)
Injury	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Post procedural complication	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Skull fracture	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Procedural pain	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Rib fracture	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Road traffic accident	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Investigations
Blood calcium decreased	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Blood calcium increased	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Blood creatinine increased	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Full blood count decreased	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Blood potassium decreased	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Heart rate decreased	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Heart rate increased	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Heart rate irregular	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Metabolism and nutrition disorders
Dehydration	2/349 (0.6%)		2/339 (0.6%)		1/308 (0.3%)		1/68 (1.5%)		0/69 (0%)
Diabetes mellitus	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Hypercalcemia	2/349 (0.6%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		1/69 (1.4%)
Hypocalcemia	3/349 (0.9%)		4/339 (1.2%)		3/308 (1%)		0/68 (0%)		0/69 (0%)
Hypoglycemia	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Fluid retention	0/349 (0%)		2/339 (0.6%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Hyperkalemia	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Back disorder	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Back pain	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Flank pain	0/349 (0%)		2/339 (0.6%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Muscle spasms	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Muscular weakness	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Musculoskeletal pain	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Spinal column stenosis	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Arthritis	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Pain in extremity	0/349 (0%)		2/339 (0.6%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm malignant	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Colon cancer	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Lung cancer metastatis	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Neoplasm malignant	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Pancreatic carcinoma	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Prostate cancer	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Squamous carcinoma of skin	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
b-cell lymphoma	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Leukemia	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Myelodysplastic syndrome	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Nervous system disorders
Carpal tunnel syndrome	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Cerebrovascular accident	3/349 (0.9%)		3/339 (0.9%)		2/308 (0.6%)		0/68 (0%)		1/69 (1.4%)
Cervical radiculopathy	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Dementia	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Dizziness	1/349 (0.3%)		2/339 (0.6%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Hemorrhagic stroke	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Presyncope	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Syncope	2/349 (0.6%)		0/339 (0%)		2/308 (0.6%)		0/68 (0%)		0/69 (0%)
Cerebral hemorrhage	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Loss of consciousness	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Seizure	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Tremor	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Psychiatric disorders
Depression	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Anxiety	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Renal and urinary disorders
Calculus urinary	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Chronic kidney disease	1/349 (0.3%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Nephrolithiasis	1/349 (0.3%)		2/339 (0.6%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Nephropathy	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Renal failure	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Reproductive system and breast disorders
Prostatic calcification	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary edema	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Asthma	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Cough	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Dypsnea	4/349 (1.1%)		4/339 (1.2%)		2/308 (0.6%)		1/68 (1.5%)		1/69 (1.4%)
Hypoxia	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Pneumothorax	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Pulmonary edema	2/349 (0.6%)		1/339 (0.3%)		2/308 (0.6%)		0/68 (0%)		0/69 (0%)
Respiratory distress	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Chronic obstructive pulmonary disease	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Pleural effusion	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Pulmonary embolus	1/349 (0.3%)		1/339 (0.3%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Pulmonary fibrosis	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Skin and subcutaneous tissue disorders
Dermal cyst	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Hyperhidrosis	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		0/68 (0%)		1/69 (1.4%)
Surgical and medical procedures
Cardiac pacemaker insertion	1/349 (0.3%)		2/339 (0.6%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Surgery	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Tooth extraction	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Vascular disorders
Deep vein thrombosis	2/349 (0.6%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		2/69 (2.9%)
Hypertension	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Hypertensive crisis	1/349 (0.3%)		0/339 (0%)		0/308 (0%)		1/68 (1.5%)		0/69 (0%)
Hypotension	1/349 (0.3%)		2/339 (0.6%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Internal hemorrhage	1/349 (0.3%)		1/339 (0.3%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Thrombosis	3/349 (0.9%)		0/339 (0%)		3/308 (1%)		0/68 (0%)		0/69 (0%)
Extremity necrosis	1/349 (0.3%)		0/339 (0%)		1/308 (0.3%)		0/68 (0%)		0/69 (0%)
Orthostatic hypotension	0/349 (0%)		1/339 (0.3%)		0/308 (0%)		0/68 (0%)		0/69 (0%)
Other (Not Including Serious) Adverse Events
	Pooled Higher Doses		200 IU/d		Those With Experience on 1000 IU		Those With Experience on 2000 IU		Those With Experience on 4000 IU
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	311/349 (89.1%)		299/339 (88.2%)		250/308 (81.2%)		60/68 (88.2%)		63/69 (91.3%)
Gastrointestinal disorders
Diarrhea	26/349 (7.4%)		19/339 (5.6%)		16/308 (5.2%)		4/68 (5.9%)		6/69 (8.7%)
Nausea	65/349 (18.6%)		57/339 (16.8%)		44/308 (14.3%)		9/68 (13.2%)		13/69 (18.8%)
Vomiting	38/349 (10.9%)		31/339 (9.1%)		25/308 (8.1%)		7/68 (10.3%)		7/69 (10.1%)
Infections and infestations
Influenza	14/349 (4%)		17/339 (5%)		9/308 (2.9%)		2/68 (2.9%)		3/69 (4.3%)
Injury, poisoning and procedural complications
Contusion	112/349 (32.1%)		92/339 (27.1%)		71/308 (23.1%)		23/68 (33.8%)		24/69 (34.8%)
Fall	212/349 (60.7%)		207/339 (61.1%)		153/308 (49.7%)		44/68 (64.7%)		47/69 (68.1%)
Ligament sprain	20/349 (5.7%)		15/339 (4.4%)		14/308 (4.5%)		2/68 (2.9%)		4/69 (5.8%)
Muscle strain	58/349 (16.6%)		49/339 (14.5%)		37/308 (12%)		5/68 (7.4%)		18/69 (26.1%)
Skin abrasion	95/349 (27.2%)		85/339 (25.1%)		54/308 (17.5%)		22/68 (32.4%)		23/69 (33.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	23/349 (6.6%)		34/339 (10%)		20/308 (6.5%)		3/68 (4.4%)		0/69 (0%)
Arthritis	26/349 (7.4%)		22/339 (6.5%)		18/308 (5.8%)		4/68 (5.9%)		4/69 (5.8%)
Back pain	22/349 (6.3%)		14/339 (4.1%)		14/308 (4.5%)		4/68 (5.9%)		4/69 (5.8%)
Nervous system disorders
Dizziness	26/349 (7.4%)		25/339 (7.4%)		18/308 (5.8%)		3/68 (4.4%)		6/69 (8.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.