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A Severity-Adapted Clinical Trial of Diminished Bone Mineral Density in Acute Lymphoblastic Leukemia Survivors

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ClinicalTrials.gov Identifier: NCT00186901
Recruitment Status : Completed
First Posted : September 16, 2005
Results First Posted : March 27, 2012
Last Update Posted : May 10, 2017
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Leukemia, Lymphoblastic, Acute
Osteoporosis
Interventions Drug: Calcium carbonate (Tums), vitamin D
Other: Placebo
Enrollment 429
Recruitment Details 429 patients were recruited at St. Jude Children's Research Hospital between August 7, 2000 and July 27, 2006. 4 patients were found to be ineligible and 1 patient was taken off study per the PI's request. 424 patients were available at baseline.
Pre-assignment Details 424 total patients were enrolled on the study. 149 patients were ineligible for randomization. 275 patients were identified with Bone Mineral Density (BMD) Z-scores > 0 and thus were eligible for intervention and were randomized to receive either Calcium and Vitamin D supplementation or placebo.
Arm/Group Title Placebo Group Supplement Group Patients Ineligible for Randomization
Hide Arm/Group Description Nutritional counseling + placebo Nutritional counseling + supplementation with calcium, 1000mg/day + vitamin D, 800 units/day, for a 2 year period 424 patients were enrolled into the study, 149 were ineligible for randomization.
Period Title: Overall Study
Started 134 141 149
Baseline 134 141 0
12 Month Follow-up 117 122 0
24 Month Follow-up 106 107 0
Completed 85 96 0
Not Completed 49 45 149
Reason Not Completed
Pregnancy             6             3             0
Lost to Follow-up             6             3             0
Bone Mineral Density dropped > 5%             9             7             0
ALL relapse or second malignancy             1             2             0
Withdrawal by Subject             4             5             0
Open label             3             2             0
Limited adherence to study requirements             20             23             0
Bone Mineral Density > 0             0             0             149
Arm/Group Title Placebo Group Supplement Group Patients Ineligible for Randomization Total
Hide Arm/Group Description Nutritional counseling + placebo Nutritional counseling + supplementation with calcium, 1000mg/day + vitamin D, 800 units/day, for a 2 year period 424 patients were enrolled into the study, 149 were ineligible for randomization. Total of all reporting groups
Overall Number of Baseline Participants 134 141 149 424
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 134 participants 141 participants 149 participants 424 participants
17.9  (5.6) 17.6  (6.3) 19.2  (6.6) 17.8  (5.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 134 participants 141 participants 149 participants 424 participants
Female
56
  41.8%
63
  44.7%
87
  58.4%
206
  48.6%
Male
78
  58.2%
78
  55.3%
62
  41.6%
218
  51.4%
1.Primary Outcome
Title Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD)
Hide Description The effect of taking calcium and vitamin D supplements was measured using Quantitative Computed Tomography (QCT) to calculate a QTC Z score. A standardized Z-score was calculated to indicate the difference between the patient’s Bone Mineral Density (BMD) and the mean value for age and gender-appropriate controls. Z-scores from 0 to +2 are considered normal, above +2 are considered to be elevated, from 0 to -1 are considered to represent a mild BMD deficit, between -1 and -2 are considered to represent moderate deficits, and below -2 are considered to represent severe deficits.
Time Frame Baseline, 12 months, 24 months, and at 36 months or study end
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Of the 275 pts identified with BMD z-scores < 0, 134 were randomized to the placebo group and 141 to the supplement group. Bone Mineral Density QCT Z-scores were calculated at baseline, 12 months, 24 months, and at 36 months or study end.
Arm/Group Title Placebo Supplement
Hide Arm/Group Description:
Placebo Group (Placebo Comparator 1A): Patients who received placebo pills.
CVD Supplement Group (Experimental 1B): Patients who received calcium and vitamin D supplementation.
Overall Number of Participants Analyzed 134 141
Median (Full Range)
Unit of Measure: Z-Score
Baseline
-0.95
(-3.09 to -0.05)
-0.97
(-3.94 to -0.04)
12 Months
-0.87
(-3.23 to 0.85)
-1.04
(-4.32 to 0.58)
24 Months
-0.72
(-2.61 to 0.91)
-0.76
(-3.75 to 1.23)
36 Months (study end)
-0.56
(-2.96 to 1.36)
-0.61
(-4.23 to 2.02)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Supplement
Comments Baseline where N=134
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.86
Comments [Not Specified]
Method Wilcoxon Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -0.02
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Supplement
Comments 12 Month BMD Z-Score Calculation where N=109
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.99
Comments [Not Specified]
Method Wilcoxon Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -0.17
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Supplement
Comments 24 Month BMD Z-Score calculation where N=91
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.54
Comments [Not Specified]
Method Wilcoxon Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -0.04
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Supplement
Comments 36 Month (End of Study) BMD Z-Score calculation where N=84
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.31
Comments [Not Specified]
Method Wilcoxon Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -0.04
Estimation Comments [Not Specified]
2.Primary Outcome
Title Bone Mineral Density in Male and Female ALL Survivors
Hide Description Using bone mineral density Z-score, assess relationship between predisposing factors (gender) and bone mineral density; a negative value indicates a deficit in bone mineral density.
Time Frame Baseline
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Baseline participants were assessed to determine whether gender was a pre-disposing factor for bone mineral density.
Arm/Group Title Male Female
Hide Arm/Group Description:
218 males were eligible for the study
206 females were eligible for the study
Overall Number of Participants Analyzed 218 206
Median (Standard Error)
Unit of Measure: Z-score
-0.62  (1.18) -0.3  (1.18)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Male, Female
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -0.32
Estimation Comments [Not Specified]
3.Primary Outcome
Title Bone Mineral Density by Race of ALL Survivors
Hide Description Using bone mineral density Z-score, assess relationship between predisposing factors (race) and bone mineral density; a negative value indicates a deficit in bone mineral density.
Time Frame Baseline
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Assess baseline participants to determine whether race contributed to bone mineral density.
Arm/Group Title White Non-white
Hide Arm/Group Description:
365 white patients were eligible for the study
59 non-white were eligible for the study
Overall Number of Participants Analyzed 365 59
Median (Standard Error)
Unit of Measure: Z-score
-0.54  (1.14) 0.15  (1.56)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection White, Non-white
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0023
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -0.69
Estimation Comments [Not Specified]
4.Primary Outcome
Title Bone Mineral Density by Age Group of ALL Survivors
Hide Description Using bone mineral density Z-score, assess relationship between predisposing factors (age groups) and bone mineral density; a negative value indicates a deficit in bone mineral density.
Time Frame Baseline
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Assess baseline participants to determine whether age was a contributing factor in bone mineral density.
Arm/Group Title 9 to 13 Years 13 to 18 Years 18 to 22 Years Above 22 Years
Hide Arm/Group Description:
98 patients between the ages of 9 and 13 were eligible for the study
139 patients between the ages of 13 and 18 were eligible for the study
74 patients between the ages of 18 and 22 were eligible for the study
113 patients greater than 22 years of age were eligible for the study
Overall Number of Participants Analyzed 98 139 74 113
Median (Standard Error)
Unit of Measure: Z-score
-0.6  (1.1) -0.54  (1.21) -0.59  (1.2) -0.25  (1.29)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 9 to 13 Years, 13 to 18 Years, 18 to 22 Years, Above 22 Years
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0092
Comments [Not Specified]
Method Kruskal-Wallis
Comments [Not Specified]
5.Secondary Outcome
Title Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density.
Hide Description To compare the bone mineral density scores determined by Quantitative Computed Tomography (QCT) with those determined by dual energy x-ray absorptiometry (DXA) scan. 121 patients at baseline were assessed by both method the QCT and DXA methods to assess Bone Mineral Density.
Time Frame Baseline
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
275 patients were assessed at baseline and received a QCT Scan. 121 patients were also assessed using the DEXA Scan. Comparison of the two methods used 121 paired studies to arrive at a correlation coefficient.
Arm/Group Title Placebo - (QCT) Placebo - (DXA) Supplement - (QCT) Supplement - (DXA)
Hide Arm/Group Description:
134 patients were assessed at baseline using the QCT scan.
60 of the 134 baseline patients also had a DXA scan.
141 patients were assessed at baseline using the QCT scan.
61 of the 141 baseline patients also had a DXA scan.
Overall Number of Participants Analyzed 134 60 141 61
Mean (Standard Deviation)
Unit of Measure: Z-score
-1.06  (0.70) -1.30  (1.21) -1.09  (0.74) -1.18  (1.02)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo - (QCT), Placebo - (DXA), Supplement - (QCT), Supplement - (DXA)
Comments 275 received a QCT and 121 received a DXA scan. 121 paired scans were evaluated.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Z-test
Comments [Not Specified]
Method of Estimation Estimation Parameter Correlation coefficient
Estimated Value 0.41
Confidence Interval (2-Sided) 95%
0.25 to 0.55
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density.
Hide Description To compare the bone mineral density scores determined by Quantitative Computed Tomography (QCT) with those determined by dual energy x-ray absorptiometry (DXA) scan. 218 patients were assessed at 12 months for QCT. 94 were evaluated using DXA. 94 patients received both scans.
Time Frame 12 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
218 patients were assessed at the 12 months interval and received a QCT Scan. 94 patients were also assessed using the DXA Scan. Comparison of the two methods used 94 paired studies to arrive at a correlation.
Arm/Group Title Placebo - (QCT) Placebo - (DXA) Supplement - (QCT) Supplement - (DXA)
Hide Arm/Group Description:
109 patients were assessed at 12 months using the QCT scan.
47 of the 109 patients assessed at 12 months also had a DXA scan.
109 patients were assessed at 12 months using the QCT scan.
47 of the 109 patients assessed at 12 months also had a DXA scan.
Overall Number of Participants Analyzed 109 47 109 47
Mean (Standard Deviation)
Unit of Measure: Z-score
-1.02  (0.87) -1.20  (1.36) -1.04  (0.89) -0.79  (0.93)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo - (QCT), Placebo - (DXA), Supplement - (QCT), Supplement - (DXA)
Comments 218 patients were assessed at 12 months and received a QCT Scan. 94 patients were also assessed using the DEXA Scan. Comparison of the two methods used 94 paired studies to arrive at a correlation coefficient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Z-test
Comments [Not Specified]
Method of Estimation Estimation Parameter Correlation coefficient
Estimated Value 0.54
Confidence Interval (2-Sided) 95%
0.38 to 0.67
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density.
Hide Description To compare the bone mineral density scores determined by Quantitative Computed Tomography (QCT) with those determined by dual energy x-ray absorptiometry (DXA) scan. 188 patients were assessed at 24 months by the QCT method and 90 were evaluated using the DXA methods to assess Bone Mineral Density. 90 patients received both scans.
Time Frame 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
188 patients were assessed at the 24 months interval and received a QCT Scan. 90 patients were also assessed using the DXA Scan. Comparison of the two methods used 90 paired studies to arrive at a correlation.
Arm/Group Title Placebo - (QCT) Placebo - (DXA) Supplement - (QCT) Supplement - (DXA)
Hide Arm/Group Description:
91 patients were assessed at 24 months using the QCT scan.
39 of the 91 patients assessed at 24 months also had a DXA scan.
97 patients were assessed at 24 months using the QCT scan.
51 of the 97 patients assessed at 24 months also had a DXA scan.
Overall Number of Participants Analyzed 91 39 97 51
Mean (Standard Deviation)
Unit of Measure: Z-score
-0.75  (0.82) -0.77  (1.31) -0.84  (0.86) -0.60  (1.07)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo - (QCT), Placebo - (DXA), Supplement - (QCT), Supplement - (DXA)
Comments 188 patients were assessed at baseline and received a QCT Scan. 90 patients were also assessed using the DEXA Scan. Comparison of the two methods used 90 paired studies to arrive at a correlation coefficient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Z-test
Comments [Not Specified]
Method of Estimation Estimation Parameter Correlation coefficient
Estimated Value 0.53
Confidence Interval (2-Sided) 95%
0.36 to 0.66
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density.
Hide Description To compare the bone mineral density scores determined by Quantitative Computed Tomography (QCT) with those determined by dual energy x-ray absorptiometry (DXA) scan. 180 patients were assessed at 36 months by the QCT method and 89 were evaluated using the DXA methods to assess Bone Mineral Density. 89 patients received both scans.
Time Frame 36 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
180 patients were assessed at the 36 months interval and received a QCT Scan. 89 patients were also assessed using the DEXA Scan. Comparison of the two methods produced 89 paired studies to arrive at a correlation.
Arm/Group Title Placebo - (QCT) Placebo - (DXA) Supplement - (QCT) Supplement - (DXA)
Hide Arm/Group Description:
84 patients were assessed at 36 months using the QCT scan.
36 of the 84 patients assessed at 36 months also had a DXA scan.
96 patients were assessed at 36 months using the QCT scan.
53 of the 96 patients assessed at 36 months also had a DXA scan.
Overall Number of Participants Analyzed 84 36 96 53
Median (Standard Deviation)
Unit of Measure: Z-score
-0.54  (0.86) -0.63  (1.14) -0.71  (0.98) -0.63  (1.00)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo - (QCT), Placebo - (DXA), Supplement - (QCT), Supplement - (DXA)
Comments 180 patients were assessed at 36 months and received a QCT Scan. 89 patients were also assessed using the DXA Scan. Comparison of the two methods used 89 paired studies to arrive at a correlation coefficient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Z-test
Comments [Not Specified]
Method of Estimation Estimation Parameter Correlation coefficient
Estimated Value 0.48
Confidence Interval (2-Sided) 95%
0.30 to 0.63
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Mean QCT Z-Score by Apa1 Vitamin D Receptor Genotype
Hide Description The Apa1 Vitamin D Receptor has been associated with bone mineral density and bone turnover markers in various patient cohorts but has not been investigated I survivors of childhood
Time Frame At enrollment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Of the 424 patients screened, 417 participants consented for genetic testing. Of the 417 patients screened for the Apa 1 vitamin D receptor, only 68 had the AA genotype, 104 had the Aa genotype, and 49 had the aa genotype.
Arm/Group Title Apa 1 - AA Genotype Apa 1 - Aa Genotype Apa 1 - aa Genotype
Hide Arm/Group Description:
The AA genotype was observed in 68 (16.31%) out of 417 participants, with a median BMD Z score (a unit-less measure comparing to the age and gender matched national average) of -0.56.
The Aa genotype was observed in 104 (24.94%) out of 417 participants, with a median BMD Z score of -0.44.
The aa genotype was present in 49 (11.75%) out of 417 participants, with a median BMD Z score of -0.57.
Overall Number of Participants Analyzed 68 104 49
Mean (Standard Deviation)
Unit of Measure: QCT Z-Score
-0.56  (1.27) -0.44  (1.28) -0.57  (1.13)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apa 1 - AA Genotype, Apa 1 - Aa Genotype, Apa 1 - aa Genotype
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.40
Comments [Not Specified]
Method Kruskal Wallis
Comments [Not Specified]
10.Secondary Outcome
Title Mean QCT Z-Score by Bsm 1 Vitamin D Receptor Genotype
Hide Description The Bsm1 Vitamin D Receptor has been associated with bone mineral density and bone turnover markers in various patient cohorts but has not been investigated I survivors of childhood
Time Frame At enrollment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Of the 424 patients screened, 417 participants consented for genetic testing. Of the 417 patients screened for the Bsm 1 vitamin D receptor, only 41 had the BB genotype, 65 had the Bb genotype, and 77 had the bb genotype.
Arm/Group Title Bsm - BB Genotype Bsm - Bb Genotype Bsm - bb Genotype
Hide Arm/Group Description:
The BB genotype was observed in 41 (09.83%) out of 417 participants, with a median BMD Z score (a unit-less measure comparing to the age and gender matched national average) of -0.5.
The Bb genotype was observed in 65 (15.59%) out of 417 participants, with a median BMD Z score of -0.17.
The bb genotype was observed in 77 (18.47%) out of 417 participants, with a median BMD Z score of -0.17.
Overall Number of Participants Analyzed 41 65 77
Mean (Standard Deviation)
Unit of Measure: QCT Z-Score
-0.5  (1.2) -0.17  (1.25) -0.17  (1.24)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bsm - BB Genotype, Bsm - Bb Genotype, Bsm - bb Genotype
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.21
Comments [Not Specified]
Method Kruskal Wallis
Comments [Not Specified]
Time Frame Patients were assessed for adverse events from August, 2000 through July, 2006.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Group Supplement Group Patients Ineligible for Randomization
Hide Arm/Group Description Nutritional counseling + placebo Nutritional counseling + supplementation with calcium, 1000mg/day + vitamin D, 800 units/day, for a 2 year period 424 patients were enrolled into the study, 149 were ineligible for randomization.
All-Cause Mortality
Placebo Group Supplement Group Patients Ineligible for Randomization
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Group Supplement Group Patients Ineligible for Randomization
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/134 (0.00%)   0/141 (0.00%)   0/149 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Group Supplement Group Patients Ineligible for Randomization
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/134 (0.00%)   0/141 (0.00%)   0/149 (0.00%) 
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Sue Kaste, DO
Organization: St. Jude Children's Research Hospital
Phone: 866-278-5833
Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00186901     History of Changes
Other Study ID Numbers: BONEII
First Submitted: September 12, 2005
First Posted: September 16, 2005
Results First Submitted: December 20, 2011
Results First Posted: March 27, 2012
Last Update Posted: May 10, 2017