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A Two Part Study (306A/306B) to Assess Droxidopa in Treatment of NOH in Patients With Parkinson's Disease (306A/306B)

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ClinicalTrials.gov Identifier: NCT01176240
Recruitment Status : Completed
First Posted : August 5, 2010
Results First Posted : May 20, 2014
Last Update Posted : May 20, 2014
Sponsor:
Information provided by (Responsible Party):
Chelsea Therapeutics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Orthostatic Hypotension
Parkinson's Disease
Interventions Drug: Droxidopa
Other: Placebo
Enrollment 225
Recruitment Details  
Pre-assignment Details

Post-randomization, up to 2 weeks dose titration followed by 8 wks at optimal dose.

The first 51 patients enrolled in the study were analyzed as a separate group in an interim analysis (Study 306A).

The final 171 patients remained blinded until the end of the study and analyzed as a separate study (Study 306B).

Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Period Title: Study 306A
Started 24 27
Completed 21 24
Not Completed 3 3
Reason Not Completed
Lack of Efficacy             2             1
Protocol Violation             0             1
Withdrawal by Subject             0             1
Stop due to diverse problems             1             0
Period Title: Study 306B
Started 89 85
Took at Least 1 Dose of Study Drug 87 [1] 84 [2]
1 wk of Stable Dosing and Visit 4 69 78
2 wk of Stable Dosing and Visit 5 68 75
4 wk of Stable Dosing and Visit 6 67 73
Completed 63 68
Not Completed 26 17
Reason Not Completed
Lack of Efficacy             5             3
Adverse Event             10             5
Protocol Violation             2             3
Withdrawal by Subject             4             1
Physician Decision             2             1
Supine Hypertension             1             2
Lost to Follow-up             0             1
withdrew prior to dosing             2             1
[1]
Two randomized patients discontinued before receiving study drug.
[2]
One randomized patient discontinued before receiving study drug.
Arm/Group Title Study 306A: Droxidopa Study 306A: Placebo Study 306B: Droxidopa Study 306B: Placebo Total
Hide Arm/Group Description

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Total of all reporting groups
Overall Number of Baseline Participants 24 27 87 84 222
Hide Baseline Analysis Population Description
The population only includes those patients who were randomized and took at least one dose of study drug (n=222). The first 51 patients enrolled in the study were analyzed as a separate group in an interim analysis (Study 306A). The final 171 patients remained blinded until the end of the study and analyzed as a separate study (Study 306B).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 24 participants 27 participants 87 participants 84 participants 222 participants
72.2  (7.30) 72.9  (7.76) 72.5  (7.64) 72.2  (7.97) 72.4  (7.78)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 27 participants 87 participants 84 participants 222 participants
Female
10
  41.7%
10
  37.0%
27
  31.0%
30
  35.7%
77
  34.7%
Male
14
  58.3%
17
  63.0%
60
  69.0%
54
  64.3%
145
  65.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 27 participants 87 participants 84 participants 222 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
1
   1.1%
0
   0.0%
1
   0.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
2
   7.4%
2
   2.3%
1
   1.2%
5
   2.3%
White
24
 100.0%
25
  92.6%
84
  96.6%
83
  98.8%
216
  97.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 24 participants 27 participants 87 participants 84 participants 222 participants
24 27 87 84 222
1.Primary Outcome
Title 306A Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ)
Hide Description

The primary efficacy endpoint for 306A is the relative mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to end of study. The OHQ is the average of two sub-scales, the Orthostatic Hypotension Symptom Assessment Scale (OHSA) and the Orthostatic Hypotension Daily Activities Scale (OHDAS). Each asks the patient to rate their symptoms or disease impact over the past week. The OHSA sub-scale is the average of six items: 1) Dizziness, lightheadedness, feeling faint or feeling like you might black out; 2) Problems with vision; 3) Weakness; 4) Fatigue; 5) Trouble concentrating; and 6) Head/neck discomfort. The OHDAS sub-scale is the average of four items: 1) Standing for a short time; 2) Standing for a long time; 3) Walking for a short time; and 4) Walking for a long time. Each item is scored on a Likert scale from 0 to 10, with 10 being the most severe.

For the change from baseline, negative numbers represent improvement from baseline in OHQ score.

Time Frame Baseline, Week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
LOCF was used to impute values for patients who did not have an end of study visit.
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 24 27
Mean (Standard Deviation)
Unit of Measure: units on a scale
-2.2  (2.44) -2.1  (2.49)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Droxidopa, Placebo
Comments Study 306A was initially designed as a blinded interim analysis by an independent DMC to ensure that the overall study was adequately powered. Study 306A was not powered to provide statistical significance as a stand alone study. Thus, no additional efficacy end points were prospectively defined beyond the primary end point.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.978
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model that includes treatment as a factor and baseline OHQ composite score as a co-variate.
2.Primary Outcome
Title 306B Efficacy: Change in Dizziness/Lightheadedness/Feeling Faint/Feeling Like You Might Black Out (OHSA Item 1)
Hide Description OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 1 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame Baseline, Week1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The primary analysis was defined as those patients who completed 1 week of dosing at the identified optimal dose of study medication and completed the visit 4 (1 week) efficacy evaluation. Patients who did not have week 1 efficacy data were excluded from the analysis.
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 69 78
Mean (Standard Deviation)
Unit of Measure: units on a scale
-2.3  (2.95) -1.3  (3.16)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Droxidopa, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.018
Comments Statistical analysis plan involved a hierarchical assessment of secondary endpoints to prevent inflation of type I errors.
Method Mantel Haenszel
Comments Mantel-Haenszel statistic comparing treatment groups based on rank statistics adjusted for the covariate OHSA Item 1 value at baseline.
3.Secondary Outcome
Title 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 2 (Visit 5)
Hide Description OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 2 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame Baseline, Week2
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 68 75
Mean (Standard Deviation)
Unit of Measure: units on a scale
-1.9  (2.86) -1.6  (2.97)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Droxidopa, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.60
Comments Statistical analysis plan involved a hierarchical assessment of secondary endpoints to prevent inflation of type I errors. As the first secondary endpoint was not positive, statistical analysis was not performed on additional secondary endpoints.
Method Wilcoxon (Mann-Whitney)
Comments Mantel-Haenszel statistic comparing treatment groups based on rank statistics adjusted for the covariate OHSA Item 1 value at baseline.
4.Secondary Outcome
Title 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 4 (Visit 6)
Hide Description OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 4 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame Baseline, Week4
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 67 73
Mean (Standard Deviation)
Unit of Measure: units on a scale
-2.0  (3.08) -1.5  (2.74)
5.Secondary Outcome
Title 306B Efficacy: Change in Systolic Blood Pressure (SBP) Measurements Post Standing From Baseline to Week 1
Hide Description Measure: Lowest standing systolic blood pressure reading of immediately post standing and 3 minutes post standing. Change: standing systolic blood pressure at Week 1 (Visit 4) minus standing systolic blood pressure at baseline. A positive score indicates an improvement in standing systolic blood pressure during the double-blind randomized phase relative to value at baseline.
Time Frame Baseline, Week 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
One droxidopa patient did not complete the standing blood pressure measurements of the orthostatic standing test at visit 4 (one week of stable dosing)
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 68 78
Mean (Standard Deviation)
Unit of Measure: mmHg
6.4  (18.85) 0.7  (20.18)
6.Secondary Outcome
Title 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 8 (Visit 7)
Hide Description OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 8 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame Baseline, Week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The analysis was defined as those patients who completed 8 week of dosing and completed the visit 7 (8 week) efficacy evaluation. Patients who did not have week 8 efficacy data were excluded from the analysis. Of note, 2 patients completed the 8 week double blind study, but did not complete the efficacy evaluations at the final visit.
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 63 68
Mean (Standard Deviation)
Unit of Measure: units on a scale
-2.1  (3.03) -1.5  (2.91)
7.Secondary Outcome
Title 306B Efficacy: Rate of Patient Reported Falls
Hide Description The average number of patient reported falls per week.
Time Frame up to 10 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The primary analysis was defined as those patients who completed 1 week of dosing at the identified optimal dose of study medication and completed the visit 4 (1 week) efficacy evaluation. Patients who did not have week 1 efficacy data were excluded from the analysis.
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 69 78
Mean (Standard Deviation)
Unit of Measure: falls per week
0.4  (0.84) 2.0  (12.95)
8.Secondary Outcome
Title 306B Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ)
Hide Description

The relative mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to end of study. The OHQ is the average of two sub-scales, the Orthostatic Hypotension Symptom Assessment Scale (OHSA) and the Orthostatic Hypotension Daily Activities Scale (OHDAS). Each asks the patient to rate their symptoms or disease impact over the past week. The OHSA sub-scale is the average of six items: 1) Dizziness, lightheadedness, feeling faint or feeling like you might black out; 2) Problems with vision; 3) Weakness; 4) Fatigue; 5) Trouble concentrating; and 6) Head/neck discomfort. The OHDAS sub-scale is the average of four items: 1) Standing for a short time; 2) Standing for a long time; 3) Walking for a short time; and 4) Walking for a long time. Each item is scored on a Likert scale from 0 to 10, with 10 being the most severe.

For the change from baseline, negative numbers represent improvement from baseline in OHQ score.

Time Frame Baseline, Week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The primary analysis was defined as those patients who completed 8 week of dosing and completed the visit 7 (8 week) efficacy evaluation. Patients who did not have week 8 efficacy data were excluded from the analysis. Of note, 2 patients completed the 8 week double blind study, but did not complete the efficacy evaluations at the final visit.
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 63 68
Mean (Standard Deviation)
Unit of Measure: units on a scale
-2.2  (2.29) -2.0  (2.18)
9.Post-Hoc Outcome
Title 306A Efficacy: Patient Reported Falls
Hide Description The total number of patient reported falls during the 8 week treatment period
Time Frame Baseline, Week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 24 27
Measure Type: Number
Unit of Measure: total falls per group
79 192
10.Post-Hoc Outcome
Title Study 306A: Change in Dizziness/Lightheadedness/Feeling Faint/Feeling Like You Might Black Out (OHSA Item 1) From Baseline to Week 1
Hide Description OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 1 minus score at baseline. A negative score indicates improvement in symptoms during the double-blind randomized phase relative to value at baseline.
Time Frame Baseline, Week 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Last observation carried forward was used to impute missing values.
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description:

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Placebo matched control

Placebo: Placebo

Overall Number of Participants Analyzed 24 27
Mean (Standard Deviation)
Unit of Measure: units on a scale
-3.1  (3.39) -1.6  (3.12)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Droxidopa, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.238
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model that includes treatment as a factor and baseline OHQ composite score as a co-variate.
Time Frame [Not Specified]
Adverse Event Reporting Description

Subjects with more than 1 of a given AE, the subject is counted only once for that AE. Subject with more than one AE in a system organ class (SOC), the subject is counted only once in that SOC.

Only dosed patients included in Safety Set.

Droxidopa Safety Set includes 3 patients randomized to placebo who were mistakenly dosed with droxidopa.

 
Arm/Group Title Droxidopa Placebo
Hide Arm/Group Description

droxidopa active drug

Droxidopa: 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Droxidopa Safety set includes 3 patients randomized to placebo who were mistakenly dosed with droxidopa for short periods of time during the trial.

Placebo matched control

Placebo: Placebo

Placebo Safety set excludes 3 patients randomized to placebo who were mistakenly dosed with droxidopa for short periods of time during the trial.

All-Cause Mortality
Droxidopa Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Droxidopa Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/114 (4.39%)      4/108 (3.70%)    
Cardiac disorders     
Atrial fibrillation  1/114 (0.88%)  1 0/108 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain upper  1/114 (0.88%)  1 0/108 (0.00%)  0
Faecaloma  1/114 (0.88%)  1 0/108 (0.00%)  0
Inguinal hernia  1/114 (0.88%)  1 0/108 (0.00%)  0
General disorders     
Asthenia  0/114 (0.00%)  0 1/108 (0.93%)  1
Infections and infestations     
Bronchitis viral  1/114 (0.88%)  1 0/108 (0.00%)  0
Upper respiratory tract infection bacterial  1/114 (0.88%)  1 0/108 (0.00%)  0
Viral infection  0/114 (0.00%)  0 1/108 (0.93%)  1
Injury, poisoning and procedural complications     
Fibula fracture  0/114 (0.00%)  0 1/108 (0.93%)  1
Nervous system disorders     
Presyncope  1/114 (0.88%)  1 0/108 (0.00%)  0
Syncope  0/114 (0.00%)  0 2/108 (1.85%)  2
Psychiatric disorders     
Mental status changes  1/114 (0.88%)  1 0/108 (0.00%)  0
Vascular disorders     
Hypertension  1/114 (0.88%)  1 0/108 (0.00%)  0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Droxidopa Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   54/114 (47.37%)      52/108 (48.15%)    
Gastrointestinal disorders     
Nausea  10/114 (8.77%)  13 5/108 (4.63%)  5
Diarrhoea  4/114 (3.51%)  4 8/108 (7.41%)  9
General disorders     
Fatigue  8/114 (7.02%)  8 6/108 (5.56%)  7
Oedema peripheral  5/114 (4.39%)  5 6/108 (5.56%)  6
Injury, poisoning and procedural complications     
Contusion  6/114 (5.26%)  7 12/108 (11.11%)  14
Excoriation  6/114 (5.26%)  6 8/108 (7.41%)  8
Skin laceration  5/114 (4.39%)  10 10/108 (9.26%)  15
Investigations     
Blood pressure increased  4/114 (3.51%)  9 7/108 (6.48%)  7
Nervous system disorders     
Headache  15/114 (13.16%)  19 8/108 (7.41%)  8
Dizziness  11/114 (9.65%)  13 5/108 (4.63%)  6
Vascular disorders     
Hypertension  7/114 (6.14%)  10 1/108 (0.93%)  2
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Results Point of Contact
Name/Title: Chief Scientific Officer
Organization: Chelsea Therapeutics Inc.
Phone: 704-973-4202
Publications:
Malamut, R., Freeman, R., Gilden, J., Tulloch, J., Kaufmann, H., 2005. A multi-center, double-blind, randomized, placebo controlled, cross-over study to assess the clinical benefit of midodrine in patients with neurogenic orthostatic hypotension. Clin. Auto. Res. 15 (5) 337[abstract].
Narabayashi, H., Nakanishi, T., Kanazawa, I., Yoshida, M., Mizuno, Y., Yanagisawa, N., Kondo, T. 1987. Clinical effects of L-threo-3,4-dihydroxyphenylserine in Parkinson's disease and Parkinson syndrome: Results of multi-center open study at 45 institutions. Yakuri To Chiryo (Jpn. Pharmacol. Ther.) 15(Suppl. 2):411 to 443.
Sobue, I., Senda, Y., Suzuki, T., Narabayashi, I., Hirayama, K. 1987. Clinical effects of L-threo-3,4-dihydroxyphenylserine on orthostatic hypotension in Shy-Drager Syndrome and its related diseases. Shinkei Naika Chiryo [Neurol. Ther.] 4(2):199-208.
Responsible Party: Chelsea Therapeutics
ClinicalTrials.gov Identifier: NCT01176240     History of Changes
Other Study ID Numbers: Droxidopa NOH306 (306A / 306B)
First Submitted: July 30, 2010
First Posted: August 5, 2010
Results First Submitted: March 18, 2014
Results First Posted: May 20, 2014
Last Update Posted: May 20, 2014