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The Safety/Efficacy of Rifaximin With/Without Lactulose in Participants With A History of Recurrent Hepatic Encephalopathy

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ClinicalTrials.gov Identifier: NCT01842581
Recruitment Status : Completed
First Posted : April 29, 2013
Results First Posted : September 9, 2019
Last Update Posted : September 9, 2019
Sponsor:
Information provided by (Responsible Party):
Bausch Health Americas, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Hepatic Encephalopathy
Cirrhosis
Interventions Drug: Rifaximin
Drug: Lactulose
Enrollment 222
Recruitment Details  
Pre-assignment Details A total of 222 participants with cirrhosis and in remission from demonstrated hepatic encephalopathy (HE) were enrolled and randomized in a 1:1 ratio to either Rifaximin 550 mg BID or Rifaximin 550 mg BID + Lactulose treatment arm.
Arm/Group Title Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Hide Arm/Group Description Participants received rifaximin 550 milligrams (mg) tablet orally twice daily (BID) for 24 weeks. Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Period Title: Overall Study
Started 113 109
Received at Least 1 Dose of Study Drug 113 108
Completed 69 79
Not Completed 44 30
Reason Not Completed
Adverse Event             6             4
HE breakthrough             26             13
Liver transplant             2             0
Lost to Follow-up             2             5
Withdrawal by Subject             5             7
Other than specified             3             1
Arm/Group Title Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose Total
Hide Arm/Group Description Participants received rifaximin 550 mg tablet orally BID for 24 weeks. Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day. Total of all reporting groups
Overall Number of Baseline Participants 113 108 221
Hide Baseline Analysis Population Description
Intent-to-treat (ITT) population included all randomized participants who received at least 1 dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 113 participants 108 participants 221 participants
58.1  (9.51) 58.8  (9.49) 58.4  (9.49)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 113 participants 108 participants 221 participants
Female
44
  38.9%
38
  35.2%
82
  37.1%
Male
69
  61.1%
70
  64.8%
139
  62.9%
Lactulose Usage Prior to First Dose  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 113 participants 108 participants 221 participants
Yes
100
  88.5%
100
  92.6%
200
  90.5%
No
13
  11.5%
8
   7.4%
21
   9.5%
1.Primary Outcome
Title Number of Participants Reporting a First Breakthrough HE Episode
Hide Description A breakthrough HE episode was defined as an increase of the Conn score to Grade greater than or equal to (≥) 2 (ie, 0 or 1 to ≥ 2). Conn score is widely used as a measure of mental state in HE. The scale used in Conn scoring system include: Grade 0=No personality or behavioral abnormality; Grade 1=Trivial lack of awareness, euphoria, or anxiety; shortened attention span, impairment of addition or subtraction; Grade 2=Lethargy, disorientation for time, obvious personality change, inappropriate behaviour; Grade 3=Somnolence to semi-stupor, responsive to stimuli, confused, gross disorientation, bizarre behaviour; Grade 4=Coma, unable to test mental state. The time to the first breakthrough HE episode was defined as the duration between the date of first dose of study drug and the date of first breakthrough HE episode. Number of participants reporting a first breakthrough HE episode during randomization to Month 6 is presented.
Time Frame From randomization (Day 1) up to Day 170
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all randomized participants who received at least 1 dose of study drug.
Arm/Group Title Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Hide Arm/Group Description:
Participants received rifaximin 550 mg tablet orally BID for 24 weeks.
Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Overall Number of Participants Analyzed 113 108
Measure Type: Count of Participants
Unit of Measure: Participants
28
  24.8%
15
  13.9%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rifaximin 550 mg BID, Rifaximin 550 mg BID + Lactulose
Comments Hazard ratio estimate (hazard of breakthrough HE for rifaximin compared to rifaximin + lactulose) obtained from Cox proportional hazards model with effect for treatment, stratified by analysis region.
Type of Statistical Test Non-Inferiority
Comments Threshold for significance=upper bound of the 2-sided 95% confidence interval (CI) for hazard ratio less than (<) 1.56.
Statistical Test of Hypothesis P-Value 0.0359
Comments [Not Specified]
Method Score statistics
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.959
Confidence Interval (2-Sided) 95%
1.045 to 3.672
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Participants Who Were Hospitalized Due to HE Episode
Hide Description An HE-related hospitalization was defined as a hospitalization directly resulting from HE, or when HE events occurred during hospitalization. The time to first HE-related hospitalization was defined as the duration between the date of first dose of study drug and the date of first HE-related hospitalization. Number of participants who were hospitalized due to HE episode during randomization to Month 6 is presented.
Time Frame From randomization (Day 1) up to Day 170
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all randomized participants who received at least 1 dose of study drug.
Arm/Group Title Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Hide Arm/Group Description:
Participants received rifaximin 550 mg tablet orally BID for 24 weeks.
Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Overall Number of Participants Analyzed 113 108
Measure Type: Count of Participants
Unit of Measure: Participants
23
  20.4%
14
  13.0%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rifaximin 550 mg BID, Rifaximin 550 mg BID + Lactulose
Comments Analysis was performed using log-rank test stratified by analysis region. Hazard ratio estimate (hazard of breakthrough HE for rifaximin compared to rifaximin + lactulose) obtained from Cox proportional hazards model with effect for treatment, stratified by analysis region.
Type of Statistical Test Superiority
Comments 2-sided test at a significance level of 0.05.
Statistical Test of Hypothesis P-Value 0.0985
Comments Threshold for significance at 0.05 level.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.739
Confidence Interval (2-Sided) 95%
0.894 to 3.382
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Number of Participants Who Died Due to Any Reason
Hide Description [Not Specified]
Time Frame From randomization (Day 1) up to end of study (Day 186)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Arm/Group Title Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Hide Arm/Group Description:
Participants received rifaximin 550 mg tablet orally BID for 24 weeks.
Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Overall Number of Participants Analyzed 113 108
Measure Type: Count of Participants
Unit of Measure: Participants
2
   1.8%
2
   1.9%
4.Other Pre-specified Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Hide Description An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAE was defined as an AE that occurred from first dose of study drug until last dose of study drug plus 5 days (for non-fatal AEs) or plus 30 days (for fatal AEs).A summary of non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame From randomization (Day 1) up to end of study (Day 186)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Arm/Group Title Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Hide Arm/Group Description:
Participants received rifaximin 550 mg tablet orally BID for 24 weeks.
Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Overall Number of Participants Analyzed 113 108
Measure Type: Count of Participants
Unit of Measure: Participants
99
  87.6%
81
  75.0%
5.Other Pre-specified Outcome
Title Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at Day 170
Hide Description CLDQ was used to measure health-related quality of life. CLDQ includes 29 items in the following 6 domains: abdominal symptoms (3 items), fatigue (5 items), systemic symptoms (5 items), activity (3 items), emotional function (8 items), and worry (5 items). All items were measured on a 7-point Likert scale, ranging from 0 to 6 with higher values indicating better quality of life. Each domain score of CLDQ was calculated as the mean of the responses of items in that domain. Overall CLDQ score was obtained by adding scores for each item and dividing by the total number of items. Overall CLDQ score ranged from 0 (most impairment) to 6 (least impairment) with higher scores indicating better quality of life. If at least half of the items were non-missing for a domain, mean values of the non-missing items for that domain were used as imputed values for missing values. If more than half of the items in a domain were missing, no values were imputed and domain score was considered as missing.
Time Frame Baseline, Day 170
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all randomized participants who received at least 1 dose of study drug. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoint.
Arm/Group Title Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Hide Arm/Group Description:
Participants received rifaximin 550 mg tablet orally BID for 24 weeks.
Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Overall Number of Participants Analyzed 113 108
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline Number Analyzed 113 participants 108 participants
4.13  (1.110) 4.26  (1.197)
Change at Day 170 Number Analyzed 112 participants 100 participants
0.29  (0.860) 0.08  (1.055)
6.Other Pre-specified Outcome
Title Change From Baseline in Critical Flicker Frequency (CFF) at Day 170
Hide Description The critical flicker frequency (CFF), a validated assessment of neurological function was assessed using a specialized CFF instrument. The CFF is the frequency at which the participant observes a constant light transition to a flickering light and was measured in Hertz. The CFF was measured on a continuous scale and was the mean of 8 separate fusion-to-flicker transition tests performed in rapid succession. Increases in CFF results represent improvement in neurological function in participants with HE.
Time Frame Baseline, Day 170
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all randomized participants who received at least 1 dose of study drug. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoint.
Arm/Group Title Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Hide Arm/Group Description:
Participants received rifaximin 550 mg tablet orally BID for 24 weeks.
Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Overall Number of Participants Analyzed 113 108
Mean (Standard Deviation)
Unit of Measure: hertz
Baseline Number Analyzed 113 participants 108 participants
35.14  (7.767) 34.64  (7.290)
Change at Day 170 Number Analyzed 111 participants 101 participants
1.09  (7.266) 2.10  (6.699)
Time Frame From randomization (Day 1) up to end of study (Day 186)
Adverse Event Reporting Description Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
 
Arm/Group Title Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Hide Arm/Group Description Participants received rifaximin 550 mg tablet orally BID for 24 weeks. Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
All-Cause Mortality
Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Affected / at Risk (%) Affected / at Risk (%)
Total   43/113 (38.05%)   35/108 (32.41%) 
Blood and lymphatic system disorders     
Anaemia  1  5/113 (4.42%)  1/108 (0.93%) 
Coagulopathy  1  0/113 (0.00%)  1/108 (0.93%) 
Thrombocytopenia  1  1/113 (0.88%)  0/108 (0.00%) 
Cardiac disorders     
Acute myocardial infarction  1  0/113 (0.00%)  1/108 (0.93%) 
Atrial fibrillation  1  0/113 (0.00%)  1/108 (0.93%) 
Cardiac failure congestive  1  1/113 (0.88%)  1/108 (0.93%) 
Supraventricular tachycardia  1  0/113 (0.00%)  2/108 (1.85%) 
Gastrointestinal disorders     
Abdominal pain  1  1/113 (0.88%)  1/108 (0.93%) 
Ascites  1  2/113 (1.77%)  7/108 (6.48%) 
Diarrhoea  1  1/113 (0.88%)  0/108 (0.00%) 
Gastrointestinal haemorrhage  1  1/113 (0.88%)  2/108 (1.85%) 
Haematemesis  1  1/113 (0.88%)  0/108 (0.00%) 
Haematochezia  1  1/113 (0.88%)  0/108 (0.00%) 
Nausea  1  2/113 (1.77%)  0/108 (0.00%) 
Upper gastrointestinal haemorrhage  1  1/113 (0.88%)  1/108 (0.93%) 
Vomiting  1  1/113 (0.88%)  0/108 (0.00%) 
General disorders     
Asthenia  1  1/113 (0.88%)  0/108 (0.00%) 
Chest pain  1  1/113 (0.88%)  0/108 (0.00%) 
Non-cardiac chest pain  1  1/113 (0.88%)  0/108 (0.00%) 
Systemic inflammatory response syndrome  1  1/113 (0.88%)  0/108 (0.00%) 
Hepatobiliary disorders     
Chronic hepatic failure  1  1/113 (0.88%)  0/108 (0.00%) 
Hepatic cirrhosis  1  0/113 (0.00%)  1/108 (0.93%) 
Hepatic failure  1  1/113 (0.88%)  0/108 (0.00%) 
Hepatitis  1  1/113 (0.88%)  0/108 (0.00%) 
Hepatorenal syndrome  1  1/113 (0.88%)  0/108 (0.00%) 
Infections and infestations     
Bronchitis  1  2/113 (1.77%)  0/108 (0.00%) 
Cellulitis  1  3/113 (2.65%)  1/108 (0.93%) 
Diverticulitis  1  0/113 (0.00%)  1/108 (0.93%) 
Gastroenteritis  1  0/113 (0.00%)  1/108 (0.93%) 
Herpes zoster  1  1/113 (0.88%)  0/108 (0.00%) 
Necrotising fasciitis  1  0/113 (0.00%)  1/108 (0.93%) 
Peritonitis bacterial  1  2/113 (1.77%)  2/108 (1.85%) 
Pneumococcal bacteraemia  1  1/113 (0.88%)  0/108 (0.00%) 
Pneumonia  1  1/113 (0.88%)  2/108 (1.85%) 
Sepsis  1  1/113 (0.88%)  1/108 (0.93%) 
Septic shock  1  1/113 (0.88%)  1/108 (0.93%) 
Staphylococcal bacteraemia  1  0/113 (0.00%)  1/108 (0.93%) 
Urinary tract infection  1  1/113 (0.88%)  4/108 (3.70%) 
Injury, poisoning and procedural complications     
Craniocerebral injury  1  1/113 (0.88%)  0/108 (0.00%) 
Incisional hernia  1  0/113 (0.00%)  1/108 (0.93%) 
Multiple drug overdose  1  0/113 (0.00%)  1/108 (0.93%) 
Subdural haematoma  1  1/113 (0.88%)  0/108 (0.00%) 
Metabolism and nutrition disorders     
Dehydration  1  1/113 (0.88%)  0/108 (0.00%) 
Fluid overload  1  1/113 (0.88%)  2/108 (1.85%) 
Hyperglycaemia  1  1/113 (0.88%)  1/108 (0.93%) 
Hyperkalaemia  1  2/113 (1.77%)  0/108 (0.00%) 
Hyponatraemia  1  0/113 (0.00%)  1/108 (0.93%) 
Musculoskeletal and connective tissue disorders     
Lumbar spinal stenosis  1  0/113 (0.00%)  1/108 (0.93%) 
Muscular weakness  1  0/113 (0.00%)  1/108 (0.93%) 
Synovitis  1  0/113 (0.00%)  1/108 (0.93%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Colon cancer  1  0/113 (0.00%)  1/108 (0.93%) 
Nervous system disorders     
Alcoholic seizure  1  1/113 (0.88%)  0/108 (0.00%) 
Altered state of consciousness  1  0/113 (0.00%)  1/108 (0.93%) 
Cerebrovascular accident  1  1/113 (0.88%)  0/108 (0.00%) 
Convulsion  1  0/113 (0.00%)  1/108 (0.93%) 
Dizziness  1  0/113 (0.00%)  1/108 (0.93%) 
Headache  1  1/113 (0.88%)  0/108 (0.00%) 
Hepatic encephalopathy  1  21/113 (18.58%)  10/108 (9.26%) 
Presyncope  1  0/113 (0.00%)  1/108 (0.93%) 
Spinal claudication  1  0/113 (0.00%)  1/108 (0.93%) 
Subarachnoid haemorrhage  1  1/113 (0.88%)  0/108 (0.00%) 
Toxic encephalopathy  1  1/113 (0.88%)  0/108 (0.00%) 
Psychiatric disorders     
Anxiety disorder  1  1/113 (0.88%)  0/108 (0.00%) 
Suicidal ideation  1  1/113 (0.88%)  0/108 (0.00%) 
Renal and urinary disorders     
Calculus ureteric  1  1/113 (0.88%)  0/108 (0.00%) 
Oliguria  1  1/113 (0.88%)  0/108 (0.00%) 
Renal failure  1  1/113 (0.88%)  0/108 (0.00%) 
Renal failure acute  1  6/113 (5.31%)  3/108 (2.78%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  1/113 (0.88%)  0/108 (0.00%) 
Dyspnoea  1  1/113 (0.88%)  0/108 (0.00%) 
Hepatic hydrothorax  1  0/113 (0.00%)  1/108 (0.93%) 
Hypoxia  1  0/113 (0.00%)  1/108 (0.93%) 
Pleural effusion  1  1/113 (0.88%)  2/108 (1.85%) 
Pneumothorax  1  0/113 (0.00%)  1/108 (0.93%) 
Pulmonary hypertension  1  0/113 (0.00%)  1/108 (0.93%) 
Respiratory failure  1  0/113 (0.00%)  2/108 (1.85%) 
Surgical and medical procedures     
Liver transplant  1  2/113 (1.77%)  0/108 (0.00%) 
Vascular disorders     
Hypovolaemic shock  1  1/113 (0.88%)  0/108 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Rifaximin 550 mg BID Rifaximin 550 mg BID + Lactulose
Affected / at Risk (%) Affected / at Risk (%)
Total   68/113 (60.18%)   53/108 (49.07%) 
Blood and lymphatic system disorders     
Anaemia  1  6/113 (5.31%)  2/108 (1.85%) 
Gastrointestinal disorders     
Abdominal distension  1  3/113 (2.65%)  7/108 (6.48%) 
Abdominal pain  1  8/113 (7.08%)  8/108 (7.41%) 
Ascites  1  7/113 (6.19%)  10/108 (9.26%) 
Constipation  1  18/113 (15.93%)  9/108 (8.33%) 
Diarrhoea  1  5/113 (4.42%)  13/108 (12.04%) 
Flatulence  1  1/113 (0.88%)  6/108 (5.56%) 
Nausea  1  16/113 (14.16%)  11/108 (10.19%) 
Vomiting  1  6/113 (5.31%)  6/108 (5.56%) 
General disorders     
Asthenia  1  6/113 (5.31%)  2/108 (1.85%) 
Fatigue  1  16/113 (14.16%)  9/108 (8.33%) 
Oedema peripheral  1  19/113 (16.81%)  15/108 (13.89%) 
Hepatobiliary disorders     
Jaundice  1  4/113 (3.54%)  6/108 (5.56%) 
Infections and infestations     
Urinary tract infection  1  12/113 (10.62%)  5/108 (4.63%) 
Metabolism and nutrition disorders     
Decreased appetite  1  8/113 (7.08%)  5/108 (4.63%) 
Musculoskeletal and connective tissue disorders     
Muscle spasms  1  9/113 (7.96%)  11/108 (10.19%) 
Nervous system disorders     
Headache  1  7/113 (6.19%)  5/108 (4.63%) 
Psychiatric disorders     
Anxiety  1  6/113 (5.31%)  10/108 (9.26%) 
Depression  1  3/113 (2.65%)  6/108 (5.56%) 
Insomnia  1  13/113 (11.50%)  15/108 (13.89%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  6/113 (5.31%)  5/108 (4.63%) 
Dyspnoea  1  7/113 (6.19%)  10/108 (9.26%) 
Skin and subcutaneous tissue disorders     
Pruritus generalised  1  11/113 (9.73%)  6/108 (5.56%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.0
The rifaximin monotherapy arm included a subset of rifaximin/lactulose dependent participants for whom lactulose was withdrawn upon randomization (88.5% of participants in that group), which led to earlier HE breakthrough in this subset.
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.
Please contact Sponsor directly for additional information.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Director of Clinical Operations
Organization: Bausch Health Americas, Inc.
EMail: Lindsey.Mathew@bauschhealth.com
Layout table for additonal information
Responsible Party: Bausch Health Americas, Inc.
ClinicalTrials.gov Identifier: NCT01842581     History of Changes
Other Study ID Numbers: RFHE4044
First Submitted: April 16, 2013
First Posted: April 29, 2013
Results First Submitted: August 15, 2019
Results First Posted: September 9, 2019
Last Update Posted: September 9, 2019