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Trial record 1 of 1 for:    nct01176565
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Antihypertensive Treatment of Acute Cerebral Hemorrhage-II (ATACH-II)

This study has been terminated.
(Planned interim analysis: no significant outcome differences between groups)
Sponsor:
Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)
Medical University of South Carolina
Johns Hopkins University
University of Michigan
Neurocritical Care Research Network
National Cerebral and Cardiovascular Center
Japan Cardiovascular Research Foundation
Beijing Tiantan Hospital
China Medical University Hospital
University Hospital Heidelberg
Seoul National University Hospital
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01176565
First received: August 4, 2010
Last updated: March 13, 2017
Last verified: March 2017
Results First Received: January 1, 2017  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Investigator, Outcomes Assessor;   Primary Purpose: Treatment
Condition: Intracerebral Hemorrhage
Intervention: Drug: Intravenous nicardipine hydrochloride

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
A total of 8,532 patients who presented to enrolling sites for emergency care within 6 hours of symptom onset and were found to have non-traumatic intracerebral hemorrhage (ICH) on head CT imaging were screened for eligibility beginning January 7, 2011. A total of 1000 patients were enrolled in the trial between May 15, 2011 and September 14, 2015.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Consent for participation was obtained from the patient or their allowable representative prior to randomization. All patients randomized were considered as enrolled. Treatment to lower systolic blood pressure (SBP) to the assigned range had to begin within 4.5 hours from symptom onset. Treatment for elevated SBP was not delayed for randomization.

Reporting Groups
  Description
Standard SBP Reduction Arm

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: IV nicardipine is initiated at a rate of 5 mg/hr, is continued, and is increased by 2.5 mg/hr increments every 15 min until the target SBP or maximum dose of 15 mg/hr is reached.

If SBP was greater then the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Intensive SBP Reduction Arm

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: IV nicardipine is initiated at a rate of 5 mg/hr, is continued, and is increased by 2.5 mg/hr increments every 15 min until the target SBP or maximum dose of 15 mg/hr is reached.

If SBP was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.


Participant Flow:   Overall Study
    Standard SBP Reduction Arm   Intensive SBP Reduction Arm
STARTED   500   500 
COMPLETED   480   481 
NOT COMPLETED   20   19 
Lost to Follow-up                12                16 
Withdrawal by Subject                7                1 
Not Analyzed (any other reason)                1                2 



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Subjects were randomized to standard vs. intensive SBP control. Below-range SBP was not artifically elevated in the standard SBP reduction arm; euvolemic fluid balance was maintained but spontaneous recovery was not prevented. For below-range SBP in the intensive SBP control arm, nicardipine was discontinued and if needed IV fluid bolus was given.

Reporting Groups
  Description
Standard SBP Reduction Arm

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: IV nicardipine is initiated at a rate of 5 mg/hr, is continued, and is increased by 2.5 mg/hr increments every 15 min until the target SBP or maximum dose of 15 mg/hr is reached.

If SBP was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Intensive SBP Reduction Arm

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: IV nicardipine is initiated at a rate of 5 mg/hr, is continued, and is increased by 2.5 mg/hr increments every 15 min until the target SBP or maximum dose of 15 mg/hr is reached.

If SBP was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Total Total of all reporting groups

Baseline Measures
   Standard SBP Reduction Arm   Intensive SBP Reduction Arm   Total 
Overall Participants Analyzed 
[Units: Participants]
 500   500   1000 
Age 
[Units: Years]
Mean (Standard Deviation)
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   61.9  (13.1)   62  (13.1)   61.93  (13.1) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
Female      184  36.8%      196  39.2%      380  38.0% 
Male      316  63.2%      304  60.8%      620  62.0% 
Ethnicity (NIH/OMB) [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
Hispanic or Latino      41   8.2%      38   7.6%      79   7.9% 
Not Hispanic or Latino      446  89.2%      446  89.2%      892  89.2% 
Unknown or Not Reported      13   2.6%      16   3.2%      29   2.9% 
[1]

Ethnicity describes persons who have (versus have not) self-identified as being of Cuban, Mexican, Puerto Rican, Cuban, South or Central American, or other Spanish culture or origin, regardless of race.

Data are analyzed according to the ethnicity and race of patients included to determine whether there are population differences in health measures or treatment responses that differ. Whether recruitment included an adequate diversity within the affected population is important to understanding the generalizability of results that were obtained and whether further research may be indicated.

Race/Ethnicity, Customized [1] 
[Units: Participants]
Count of Participants
     
Race       
Participants Analyzed 
[Units: Participants]
 500   500   1000 
Asian      285  57.0%      277  55.4%      562  56.2% 
Black      58  11.6%      73  14.6%      131  13.1% 
White      145  29.0%      142  28.4%      287  28.7% 
Other or unknown      12   2.4%      8   1.6%      20   2.0% 
[1] Race and ethnicity were recorded according to how a person identified themselves, not according to genetic testing or observation. The number of persons who reported American Indian, Alaska Native, Native Hawaiian of other Pacific Islander, or of having origins within more than one race has been included in the "other or unknown" category because the number of persons enrolled in the study from each of these categories was too small to provide a meaningful analysis that would examine these groups individually. Asian race included patients enrolled in Asian countries and non-Asian countries.
Recruited at site in Asia [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   273   264   537 
[1] Defined as patients who were enrolled at a clinical site geographically located within regions including Japan, China, Taiwan, or South Korea. Data from these patients were analyzed separately in addition to being part of the full group and other race/ethnicity analyses to examine for potential population differences surrounding intracerebral hemorrhage (ICH) events and recovery that are regional in nature.
First Glasgow Coma Scale Score assessed upon hospital emergency department (ED) arrival [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
ED arrival GCS score = 3 - 11      74  14.8%      73  14.6%      147  14.7% 
ED arrival GCS score = 12 - 14      142  28.4%      152  30.4%      294  29.4% 
ED arrival GCS score = 15      284  56.8%      275  55.0%      559  55.9% 
[1] The Glasgow Coma Scale (GCS) score is a measure of level of consciousness. The scale quantifies response in three components: eye, motor, and verbal. A lower score indicates a reduced response and a higher score indicates a full response. At least one point is given in each category so the scale ranges from 3 to 15. A score of 3 indicates deep unconsciousness; a higher score indicates milder impairment of consciousness. The maximum score of 15 indicates consciousness is not impaired but other neurological symptoms may still be present. Estimated verbal scoring was used for intubated patients.
Systolic Blood Pressure at presentation in hospital emergency department (ED) [1] [2] 
[Units: mmHg]
Mean (Standard Deviation)
     
Participants Analyzed 
[Units: Participants]
 499   500   999 
   201.1  (26.9)   200  (27.1)   200.6  (27.0) 
[1] Blood pressure is reported as the systolic (systolic blood pressure or "SBP") reading "over" the diastolic (or DBP) reading, and is measured in millimeters of mercury (mmHg) on a gauge. SBP is a measure of the force pressing against the blood vessels when the heart contracts to push blood out to the body, and was considered most important for this study. DBP measures lingering pressure within the blood vessels as the heart fills with newly-oxygenated blood from the lungs. Hospitals selected the method that they felt was the most accurate way to report systolic blood pressures for each patient.
[2] Data were missing for 1 patient in the standard-treatment group. It was permissible for pre-arrival or post-admission qualifying SBP to be used in eligibility determination if all other criteria were met.
Median NIHSS score (range) [1] 
[Units: Units on a scale (NIHSS range 0 - 42)]
Median (Full Range)
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   11 
 (0 to 40) 
 11 
 (0 to 40) 
 11 
 (0 to 40) 
[1] The National Institutes of Health Stroke Scale (NIHSS) is a serial measure of neurologic deficit (problems in function). It uses a scale (range 0 - 42) to quantify neurologic deficits in 11 categories. The categories are measured by asking questions that indicate the patient's level of consciousness, then testing horizontal eye movements, visual fields, facial palsy, movement in each limb, sensation, language and speech, and extinction or inattention on one side of the body. A score of 0 indicates normal function without neurologic deficit. Higher scores indicate greater severity of deficit.
Intracerebral Hematoma Volume [1] [2] 
[Units: Cubic centimeters (cm3)]
Median (Full Range)
     
Participants Analyzed 
[Units: Participants]
 492   496   988 
   10.2 
 (0.98 to 79.1) 
 10.3 
 (2.3 to 85.2) 
 10.3 
 (0.98 to 85.2) 
[1] Hematoma volumes are reported in cubic centimeters (cm3), as measured by the central reader. The area of the hematoma on head CT imaging was delineated by image analysis software with the use of density thresholds on each slice, followed by manual correction. The central reader and those performing manual correction were unaware of the patient identities, treatment assignments, clinical findings, and time points of image acquisition. The software provided total volume measurements by summing up volumes (product of area and slice thickness) from all the slices containing the hematoma.
[2] A precise measure of bleeding within the brain was occasionally unable to be determined or baseline imaging wasn't submitted for analysis before data lock. This measure was missing for 8 patients in the standard treatment group and 4 in the intensive group. For eligibility, hematoma volume was estimated rapidly in 3 dimensions (ABC/2) at bedside.
Intracerebral hematoma volume greater than 30 cm3 [1] [2] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 492   496   988 
   51   45   96 
[1] Hematoma volumes are reported in cubic centimeters (cm3), as measured by the central reader. The area of the hematoma on head CT imaging was delineated by image analysis software with the use of density thresholds on each slice, followed by manual correction. The central reader and those performing manual correction were unaware of the patient identities, treatment assignments, clinical findings, and time points of image acquisition. The software provided total volume measurements by summing up volumes (product of area and slice thickness) from all the slices containing the hematoma.
[2] A precise measure of bleeding within the brain was occasionally unable to be determined or baseline imaging wasn't submitted for analysis before data lock. This measure was missing for 8 patients in the standard treatment group and 4 in the intensive group. For eligibility, hematoma volume was estimated rapidly in 3 dimensions (ABC/2) at bedside.
Intraventricular Hemorrhage [1] [2] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 492   496   988 
   142   122   264 
[1] Intraventricular hemorrhage is bleeding that is present within the ventricles, or internal fluid-filled spaces, within the brain. These spaces are usually filled with cerebrospinal fluid that also circulates around the brain and spinal column, which helps to protect and cushion the delicate brain tissue. In this study, when intraventricular hemorrhage was present it meant that bleeding had extended from another region within the brain tissue to also being present in the brain ventricles. Intraventricular blood is associated with other complications and may indicate a more severe condition.
[2] The presence of blood within a brain ventricle as opposed to the hematoma (blood clot) within surrounding brain tissue pressing in to the ventricular space occasionally can't be determined, or baseline imaging wasn't submitted for analysis. This measure was missing for 8 patients in the standard treatment group and 4 in the intensive group.
Location of Hemorrhage [1] [2] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 492   496   988 
Thalamus      180  36.6%      193  38.9%      373  37.8% 
Basal ganglia      251  51.0%      255  51.4%      506  51.2% 
Cerebral lobe      60  12.2%      48   9.7%      108  10.9% 
Cerebellum      1   0.2%      0   0.0%      1   0.1% 
[1] The primary location of hemorrhage (bleeding) in the brain tissue was recorded as being located in the basal ganglia, thalamus, or a lobar region on either the right or left side of the brain. One patient was included that had a cerebellar hemorrhage, which means that bleeding was in the lower dorsal (back) region of the brain.
[2] The primary location of bleeding within the brain is occasionally unable to be clearly determined, or baseline imaging wasn't submitted for analysis. This measure was missing for 8 patients in the standard treatment group and 4 in the intensive group.
Prior stroke/transient ischemic attack 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   84   80   164 
Other prior nervous system disorders 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   17   23   40 
History of congestive heart failure 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   21   16   37 
History of atrial fibrillation 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   16   20   36 
Myocardial infarction in the previous 3 months 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   0   1   1 
History of coronary artery disease 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   17   27   44 
History of hypertension 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   382   411   793 
History of peripheral vascular disease 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   13   9   22 
History of hyperlipidemia 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   119   122   241 
History of cardiac dysrhythmias 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   21   17   38 
History of diabetes mellitus Type 2 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   83   92   175 
Previous use of antihypertensive drugs 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   235   260   495 
Symptom onset to randomization time, minutes 
[Units: Minutes]
Mean (Standard Deviation)
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   184.7  (56.7)   182.2  (57.2)   183.5  (57) 
Symptom onset to nicardipine infusion time [1] [2] 
[Units: Minutes]
Mean (Standard Deviation)
     
Participants Analyzed 
[Units: Participants]
 479   497   976 
   165.3  (101.3)   149  (65)   157  (85.2) 
[1] To qualify, patients had to have SBP greater than 180 mmHg prior to antihypertensive treatment and SBP not below 140 mmHg at the time of randomization. Nicardipine infusion had to be able to start within 4.5 hours of symptom onset. In accordance with recommendations, treatment of significant hypertension in patients presenting with ICH was not delayed for consent and randomization. This measure captures the earliest nicardipine start time but other intravenous antihypertensive medications may have been given before then. "Zero" nicardipine start rates may not have been recorded in all cases.
[2] Data from 24 (3 intensive and 21 standard arm) patients was missing. If nicardipine wasn't needed to achieve the assigned SBP range at the time of randomization, more common in the standard arm, nicardipine was initiated at zero rate. "Zero rate" IV infusions have less consistent recording. Some patients had SBP within range without nicardipine.
Mean minimum systolic blood pressure, during the first 2 hours post randomization [1] 
[Units: mmHg]
Mean (Standard Deviation)
     
Participants Analyzed 
[Units: Participants]
 497   500   997 
   141.1  (14.8)   128.9  (16)   135  (16.6) 
[1] Data were missing for 3 subjects in the standard treatment arm. If a vasoactive IV drip medication (such as nicardipine) is not in use, then standard-of-care parameters for close monitoring of SBP are different (frequency of required monitoring is less). Patient transfer and some procedures can preclude vigilance in recording research-only SBP.
Failure to attain systolic blood pressure target within 2 hours [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   4   61   65 
[1] Elevation of systolic blood pressure is common with intracerebral hemorrhage. Recovery of normalized blood pressure may occur quickly for some patients and only after an extended time for others, and more or less medication may be needed. The systolic blood pressure goal is usually achieved incrementally, as antihypertensive medication begins to take effect to control blood pressure. A lower target SBP range may take longer or be more difficult to achieve. The goal in this study was to achieve blood pressure control within 2 hours of randomization for all patients, regardless of treatment arm.
Failure to attain systolic blood pressure target for 2 consecutive hours during 2-24 hours [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed 
[Units: Participants]
 500   500   1000 
   7   78   85 
[1] This data parameter is a measure of the success (or lack of success) with which SBP control to the assigned treatment range was consistently maintained during the 24-hour SBP control study period.


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Death or Disability According to Modified Rankin Scale Score at 90 Days (3 Months) From Randomization   [ Time Frame: 90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization ]

2.  Secondary:   Quality of Life at 90 Days Using EuroQol (EQ) Measures: EQ-5D (EuroQol Five Dimension), Consisting of Standardized EQ-5D-3L (EuroQol Five Dimension, Three-Level) Questionnaire and EQ VAS (EuroQol Visual Analog Scale) Scores   [ Time Frame: 90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization ]

3.  Secondary:   Hematoma Expansion (Number of Patients With Hematoma Expansion of 33% or Greater Between the Baseline and 24 +/- 6 Hours Head CTs, as Measured by the Central Reader for Patients With Readable Scans for Both Time Points Submitted by Data Lock.)   [ Time Frame: From the baseline head CT to the 24 +/- 6 hours from randomization head CT ]

4.  Other Pre-specified:   Neurological Deterioration Within 24 Hours, Defined by a Decrease of 2 or More Points on the GCS Score or an Increase of 4 or More Points on the NIHSS Score From Baseline, Not Related to Sedation or Hypnotic-agent Use and Sustained for at Least 8 Hours.   [ Time Frame: From randomization through the 24-hour treatment period ]

5.  Other Pre-specified:   Hypotension Within 72 Hours   [ Time Frame: From randomization through 72 hours from randomization ]

6.  Other Pre-specified:   Treatment-related Serious Adverse Event Within 72 Hours of Randomization   [ Time Frame: From randomization through 72 hours (3 days) ]

7.  Other Pre-specified:   Any Serious Adverse Event Within the 90-day Study Period   [ Time Frame: From randomization through the 90 day visit (90 ± 14 days per protocol window; up to ± 30 days data is used) or until known death, withdrawal, or loss to follow-up. ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Treatment failures, randomization window, demographics, pre-randomization treatment, low death/disability, favorable baselines, and early termination could limit generalizability of primary (all with intent-to-treat) results and some sub-analyses.


  More Information
  Hide More Information

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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Adnan I. Qureshi, MD
Organization: University of Minnesota
phone: 612-624-2431
e-mail: qureshai@gmail.com


Publications of Results:
Other Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01176565     History of Changes
Other Study ID Numbers: 1207M17921
U01NS062091 ( US NIH Grant/Contract Award Number )
U01NS061861 ( US NIH Grant/Contract Award Number )
U01NS059041 ( US NIH Grant/Contract Award Number )
U01NS056975 ( US NIH Grant/Contract Award Number )
H23-4-3 ( Other Grant/Funding Number: Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center, Japan )
Study First Received: August 4, 2010
Results First Received: January 1, 2017
Last Updated: March 13, 2017