Effects of Titrated Oral Tolvaptan 15-60 mg Once Daily (QD) on Cognitive and Neurological Function in Elderly Hyponatremic Patients (INSIGHT)
Primary Purpose
Hyponatremia
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Tolvaptan
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Hyponatremia focused on measuring Hyponatremia, Cognitive, Neurological Function, Elderly
Eligibility Criteria
Inclusion Criteria:
- Women and men 50 years of age or older.
- Serum Sodium ≥123 and ≤ 134 mEq/L [mmol/L]at screening and baseline.
- Subjects with serum sodium concentrations ≥118 and ≤122 mEq/L[mmol/L] at screening and baseline may be entered into the trial based on consultation and approval from the study medical monitor.
Exclusion Criteria:
- Conditions or history which may present a safety concern to the subject or their offspring or extreme susceptibility to hypotension with sudden fluid loss (aquaresis).
- Hyponatremia that is acute, easily reversible, artifactual, or due to a condition not associated with vasopressin excess or likely to respond to aquaretic therapy.
- Conditions associated with an independent imminent risk of morbidity and mortality.
- Conditions which may confound the assessment of endpoints, history of poor compliance, participation in a clinical trial believed by the PI or Sponsor likely to confound endpoint assessments.
- Conditions which may confound primary endpoints of cognitive function.
Sites / Locations
- Sarah. S. Olelewe, MD
- Progressive Clinical Research
- Pikes Peak Cardiology
- Innovative Research of West FL
- Coastal Nephrology Assoc. Research Center
- Rockdale Medical Research Associates
- Otis Barnum, DO
- Lillestol Research, LLC
- Carolina Research Associates
- Wayne O. Wells, MD
- Memorial Clinical Associates
- Mitchell Rosner, MD
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Active Comparator
Arm Label
1
2
Arm Description
Placebo tablet given once a day for 21 days
Tolvaptan 15 mg-60 mg tablet given once a day for 21 days.
Outcomes
Primary Outcome Measures
Change From Baseline in the Neurocognitive Composite Score of Speed Domains (NCS-SD; Sum of All Correct Speed Domain Z-Scores)
Change from baseline to Day 22 in sum of all speed domain Z-scores:Reaction Time (Simple=recognize "yes" 50 times;Choice=recognize "yes" or "no" 50 times;Digit Vigilance=match 45 digits);Psychomotor Speed (Morse Tapping=tap button for 30 seconds with right & left hands);Processing Speed (Rapid Visual Information Processing=detect consecutive sequences of 3 odd or 3 even digits;Numeric Working Memory=recognize numbers from series of 5 digits among 30;Word Recognition=remember 15 prior learned words from 30 total;results age-matched to healthy controls from Cognitive Drug Research normative data
Secondary Outcome Measures
Change From Baseline to Day 22 in the Individual Neurocognitive Domains Included in the Primary Endpoint: Reaction Time in Computer Tests
Change from baseline in the individual neurocognitive domains Z-score for Reaction Time in Computer Tests (simple reaction time test, choice reaction time test, digit vigilance test); ITT population
Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Psychomotor Speed Via Morse Tapping Test
Change from baseline to Day 22 in the individual neurocognitive domains Z-score for Psychomotor Speed (mean tap rate of Morse tapping test); ITT population
Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Processing Speed of Rapid Visual Information Processing Test, Numeric Working Memory Test, and Word Recognition Test
Change from baseline to Day 22 in the individual neurocognitive domains Z-score for Processing Speed of Rapid Visual Information Processing Test, Numeric Working Memory Test, and Word Recognition Test; ITT population
Change From Baseline in Overall Neurocognitive Composite Score
Change from Baseline to Day 22 in the overall Neurocognitive Composite Score (NCS)comprising the sum of 7 neurocognitive domain Z-scores (Reaction Time, Psychomotor Speed, Processing Speed, Continuity of Attention, Working Memory/Executive Functions, Quality of Episodic Verbal Memory, and Postural Stability); ITT population
Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)
Change from baseline to Day 22 in Gait Test (Timed Get-Up-and-Go Test=time it takes for a seated subject to rise from a chair, walk 3 meters, walk around an object and return to sit in chair. Values: under 10 sec (no difficulties), 10 to 20 sec (starting to have balance difficulty), over 30 sec (at high risk for falls and dependent in most activities of daily living and mobility); test assesses risk to elderly subjects of falling and higher scores in seconds indicate higher risk of falling; ITT population
Change From Baseline in Postural Stability Test
Change from baseline to Day 22 in Postural Stability Test Z-score (This test measures gross motor control. The ability to stand upright without moving is assessed using the SWAY meter that is modeled on the Wright Ataxiameter. A cord from the meter is attached to the subject who is required to stand as still as possible with feet apart and eyes closed for 1 minute. The test is then repeated with eyes open for 1 minute. The outcomes of these tests are combined and measured as a movement Z-score. Higher result=better postural stability); ITT population
Change From Baseline in Serum Sodium; ITT Population
Change from Baseline to Day 22 in Serum Sodium; ITT population
Number of Patients With Vital Sign Abnormalities: Blood Pressure
Incidence of abnormal systolic & diastolic blood pressure values post-baseline (abnormal systolic values: >=180 mmHg + increase of >=20 mmHg, <= 90 mmHg + decrease >=20 mmHg; abnormal diastolic values: >=105 mmHg+increase of >=15 mmHg, <=50 mmHg + decrease of >= 15 mmHg)
Number of Patients With Vital Sign Abnormalities: Pulse Rate
Incidence of abnormal pulse rate post-baseline [abnormal values: >=120 beats per minute (bpm) + increase of >=15 bpm; <=50 bpm + decrease of >=15 bpm]
Number of Patients With Vital Sign Abnormalities: Body Weight
Incidence of clinically significant body weight change post-baseline (defined as change upward or downward of >=7%)
Number of Patients With Vital Sign Abnormalities: Body Temperature
Incidence of potentially clinically significant changes in body temperature post-baseline (defined as an increase of >=1.1 to >=38.3 degrees Celsius)
Number of Patients With Hematology Laboratory Abnormalities: Hemoglobin
Incidence of clinically significant hemoglobin abnormalities post-baseline (normal range=11.8-16.8 g/dL)
Number of Patients With Hematology Laboratory Abnormalities: Activated Partial Thromboplastin Time (aPTT)
Incidence of potentially clinically significant Activated Partial Thromboplastin Time (aPTT) levels post-baseline (normal range=22-34 seconds)
Number of Patients With Hematology Laboratory Abnormalities: Lymphocytes
Incidence of potentially clinically significant lymphocyte count post-baseline (normal range = 16-46%)
Number of Patients With Hematology Laboratory Abnormalities: Neutrophils
Incidence of potentially clinically significant neutrophil count post-baseline (normal range=1.8-8 thousands/microliter)
Number of Patients With Serum Chemistry Laboratory Abnormalities: Blood Urea Nitrogen (BUN)
Incidence of potentially clinically significant BUN levels post-baseline (normal range=7-30 mg/dL)
Number of Patients With Serum Chemistry Laboratory Abnormalities: Uric Acid
Incidence of potentially clinically significant uric acid levels post-baseline (normal range=4-8.5 mg/dL)
Number of Patients With Serum Chemistry Laboratory Abnormalities: Cholesterol
Incidence of potentially clinically significant cholesterol levels post-baseline (normal range=0-199 mg/dL)
Number of Patients With Serum Chemistry Laboratory Abnormalities: Glucose
Incidence of potentially clinically significant glucose levels post-baseline (normal range=70-125 mg/dL)
Number of Patients With Serum Chemistry Laboratory Abnormalities: Magnesium
Incidence of potentially clinically significant magnesium levels post-baseline (normal range=1.2-2 mEq/L)
Number of Patients With Electrocardiogram (ECG) Abnormalities: QT >500 Milliseconds (Msec)
Incidence of potentially clinically significant ECG abnormalities (QT>500 msec) post-baseline
Number of Patients With Electrocardiogram (ECG) Abnormalities: QRS Interval
Incidence of potentially clinically significant ECG abnormalities involving QRS interval (change > 100 msec)
Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcB Increase 30-60 Msec
Incidence of potentially clinically significant ECG abnormalities (QTcB increase 30-60 msec)
Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcF Increase 30-60 Msec
Incidence of potentially clinically significant ECG abnormalities (QTcF increase 30-60 msec post-baseline)
Number of Patients With Electrocardiogram (ECG) Abnormalities: ST Segment
Incidence of potentially clinically significant ECG abnormalities: ST Segment
Number of Patients With Electrocardiogram (ECG) Abnormalities: T Wave
Incidence of potentially clinically significant ECG abnormalities: T wave
Number of Patients With Electrocardiogram (ECG) Abnormalities: Right Bundle Branch Block (RBBB), Left Bundle Branch Block (LBBB), Myocardial Infarction (MI)
Incidence of potentially clinically significant ECG abnormalities: Right bundle branch block (RBBB), Left bundle branch block (LBBB), myocardial infarction (MI)
Number of Patients With Electrocardiogram (ECG) Abnormalities: Arrhythmia
Incidence of potentially clinically significant ECG abnormalities: arrhythmia
Full Information
NCT ID
NCT00550459
First Posted
October 25, 2007
Last Updated
April 26, 2011
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
Otsuka Pharmaceutical Co., Ltd.
1. Study Identification
Unique Protocol Identification Number
NCT00550459
Brief Title
Effects of Titrated Oral Tolvaptan 15-60 mg Once Daily (QD) on Cognitive and Neurological Function in Elderly Hyponatremic Patients
Acronym
INSIGHT
Official Title
A Pilot, Phase 3B, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of the Effects of Titrated Oral Tolvaptan 15, 30, or 60 mg QD on Cognitive and Neurological Function in Elderly Hyponatremic Patients
Study Type
Interventional
2. Study Status
Record Verification Date
April 2011
Overall Recruitment Status
Completed
Study Start Date
August 2007 (undefined)
Primary Completion Date
February 2009 (Actual)
Study Completion Date
March 2009 (Actual)
3. Sponsor/Collaborators
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
Otsuka Pharmaceutical Co., Ltd.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Demonstrate an improvement in the composite scores of validated neurocognitive tests in elderly subjects with chronic sub-clinical (i.e., asymptomatic) hyponatremia.
Detailed Description
Subjects will be randomized, with stratification by baseline sodium <130 or ≥ 130 mEq/L[mmol/L] to receive either tolvaptan 15 mg tablet or matching placebo tablet at doses of 15, 30 or 60 mg for 21 days. During this period, fluid restrictions should be loosened or suspended, until the subject's response to therapy can be evaluated, typically over the first few days of therapy. Fluid restriction may be reinstituted at any time in subjects whose sodium fails to improve or worsens with study therapy. A forced-titration up to 60 mg of study drug by day 3 to 7 will be based on the subject's serum sodium Subjects entering the study with a serum sodium concentration less than 130 mEq/L[mmol/L] may be fluid restricted if necessary at the discretion of the Investigator. Subjects should be monitored closely during the first 24 hours of treatment for dosing titration. The total dosing duration will be up to 21 days (plus 3 day treatment window). Subjects will return to the clinic on Day 22 (+3 days) for assessments and will complete a follow-up visit on Day 28 (+2 days).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyponatremia
Keywords
Hyponatremia, Cognitive, Neurological Function, Elderly
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
57 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Placebo Comparator
Arm Description
Placebo tablet given once a day for 21 days
Arm Title
2
Arm Type
Active Comparator
Arm Description
Tolvaptan 15 mg-60 mg tablet given once a day for 21 days.
Intervention Type
Drug
Intervention Name(s)
Tolvaptan
Other Intervention Name(s)
OPC-41061
Intervention Description
15-60 mg oral tablet given once a day for 21 days.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo tablet given once daily for 21 days
Primary Outcome Measure Information:
Title
Change From Baseline in the Neurocognitive Composite Score of Speed Domains (NCS-SD; Sum of All Correct Speed Domain Z-Scores)
Description
Change from baseline to Day 22 in sum of all speed domain Z-scores:Reaction Time (Simple=recognize "yes" 50 times;Choice=recognize "yes" or "no" 50 times;Digit Vigilance=match 45 digits);Psychomotor Speed (Morse Tapping=tap button for 30 seconds with right & left hands);Processing Speed (Rapid Visual Information Processing=detect consecutive sequences of 3 odd or 3 even digits;Numeric Working Memory=recognize numbers from series of 5 digits among 30;Word Recognition=remember 15 prior learned words from 30 total;results age-matched to healthy controls from Cognitive Drug Research normative data
Time Frame
baseline and Day 22
Secondary Outcome Measure Information:
Title
Change From Baseline to Day 22 in the Individual Neurocognitive Domains Included in the Primary Endpoint: Reaction Time in Computer Tests
Description
Change from baseline in the individual neurocognitive domains Z-score for Reaction Time in Computer Tests (simple reaction time test, choice reaction time test, digit vigilance test); ITT population
Time Frame
baseline and Day 22
Title
Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Psychomotor Speed Via Morse Tapping Test
Description
Change from baseline to Day 22 in the individual neurocognitive domains Z-score for Psychomotor Speed (mean tap rate of Morse tapping test); ITT population
Time Frame
baseline and Day 22
Title
Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Processing Speed of Rapid Visual Information Processing Test, Numeric Working Memory Test, and Word Recognition Test
Description
Change from baseline to Day 22 in the individual neurocognitive domains Z-score for Processing Speed of Rapid Visual Information Processing Test, Numeric Working Memory Test, and Word Recognition Test; ITT population
Time Frame
baseline and Day 22
Title
Change From Baseline in Overall Neurocognitive Composite Score
Description
Change from Baseline to Day 22 in the overall Neurocognitive Composite Score (NCS)comprising the sum of 7 neurocognitive domain Z-scores (Reaction Time, Psychomotor Speed, Processing Speed, Continuity of Attention, Working Memory/Executive Functions, Quality of Episodic Verbal Memory, and Postural Stability); ITT population
Time Frame
baseline and Day 22
Title
Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)
Description
Change from baseline to Day 22 in Gait Test (Timed Get-Up-and-Go Test=time it takes for a seated subject to rise from a chair, walk 3 meters, walk around an object and return to sit in chair. Values: under 10 sec (no difficulties), 10 to 20 sec (starting to have balance difficulty), over 30 sec (at high risk for falls and dependent in most activities of daily living and mobility); test assesses risk to elderly subjects of falling and higher scores in seconds indicate higher risk of falling; ITT population
Time Frame
baseline and Day 22
Title
Change From Baseline in Postural Stability Test
Description
Change from baseline to Day 22 in Postural Stability Test Z-score (This test measures gross motor control. The ability to stand upright without moving is assessed using the SWAY meter that is modeled on the Wright Ataxiameter. A cord from the meter is attached to the subject who is required to stand as still as possible with feet apart and eyes closed for 1 minute. The test is then repeated with eyes open for 1 minute. The outcomes of these tests are combined and measured as a movement Z-score. Higher result=better postural stability); ITT population
Time Frame
baseline and Day 22
Title
Change From Baseline in Serum Sodium; ITT Population
Description
Change from Baseline to Day 22 in Serum Sodium; ITT population
Time Frame
Baseline and Day 22
Title
Number of Patients With Vital Sign Abnormalities: Blood Pressure
Description
Incidence of abnormal systolic & diastolic blood pressure values post-baseline (abnormal systolic values: >=180 mmHg + increase of >=20 mmHg, <= 90 mmHg + decrease >=20 mmHg; abnormal diastolic values: >=105 mmHg+increase of >=15 mmHg, <=50 mmHg + decrease of >= 15 mmHg)
Time Frame
28 days
Title
Number of Patients With Vital Sign Abnormalities: Pulse Rate
Description
Incidence of abnormal pulse rate post-baseline [abnormal values: >=120 beats per minute (bpm) + increase of >=15 bpm; <=50 bpm + decrease of >=15 bpm]
Time Frame
28 days
Title
Number of Patients With Vital Sign Abnormalities: Body Weight
Description
Incidence of clinically significant body weight change post-baseline (defined as change upward or downward of >=7%)
Time Frame
28 days
Title
Number of Patients With Vital Sign Abnormalities: Body Temperature
Description
Incidence of potentially clinically significant changes in body temperature post-baseline (defined as an increase of >=1.1 to >=38.3 degrees Celsius)
Time Frame
28 days
Title
Number of Patients With Hematology Laboratory Abnormalities: Hemoglobin
Description
Incidence of clinically significant hemoglobin abnormalities post-baseline (normal range=11.8-16.8 g/dL)
Time Frame
28 days
Title
Number of Patients With Hematology Laboratory Abnormalities: Activated Partial Thromboplastin Time (aPTT)
Description
Incidence of potentially clinically significant Activated Partial Thromboplastin Time (aPTT) levels post-baseline (normal range=22-34 seconds)
Time Frame
28 days
Title
Number of Patients With Hematology Laboratory Abnormalities: Lymphocytes
Description
Incidence of potentially clinically significant lymphocyte count post-baseline (normal range = 16-46%)
Time Frame
28 days
Title
Number of Patients With Hematology Laboratory Abnormalities: Neutrophils
Description
Incidence of potentially clinically significant neutrophil count post-baseline (normal range=1.8-8 thousands/microliter)
Time Frame
28 days
Title
Number of Patients With Serum Chemistry Laboratory Abnormalities: Blood Urea Nitrogen (BUN)
Description
Incidence of potentially clinically significant BUN levels post-baseline (normal range=7-30 mg/dL)
Time Frame
28 days
Title
Number of Patients With Serum Chemistry Laboratory Abnormalities: Uric Acid
Description
Incidence of potentially clinically significant uric acid levels post-baseline (normal range=4-8.5 mg/dL)
Time Frame
28 days
Title
Number of Patients With Serum Chemistry Laboratory Abnormalities: Cholesterol
Description
Incidence of potentially clinically significant cholesterol levels post-baseline (normal range=0-199 mg/dL)
Time Frame
28 days
Title
Number of Patients With Serum Chemistry Laboratory Abnormalities: Glucose
Description
Incidence of potentially clinically significant glucose levels post-baseline (normal range=70-125 mg/dL)
Time Frame
28 days
Title
Number of Patients With Serum Chemistry Laboratory Abnormalities: Magnesium
Description
Incidence of potentially clinically significant magnesium levels post-baseline (normal range=1.2-2 mEq/L)
Time Frame
28 days
Title
Number of Patients With Electrocardiogram (ECG) Abnormalities: QT >500 Milliseconds (Msec)
Description
Incidence of potentially clinically significant ECG abnormalities (QT>500 msec) post-baseline
Time Frame
28 days
Title
Number of Patients With Electrocardiogram (ECG) Abnormalities: QRS Interval
Description
Incidence of potentially clinically significant ECG abnormalities involving QRS interval (change > 100 msec)
Time Frame
28 days
Title
Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcB Increase 30-60 Msec
Description
Incidence of potentially clinically significant ECG abnormalities (QTcB increase 30-60 msec)
Time Frame
28 days
Title
Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcF Increase 30-60 Msec
Description
Incidence of potentially clinically significant ECG abnormalities (QTcF increase 30-60 msec post-baseline)
Time Frame
28 days
Title
Number of Patients With Electrocardiogram (ECG) Abnormalities: ST Segment
Description
Incidence of potentially clinically significant ECG abnormalities: ST Segment
Time Frame
28 days
Title
Number of Patients With Electrocardiogram (ECG) Abnormalities: T Wave
Description
Incidence of potentially clinically significant ECG abnormalities: T wave
Time Frame
28 days
Title
Number of Patients With Electrocardiogram (ECG) Abnormalities: Right Bundle Branch Block (RBBB), Left Bundle Branch Block (LBBB), Myocardial Infarction (MI)
Description
Incidence of potentially clinically significant ECG abnormalities: Right bundle branch block (RBBB), Left bundle branch block (LBBB), myocardial infarction (MI)
Time Frame
28 days
Title
Number of Patients With Electrocardiogram (ECG) Abnormalities: Arrhythmia
Description
Incidence of potentially clinically significant ECG abnormalities: arrhythmia
Time Frame
28 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Women and men 50 years of age or older.
Serum Sodium ≥123 and ≤ 134 mEq/L [mmol/L]at screening and baseline.
Subjects with serum sodium concentrations ≥118 and ≤122 mEq/L[mmol/L] at screening and baseline may be entered into the trial based on consultation and approval from the study medical monitor.
Exclusion Criteria:
Conditions or history which may present a safety concern to the subject or their offspring or extreme susceptibility to hypotension with sudden fluid loss (aquaresis).
Hyponatremia that is acute, easily reversible, artifactual, or due to a condition not associated with vasopressin excess or likely to respond to aquaretic therapy.
Conditions associated with an independent imminent risk of morbidity and mortality.
Conditions which may confound the assessment of endpoints, history of poor compliance, participation in a clinical trial believed by the PI or Sponsor likely to confound endpoint assessments.
Conditions which may confound primary endpoints of cognitive function.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joseph Verbalis, MD
Organizational Affiliation
Georgetown University, Washington, DC, 20007 USA
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sarah. S. Olelewe, MD
City
Hawthorne
State/Province
California
ZIP/Postal Code
90250
Country
United States
Facility Name
Progressive Clinical Research
City
Vista
State/Province
California
ZIP/Postal Code
92083
Country
United States
Facility Name
Pikes Peak Cardiology
City
Colorado Springs
State/Province
Colorado
ZIP/Postal Code
80907
Country
United States
Facility Name
Innovative Research of West FL
City
Largo
State/Province
Florida
ZIP/Postal Code
33770
Country
United States
Facility Name
Coastal Nephrology Assoc. Research Center
City
Punta Gorda
State/Province
Florida
ZIP/Postal Code
33950
Country
United States
Facility Name
Rockdale Medical Research Associates
City
Conyers
State/Province
Georgia
ZIP/Postal Code
30094
Country
United States
Facility Name
Otis Barnum, DO
City
Natchitoches
State/Province
Louisiana
ZIP/Postal Code
71457
Country
United States
Facility Name
Lillestol Research, LLC
City
Fargo
State/Province
North Dakota
ZIP/Postal Code
58106
Country
United States
Facility Name
Carolina Research Associates
City
Columbia
State/Province
South Carolina
ZIP/Postal Code
29201
Country
United States
Facility Name
Wayne O. Wells, MD
City
Lebanon
State/Province
Tennessee
ZIP/Postal Code
37087
Country
United States
Facility Name
Memorial Clinical Associates
City
Houston
State/Province
Texas
ZIP/Postal Code
77043
Country
United States
Facility Name
Mitchell Rosner, MD
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Effects of Titrated Oral Tolvaptan 15-60 mg Once Daily (QD) on Cognitive and Neurological Function in Elderly Hyponatremic Patients
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