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This study is an international, open-label, multi-center, Phase II, multiple dose, dose-finding study to investigate the safety, tolerability and pharmacokinetic characteristics of BPS-MR tablets in male and female patients with PAH.
Patients who meet the inclusion/exclusion criteria will enter the Treatment Phase at a Baseline visit. Patients will begin taking one BPS-MR tablet (60µg) twice daily (b.i.d.) escalating by one tablet b.i.d. each week to a maximum dose of 600µg (ten tablets) b.i.d or until the patient reaches their MTD. Following the achievement of the MTD, patients will be down-titrated off BPS-MR in weekly one tablet b.i.d. decrements. Patients may, alternatively, elect to continue taking the study drug at their MTD in a separate open-label extension study.
This study is an international, open-label, multi-center, Phase II, multiple dose, dose-finding study to investigate the safety, tolerability and pharmacokinetic characteristics of BPS-MR tablets in male and female patients with PAH. All patients will be receiving background therapy with either a phosphodiesterase (PDE-5) inhibitor, endothelin receptor antagonist (ERA), or the combination of these two.
The study is divided into two phases:
Screening will be conducted on an outpatient basis within 21 days prior to the Baseline visit. Patients meeting the inclusion/exclusion criteria at the Baseline visit will enter the Treatment Phase and begin taking one BPS-MR tablet (60µg) b.i.d. and escalating by one tablet b.i.d. each week to a maximum dose of 600µg (ten tablets) b.i.d. or until the patient reaches an intolerable dose.
Patients who reach an intolerable dose will be instructed to continue treatment at the previous dose, which will be considered as their individual MTD. For example, if a patient attains a full week of six BPS-MR tablets b.i.d. (360µg) but is unable to tolerate seven tablets (420µg) then the patient will return to using six tablets of BPS-MR b.i.d. (360µg) for up to an additional week of treatment. In this scenario, BPS-MR 360µg b.i.d. is the patient's MTD. Patients who do not reach an intolerable dose and tolerate the full ten weeks of BPS-MR dosing will be considered to have their individual MTD as BPS-MR 600µg b.i.d.
When patients reach their individual MTD (either at 10 weeks or earlier) they will return to the site 3-7 days after for an End of Treatment Phase assessment to be evaluated for safety and, optionally, a PK assessment. Subsequent to the End of Treatment Phase visit patients will be instructed to begin down-titration off of BPS-MR in weekly increments. However, patients may alternatively elect to continue taking BPS-MR at their MTD in a separate open-label extension study.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Beraprost sodium modified release | Drug | Tablets 60mcg |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration. | 10 Weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants That Reported at Least One Treatment-Emergent Adverse Event (TEAE) | A treatment-emergent adverse event (TEAE) is defined as an event not present prior to the initiation of the treatment or any event already present that worsens in either intensity or frequency following exposure to the treatment. AEs occurring more than 3 days after the last day study drug was taken in the study was not included in the statistical analyses or summaries (except for subjects with adverse events leading to study drug withdrawn). Only TEAEs that occurred during the treatment period of the BPS-MR-PAH-201 study were summarized. Any adverse event starting prior to the first dose of study drug was excluded from the summary analyses and only presented in the data listings. All efficacy results are descriptive; no statistical analysis was conducted |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ted Staub, MS, MEng | Study Sponsor | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Harbor-UCLA Medical Center | Torrance | California | 90502 | United States | ||
| Allegheny General Hospital |
A Protocol Amendment was to include an optional arm investigating Beraprost Sodium Modified Release Tablets administered four times daily (QID), however, no participants were enrolled into this arm.
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| ID | Title | Description |
|---|---|---|
| FG000 | Beraprost Sodium | Beraprost Sodium Modified Release (BPS-MR) 60 mcg tablets, administered orally, twice daily (BID). Doses were escalated by 1 tablet BID weekly, as tolerated, to a maximum dose of 600 mcg BID. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| 19 Weeks |
| Change in Body Mass Index (BMI) From Baseline to Week 19 | Body Mass Index (BMI) was assessed at each study visit and taken after five minutes of seated rest. Body mass index is a value derived from the mass and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is universally expressed in units of kg/m², resulting from mass in kilograms and height in meters. | Baseline and 19 weeks |
| Change in Weight From Baseline to Week 19 | Weight was assessed at each study visit and taken after five minutes of seated rest. Weight was measured in kilograms (kg). | Baseline and 19 weeks |
| Change in Heart Rate From Baseline to Week 19 | Heart Rate was assessed at each study visit and taken after five minutes of seated rest. Heart rate is measured in beats per minute (BPM). | Baseline and 19 weeks |
| Change in Body Temperature From Baseline to Week 19 | Body Temperature was assessed at each study visit and taken after five minutes of seated rest. Body temperature was measured in degrees Celsius (C). | Baseline and 19 weeks |
| Change in Systolic Blood Pressure (SBP) From Baseline to Week 19 | Systolic blood pressure was assessed at each study visit and taken after five minutes of seated rest. Systolic blood pressure was measured in millimeters of mercury (mmHg). | Baseline and 19 weeks |
| Change in Diastolic Blood Pressure (DBP) From Baseline to Week 19 | Diastolic blood pressure was assessed at each study visit and taken after five minutes of seated rest. Diastolic blood pressure was measured in millimeters of mercury (mmHg). | Baseline and 19 weeks |
| Change in Respiratory Rate From Baseline to Week 19 | Respiratory Rate was assessed at each study visit and taken after five minutes of seated rest. Respiratory rate was measured in breaths per minute. | Baseline and 19 weeks |
| Change in Electrocardiogram Intervals From Baseline to Week 19 | Baseline and 19 weeks |
| Apparent Clearance (CL/F) of BPS-MR | Apparent clearance is defined as plasma clearance divided by absolute bioavailability per kilogram of bodyweight. | pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 67 |
| Apparent Volume of Distribution (Vz/F) of BPS-MR | pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 67 |
| Pittsburgh |
| Pennsylvania |
| 15212 |
| United States |
| UTSW Medical Center | Dallas | Texas | 8550 | United States |
| Universite Libre de Bruxelles, Hospital Erasme | Brussels | Belgium |
| Gastuiberg University Hospital | Leuven | 3000 | Belgium |
| Mater Misericordiae University Hospital Ltd. | Dublin | Ireland |
| Received at Least 1 Dose of Study Drug |
|
| COMPLETED |
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| NOT COMPLETED |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Beraprost Sodium | Beraprost Sodium Modified Release (BPS-MR) 60 mcg tablets, administered orally, twice daily (BID). Doses were escalated by 1 tablet BID weekly, as tolerated, to a maximum dose of 600 mcg BID. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
| |||||||||||||||||
| Respiratory Rate | Only Participants with both a measurement at baseline and at the given visit are presented. | Mean | Standard Deviation | Breaths per minute |
| ||||||||||||||||
| Temperature | Only Participants with both a measurement at baseline and at the given visit are presented. | Mean | Standard Deviation | degrees Celsius |
| ||||||||||||||||
| Systolic Blood Pressure (SBP) | Mean | Standard Deviation | mmHg |
| |||||||||||||||||
| Diastolic Blood Pressure (DBP) | Mean | Standard Deviation | mmHg |
| |||||||||||||||||
| Weight | Mean | Standard Deviation | kg |
| |||||||||||||||||
| Electrocardiogram (ECG) Intervals | Only Participants with both a measurement at baseline and at the given visit are presented. | Mean | Standard Deviation | msec |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration. | The Tolerability population includes all evaluable participants who achieved their MTD and had an End of Treatment visit. | Posted | Count of Participants | Participants | 10 Weeks |
|
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| |||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants That Reported at Least One Treatment-Emergent Adverse Event (TEAE) | A treatment-emergent adverse event (TEAE) is defined as an event not present prior to the initiation of the treatment or any event already present that worsens in either intensity or frequency following exposure to the treatment. AEs occurring more than 3 days after the last day study drug was taken in the study was not included in the statistical analyses or summaries (except for subjects with adverse events leading to study drug withdrawn). Only TEAEs that occurred during the treatment period of the BPS-MR-PAH-201 study were summarized. Any adverse event starting prior to the first dose of study drug was excluded from the summary analyses and only presented in the data listings. All efficacy results are descriptive; no statistical analysis was conducted | Posted | Count of Participants | Participants | 19 Weeks |
|
| ||||||||||||||||||||||||||||||||||||||
| Secondary | Change in Body Mass Index (BMI) From Baseline to Week 19 | Body Mass Index (BMI) was assessed at each study visit and taken after five minutes of seated rest. Body mass index is a value derived from the mass and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is universally expressed in units of kg/m², resulting from mass in kilograms and height in meters. | Participants with both a baseline measurement and an End of Study measurement | Posted | Mean | Standard Deviation | kilograms/meter^2 | Baseline and 19 weeks |
|
| ||||||||||||||||||||||||||||||||||||
| Secondary | Change in Weight From Baseline to Week 19 | Weight was assessed at each study visit and taken after five minutes of seated rest. Weight was measured in kilograms (kg). | Participants with both a baseline measurement and an End of Study measurement | Posted | Mean | Standard Deviation | kg | Baseline and 19 weeks |
|
| ||||||||||||||||||||||||||||||||||||
| Secondary | Change in Heart Rate From Baseline to Week 19 | Heart Rate was assessed at each study visit and taken after five minutes of seated rest. Heart rate is measured in beats per minute (BPM). | Participants with both a baseline measurement and an End of Study measurement | Posted | Mean | Standard Deviation | Beats per Minute (BPM) | Baseline and 19 weeks |
|
| ||||||||||||||||||||||||||||||||||||
| Secondary | Change in Body Temperature From Baseline to Week 19 | Body Temperature was assessed at each study visit and taken after five minutes of seated rest. Body temperature was measured in degrees Celsius (C). | Participants with both a baseline measurement and an End of Study measurement | Posted | Mean | Standard Deviation | degrees Celsius | Baseline and 19 weeks |
|
| ||||||||||||||||||||||||||||||||||||
| Secondary | Change in Systolic Blood Pressure (SBP) From Baseline to Week 19 | Systolic blood pressure was assessed at each study visit and taken after five minutes of seated rest. Systolic blood pressure was measured in millimeters of mercury (mmHg). | Participants with both a baseline measurement and an End of Study measurement | Posted | Mean | Standard Deviation | mmHg | Baseline and 19 weeks |
|
| ||||||||||||||||||||||||||||||||||||
| Secondary | Change in Diastolic Blood Pressure (DBP) From Baseline to Week 19 | Diastolic blood pressure was assessed at each study visit and taken after five minutes of seated rest. Diastolic blood pressure was measured in millimeters of mercury (mmHg). | Participants with both a baseline measurement and an End of Study measurement | Posted | Mean | Standard Deviation | mmHg | Baseline and 19 weeks |
|
| ||||||||||||||||||||||||||||||||||||
| Secondary | Change in Respiratory Rate From Baseline to Week 19 | Respiratory Rate was assessed at each study visit and taken after five minutes of seated rest. Respiratory rate was measured in breaths per minute. | Participants with both a baseline measurement and an End of Study measurement | Posted | Mean | Standard Deviation | Breaths per Minute | Baseline and 19 weeks |
|
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| Secondary | Change in Electrocardiogram Intervals From Baseline to Week 19 | Only participants with both a measurement at baseline and at the given visit are presented. | Posted | Mean | Standard Deviation | millisecond (msec) | Baseline and 19 weeks |
|
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| Secondary | Apparent Clearance (CL/F) of BPS-MR | Apparent clearance is defined as plasma clearance divided by absolute bioavailability per kilogram of bodyweight. | 9 participants participated in the optional pharmacokinetic sub-study. | Posted | Mean | Standard Deviation | L/h/kg | pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 67 |
|
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| Secondary | Apparent Volume of Distribution (Vz/F) of BPS-MR | 9 participants participated in the optional pharmacokinetic sub-study. | Posted | Mean | Standard Deviation | Liters per kilogram (L/kg) | pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 67 |
|
|
From baseline to 30 days after study treatment discontinuation, up to 7 months.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Beraprost Sodium | Beraprost Sodium Modified Release (BPS-MR) 60 mcg tablets, administered orally, twice daily (BID). Doses were escalated by 1 tablet BID weekly, as tolerated, to a maximum dose of 600 mcg BID. | 0 | 19 | 0 | 19 | 19 | 19 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Palpitations | Cardiac disorders | MedDRA 11.1 | Systematic Assessment |
| |
| Cardiac Ventricular Disorder | Cardiac disorders | MedDRA 11.1 | Systematic Assessment |
| |
| Ear Discomfort | Ear and labyrinth disorders | MedDRA 11.1 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Stomach Discomfort | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Abdominal Pain Upper | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Defaecation Urgency | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Flatulence | Gastrointestinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Pain | General disorders | MedDRA 11.1 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 11.1 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA 11.1 | Systematic Assessment |
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| Chills | General disorders | MedDRA 11.1 | Systematic Assessment |
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| Oedema Peripheral | General disorders | MedDRA 11.1 | Systematic Assessment |
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| Drug Hypersensitivity | Immune system disorders | MedDRA 11.1 | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA 11.1 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 11.1 | Systematic Assessment |
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| Skin Infection | Infections and infestations | MedDRA 11.1 | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA 11.1 | Systematic Assessment |
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| Eye Injury | Injury, poisoning and procedural complications | MedDRA 11.1 | Systematic Assessment |
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| Blood Bilirubin Increased | Investigations | MedDRA 11.1 | Systematic Assessment |
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| Lymphocyte Count Increased | Investigations | MedDRA 11.1 | Systematic Assessment |
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| Neutrophil Count Increased | Investigations | MedDRA 11.1 | Systematic Assessment |
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| Decreased Appetite | Metabolism and nutrition disorders | MedDRA 11.1 | Systematic Assessment |
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| Fluid Overload | Metabolism and nutrition disorders | MedDRA 11.1 | Systematic Assessment |
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| Pain In Extremity | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Systematic Assessment |
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| Pain In Jaw | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Systematic Assessment |
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| Neck Pain | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Systematic Assessment |
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| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Systematic Assessment |
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| Juvenile Arthritis | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 11.1 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 11.1 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Nasal Congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Oropharyngeal Pain | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Systematic Assessment |
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| Cold Sweat | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Systematic Assessment |
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| Night Sweats | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Systematic Assessment |
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| Urticaria | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Systematic Assessment |
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| Flushing | Vascular disorders | MedDRA 11.1 | Systematic Assessment |
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| Hot Flush | Vascular disorders | MedDRA 11.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Lung Biotechnology PBC Study Director | Lung Biotechnology PBC | 301-608-9292 |
| ID | Term |
|---|---|
| D000081029 | Pulmonary Arterial Hypertension |
| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| Unknown or Not Reported |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| QRS Interval |
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| QT Interval |
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| QTc Bazett |
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| QTc Friderica |
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| Title | Measurements |
|---|
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| 300 mcg |
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| 420 mcg |
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| 540 mcg |
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| 600 mcg |
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| Title | Denominators | Categories | ||||
|---|---|---|---|---|---|---|
| PR Interval |
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| QRS Interval |
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| QT Interval |
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| QTc Bazett |
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| QTc Friderica |
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| Title | Denominators | Categories | ||||
|---|---|---|---|---|---|---|
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