A Multi-Center, Open-Label, Multiple Dose, Dose Finding Study Exploring the Safety and Tolerability of Beraprost Sodium Modified Release in PAH Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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. 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: The Treatment Phase and The Down-Titration Phase 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.

Official Title
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A Multi-Center, Open-Label, Multiple Dose, Dose Finding Study Exploring the Safety and Tolerability of Beraprost Sodium Modified Release in PAH Patients

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Beraprost sodium modified release


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is male or female between the ages of 18 and 75 years of age, inclusive; Has either idiopathic or familial PAH, PAH associated with collagen vascular disease, or PAH induced by anorexigens; Is clinically stable, as determined by the investigator; Has previously undergone a cardiac catheterization which is consistent with PAH, specifically PAPm ≥25 mmHg (at rest), PCWP (or left ventricular end diastolic pressure) ≤15 mmHg, and PVR >3 wood units; Has been on a course of an endothelin receptor antagonist (ERA) or phosphodiesterase inhibitor (PDE-5) or the combination for at least 90 days at the time of the Baseline visit; Has an unencouraged six-minute walk distance (6MWD) between 300 and 600 meters at the Screening visit; Is able to communicate effectively with study personnel; Is considered to be reliable, willing, cooperative and compliant with the study protocol requirements; Provides voluntary, written informed consent before participating in the study; Is, if female, physiologically incapable of childbearing or is practicing an acceptable method of birth control (i.e., surgical sterilization, approved hormonal contraceptives, barrier methods [such as a condom or diaphragm] used with a spermicide, or an intrauterine device). Exclusion Criteria: Has pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, severe chronic obstructive pulmonary disease, pulmonary hypertension related to congenital heart disease, or chronic thromboembolic pulmonary hypertension; Is pregnant or lactating; Has a known intolerance to beraprost sodium or prostanoids; Has a pre-existing condition that could interfere with the absorption, distribution, metabolism, or excretion of drugs; Current use of tobacco products; Known history of syncope; Has, in the opinion of the Investigator, any concomitant disease other than those accepted as part of the inclusion criteria that would compromise the patient or the study; Has had a change in or discontinued any PAH medication (with the exception of anticoagulants) within 30 days prior to the Baseline visit; Has received any prostanoid therapy within the 30 days prior to the Baseline visit or be scheduled to receive additional prostanoid therapy during the study except for acute vasodilatory testing; Has received any investigational medication within 30 days prior to the Baseline visit or be scheduled to receive another investigational drug during the course of this study; In the opinion of the investigator, may be unable to comply with the study protocol; Has any preexisting disease known to cause pulmonary hypertension (e.g., obstructive lung disease, parasitic disease affecting the pulmonary system, sickle cell anemia, mitral valve stenosis, portal hypertension) other than those listed in the inclusion criteria; Has donated blood or plasma or has lost a volume of blood >450 mL within six weeks prior to the Baseline visit. Has an ongoing hemorrhagic condition (e.g. upper digestive track hemorrhage, hemoptysis, etc.) or has a pre-existing condition that, in the investigator's judgement, may increase the risk for developing hemorrhage during the study (e.g. hemophilia). However, transient hemorrhage (e.g. epistaxis, normal menstrual bleeding, gingival bleeding, hemorrhoidal hemorrhage, etc.) would not preclude enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Beraprost sodium modified release|Tablets 60mcg|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration. |  | 10 Weeks | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 |