Dose-response Study of the Safety and Efficacy of Beraprost Sodium Modified Release (BPS-MR) in Patients With Pulmonary Arterial Hypertension (PAH)

Study Overview
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Brief Summary
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This is a 12-week, international, multicenter, double-blind, three-group, dose-response study to assess the safety and efficacy of BPS-MR in patients with PAH. Eligible patients will have been previously diagnosed with PAH and will be on a stable course of an ERA and/or PDE-5 inhibitor for at least 60 days prior to Baseline. Patients will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio and will be stratified by PAH background therapy (Endothelium Receptor Antagonist (ERA), Phosphodiesterase-5 (PDE-5), and both). The treatment groups consist of one Maximum Tolerated Dose (MTD) and two Fixed Dose (FD) groups. Following randomization, patients will begin taking active drug (60µg) orally twice daily. Patients will visit their investigational site at Week 6 and Week 12 for study evaluations.

Detailed Description
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This is a 12-week, international, multicenter, double-blind, three-group, dose-response study to assess the safety and efficacy of BPS-MR in patients with PAH. Eligible patients will have been previously diagnosed with PAH and will be on a stable course of an ERA and/or PDE-5 inhibitor for at least 60 days prior to Baseline. A total of approximately 36 patients will be randomized to 1 of 3 treatment groups (12 per group) in a 1:1:1 ratio and will be stratified by PAH background therapy (ERA, PDE-5, and both). The treatment groups consist of one MTD and two FD groups. Following randomization, patients will begin taking active drug (60µg) orally twice daily. Patients will visit their investigational site at Week 6 and Week 12 for study evaluations. Between visits, clinical site personnel will contact patients by phone each week to assess tolerability, provide instructions for a change in dosage, record changes in concomitant medications, and record adverse events. Patients who complete the study will be offered the opportunity to continue taking study medication in a separate open-label continuation protocol. Patients who withdraw early from the study or who otherwise do not elect to enroll into the open-label continuation protocol will be down-titrated off of BPS-MR at the discretion of the Investigator, at a maximum decrement not to exceed one tablet (60µg) b.i.d. per day and a minimum decrement of one tablet (60µg) b.i.d. per week. Patients in the iMTD treatment group will dose escalate weekly by 60µg b.i.d. until they reach the maximum dose of 600µg b.i.d. or they reach an intolerable dose which requires them to down-titrate by 60µg b.i.d. In these instances and at the Investigator's discretion, further attempts at dose escalation may be made. The FD treatment groups will consist of a low dose group receiving 60µg b.i.d. and a high dose group receiving 240µg b.i.d. Patients in the high dose group will dose escalate weekly by 60µg b.i.d. until they reach the fixed dose of 240µg b.i.d. Once patients in these treatment groups have reached their assigned maximum dose of active drug, weekly increases in the number of placebo tablets administered will continue in order to maintain the blind. Patients will be requested to maintain a daily diary of symptoms and study drug administration for evaluation by clinical site personnel. Also, patients will be given the option to contribute blood for pharmacokinetic assessment of BPS/BPS-314d plasma concentrations at the Week 12 visit.

Official Title
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A 12-week, Double-blind, International, Multicenter, Dose-response Study of the Safety and Efficacy of Beraprost Sodium Modified Release (BPS-MR) in Patients With Pulmonary Arterial Hypertension (PAH)

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: IRB approved written informed consent has been obtained. Male or female, age 18 to 75 years (inclusive). Established diagnosis of pulmonary arterial hypertension that is either idiopathic or familial PAH, collagen vascular disease associated PAH, PAH induced by anorexigens, or PAH associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥5 years). Clinically stable PAH as determined by the Investigator. Able to walk unassisted. Has a complete, unencouraged 6MWT distance of 150 to 450 meters (inclusive) at Screening. Previous (at any time) right heart cardiac catheterization with findings consistent with PAH, specifically mean Pulmonary Arterial Pressure (PAPm) ≥25 mmHg (at rest), Pulmonary Capillary Wedge Pressure (PCWP) (or left ventricular end diastolic pressure) ≤15 mmHg, and Pulmonary Vascular Resistance (PVR) >3 mmHg/L/min. Previous (at any time) chest radiograph consistent with the diagnosis of PAH. Has been on a stable course of an ERA or/and PDE-5 inhibitor for a minimum of 60 days prior to Baseline. Women of child-bearing potential (defined as less than 1 year post-menopausal or not surgically sterile) must be using an acceptable method of birth control or practicing abstinence. If sexually active, female patients must use a double barrier method of birth control, such as a condom and spermicidal. Patient must have a negative pregnancy test at the Screening and Baseline visits. Willing and able to comply with study requirements and restrictions. Exclusion Criteria: Has pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, or chronic thromboembolic pulmonary hypertension. Has a history of interstitial lung disease, unless: Pulmonary Function Testing conducted within 6 months of the Baseline visit demonstrates a Total Lung Capacity ≥ 70 % of predicted. Has a history of obstructive lung disease, unless: Pulmonary Function Testing conducted within 6 months of the Baseline visit demonstrates a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio of ≥ 50%. Is pregnant and/or lactating. Changed or discontinued any PAH medication within 60 days prior to the Baseline visit including, but not limited to, an ERA, PDE-5 inhibitor, or calcium channel blocker (with the exception of anticoagulants). Has an ongoing hemorrhagic condition (e.g. upper digestive tract hemorrhage, hemoptysis, etc), or has a pre-existing condition that, in the Investigator's judgment may increase the risk for developing hemorrhage during the study (e.g. hemophilia). Transient hemorrhage (e.g. epistaxis, normal menstrual bleeding, gingival bleeding, hemorrhoidal hemorrhage, etc.) will not preclude enrollment. Has donated blood or plasma, or has lost a volume of blood >450mL within 6-weeks of the Baseline visit. Has received any investigational medication, device or therapy within 30 days prior to the Baseline visit or is scheduled to receive another investigational drug, device or therapy during the course of the study. Has received any prostanoid therapy at any time. Has any preexisting disease known to cause pulmonary hypertension other than collagen vascular disease. Has any musculoskeletal disease or any other disease that would limit ambulation. Has any form of unrepaired or recently repaired (< 5 years) congenital systemic-to-pulmonary shunt other than patent foramen ovale. History of pulmonary embolism or deep venous thrombosis. History of ischemic heart disease, including previous myocardial infarction, or symptomatic coronary artery disease, or history of left sided myocardial disease as evidenced by a mean PCWP (or a left ventricular end diastolic pressure) > 15 mmHg or left ventricular ejection fraction < 40% as assessed by either multigated angiogram, angiography or echocardiography, or left ventricular shortening fraction < 22% as assessed by echocardiography. Note that patients in whom abnormal left ventricular function is attributed entirely to impaired left ventricular filling due to the effects of right ventricular overload (i.e. right ventricular hypertrophy and/or dilatation) will not be excluded. Presence of atrial fibrillation (determined from 12-lead ECG at Screening). Any other clinically significant illness that, in the opinion of the Investigator, might put the patient at risk of harm during the study or might adversely affect the interpretation of the study data.

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maximum Tolerated Dose (MTD)<br>Patients in the MTD treatment group will dose escalate weekly by 60µg b.i.d. until they reach the maximum dose of 600µg b.i.d. or they reach an intolerable dose which requires them to down-titrate by 60µg b.i.d. In these instances and at the Investigator's discretion, further attempts at dose escalation may be made. | Drug: Beraprost Sodium Modified Release<br>* 60µg Tablets, twice a day for 12 weeks<br>|
| Experimental: Low Fixed Dose<br>The low dose group will receive 60µg twice a day(b.i.d.) | Drug: Beraprost Sodium Modified Release<br>* 60µg Tablets, twice a day for 12 weeks<br>|
| Experimental: High Fixed Dose<br>Patients in the high dose group will dose escalate weekly by 60µg twice a day (b.i.d.) until they reach the fixed dose of 240µg b.i.d. Once patients in these treatment groups have reached their assigned maximum dose of active drug, | Drug: Beraprost Sodium Modified Release<br>* 60µg Tablets, twice a day for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Pulmonary Vascular Resistance at Week 12 | The change in Pulmonary Vascular Resistance (PVR) was evaluated from Baseline to Week 12. PVR is expressed in Wood Units or millimeters of Mercury per Liter per minute (mmHG/L/min) | Week 12 | 
| Change From Baseline in Cardiac Output (CO) at Week 12 | The change in Cardiac Output was evaluated from Baseline to Week 12. | Week 12 | 
| Change From Baseline in Pulmonary Arterial Pressure at Week 12 | The change in mean Pulmonary Arterial Pressure (mPAP) was evaluated from Baseline to Week 12. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Six Minute Walk Distance From Baseline to Week 6 and Week 12 | Area used for the Six Minute Walk Test (6MWT) was pre-measured at 30 meters in length. Rest periods were allowed if patient could no longer continue. If patient needed to rest, he/she could stand or sit and then begin again when rested but the clock continued to run. At the end of 6 minutes, the tester called stop while stopping the watch and then measured the distance walked. For purposes of the 6MWT, if patient was assessed at Baseline using oxygen therapy, all future 6MWT were conducted in the same manner. All efficacy results are descriptive; no statistical analysis was conducted. | Baseline, Week 6 and 12 | 
| Number of Participants in Each World Health Organization (WHO) Functional Class for Pulmonary Arterial Hypertension (PAH) at Week 6 and 12 | WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). | Week 6 and Week 12 | 
| Number of Participants With at Least One Post-baseline Clinically Significant Laboratory Value | Post-baseline clinically significant values, as defined by the Investigator, for hematology, serum chemistry, coagulation and urinalysis parameters were summarized. | Up to Week 12 | 
| Number of Participants With Newly Occurring Clinically Significant ECG Abnormalities | Clinically significant ECG abnormalities at Baseline only are excluded. | Up to 12 weeks | 
| Change in Borg Dyspnea Score From Baseline to Week 6 and Week 12 | The modified 0-10 category-ratio Borg scale consists of an 11-point scale rating the maximum level of dyspnea experienced during the 6MWT. Scores range from 0 (for the best condition) and 10 (for the worst condition) with nonlinear spacing of verbal descriptors of severity corresponding to specific numbers. The participant chose the number or the verbal descriptor to reflect presumed ratio properties of sensation or symptom intensity. Only participants with both a measurement at baseline and at the given visit are presented. All efficacy results are descriptive; no statistical analysis was conducted. | Baseline, Week 6 and 12 | 
| N-Terminal ProB-type Natriuretic Peptide Level at Week 6 and Week 12 | NT-proBNP functions as a strong indicator of prognosis in patients with pulmonary arterial hypertension. | Week 6 and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAH