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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00781885

Enrollment

Registered

2008-10-29

Start date

2009-01-31

Completion date

2010-09-30

Last updated

2020-06-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Arterial Hypertension

Brief summary

Detailed description

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: 1. The Treatment Phase and 2. 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.

Interventions

DRUGBeraprost sodium modified release

Tablets 60mcg

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

1. Is male or female between the ages of 18 and 75 years of age, inclusive; 2. Has either idiopathic or familial PAH, PAH associated with collagen vascular disease, or PAH induced by anorexigens; 3. Is clinically stable, as determined by the investigator; 4. 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; 5. 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; 6. Has an unencouraged six-minute walk distance (6MWD) between 300 and 600 meters at the Screening visit; 7. Is able to communicate effectively with study personnel; 8. Is considered to be reliable, willing, cooperative and compliant with the study protocol requirements; 9. Provides voluntary, written informed consent before participating in the study; 10. 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

1. 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; 2. Is pregnant or lactating; 3. Has a known intolerance to beraprost sodium or prostanoids; 4. Has a pre-existing condition that could interfere with the absorption, distribution, metabolism, or excretion of drugs; 5. Current use of tobacco products; 6. Known history of syncope; 7. 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; 8. Has had a change in or discontinued any PAH medication (with the exception of anticoagulants) within 30 days prior to the Baseline visit; 9. 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; 10. 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; 11. In the opinion of the investigator, may be unable to comply with the study protocol; 12. 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; 13. Has donated blood or plasma or has lost a volume of blood \>450 mL within six weeks prior to the Baseline visit. 14. 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

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Number of Participants That Reported at Least One Treatment-Emergent Adverse Event (TEAE)	19 Weeks	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
Change in Body Mass Index (BMI) From Baseline to Week 19	Baseline and 19 weeks	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.
Change in Weight From Baseline to Week 19	Baseline and 19 weeks	Weight was assessed at each study visit and taken after five minutes of seated rest. Weight was measured in kilograms (kg).
Change in Heart Rate From Baseline to Week 19	Baseline and 19 weeks	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).
Change in Body Temperature From Baseline to Week 19	Baseline and 19 weeks	Body Temperature was assessed at each study visit and taken after five minutes of seated rest. Body temperature was measured in degrees Celsius (C).
Change in Electrocardiogram Intervals From Baseline to Week 19	Baseline and 19 weeks	—
Change in Diastolic Blood Pressure (DBP) From Baseline to Week 19	Baseline and 19 weeks	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).
Change in Respiratory Rate From Baseline to Week 19	Baseline and 19 weeks	Respiratory Rate was assessed at each study visit and taken after five minutes of seated rest. Respiratory rate was measured in breaths per minute.
Apparent Clearance (CL/F) of BPS-MR	pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 67	Apparent clearance is defined as plasma clearance divided by absolute bioavailability per kilogram of bodyweight.
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	—
Change in Systolic Blood Pressure (SBP) From Baseline to Week 19	Baseline and 19 weeks	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).

Countries

Belgium, Ireland, United States

Participant flow

Pre-assignment details

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.

Participants by arm

Arm	Count
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.	19
Total	19

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Physician Decision	1

Baseline characteristics

Characteristic	Beraprost Sodium
Age, Continuous	47.6 years STANDARD_DEVIATION 12.85
Body Mass Index	30.4 kg/m^2 STANDARD_DEVIATION 7.57
Diastolic Blood Pressure (DBP)	76.8 mmHg STANDARD_DEVIATION 9.14
Electrocardiogram (ECG) Intervals PR Interval	175.8 msec STANDARD_DEVIATION 28.26
Electrocardiogram (ECG) Intervals QRS Interval	99.2 msec STANDARD_DEVIATION 14.7
Electrocardiogram (ECG) Intervals QTc Bazett	437.7 msec STANDARD_DEVIATION 27.4
Electrocardiogram (ECG) Intervals QTc Friderica	422.9 msec STANDARD_DEVIATION 28.65
Electrocardiogram (ECG) Intervals QT Interval	396.5 msec STANDARD_DEVIATION 42.1
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	16 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	3 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	16 Participants
Respiratory Rate	18.5 Breaths per minute STANDARD_DEVIATION 1.61
Sex: Female, Male Female	15 Participants
Sex: Female, Male Male	4 Participants
Systolic Blood Pressure (SBP)	118.1 mmHg STANDARD_DEVIATION 10.9
Temperature	36.5 degrees Celsius STANDARD_DEVIATION 0.35
Weight	81.7 kg STANDARD_DEVIATION 20.79

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 19
other Total, other adverse events	19 / 19
serious Total, serious adverse events	0 / 19

Outcome results

Primary

Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration.

Time frame: 10 Weeks

Population: The Tolerability population includes all evaluable participants who achieved their MTD and had an End of Treatment visit.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Beraprost Sodium	Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration.	120 mcg	2 Participants
Beraprost Sodium	Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration.	180 mcg	2 Participants
Beraprost Sodium	Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration.	240 mcg	3 Participants
Beraprost Sodium	Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration.	300 mcg	2 Participants
Beraprost Sodium	Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration.	420 mcg	1 Participants
Beraprost Sodium	Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration.	540 mcg	1 Participants
Beraprost Sodium	Maximum Tolerated Dose (MTD) of BPS-MR in Pulmonary Arterial Hypertension (PAH) Patients, Following Chronic, Twice-daily Administration.	600 mcg	7 Participants

Secondary

Apparent Clearance (CL/F) of BPS-MR

Apparent clearance is defined as plasma clearance divided by absolute bioavailability per kilogram of bodyweight.

Time frame: pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 67

Population: 9 participants participated in the optional pharmacokinetic sub-study.

Arm	Measure	Value (MEAN)	Dispersion
Beraprost Sodium	Apparent Clearance (CL/F) of BPS-MR	1.51 L/h/kg	Standard Deviation 0.52

Secondary

Apparent Volume of Distribution (Vz/F) of BPS-MR

Time frame: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 67

Population: 9 participants participated in the optional pharmacokinetic sub-study.

Arm	Measure	Value (MEAN)	Dispersion
Beraprost Sodium	Apparent Volume of Distribution (Vz/F) of BPS-MR	43.6 Liters per kilogram (L/kg)	Standard Deviation 68.4

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.