Pulmonary Arterial Hypertension
Conditions
Keywords
Hypertension, Familial Primary Pulmonary Hypertension, Hypertension, Pulmonary, Lung Diseases, Vascular Diseases, Cardiovascular Diseases, Respiratory Tract Diseases, Prostacyclin, Beraprost, Epoprostenol, Platelet Aggregation Inhibitors, Vasodilator Agents, Antihypertensive Agents
Brief summary
This is a multi-center, open-label study for eligible participants who were actively participating in the BPS-314d-MR-PAH-302 double-blind study (NCT01908699) at the time the study was concluded. This open-label extension (OLE) study will evaluate the safety, tolerability, and efficacy of long-term treatment with esuberaprost sodium tablets (Beraprost Sodium 314d Modified Release tablets).
Detailed description
Participants will sign an informed consent to continue treatment for pulmonary arterial hypertension (PAH) with esuberaprost sodium tablets in this OLE study. At the Enrollment Visit for this OLE study, participants will begin a blinded transition from the BPS-314d-MR-PAH-302 double-blind study to this study over 4 weeks. The first dose for all participants in this OLE study will be 2 tablets. During this blinded transition, those participants on active study drug in the BPS-314d-MR-PAH-302 study will continue with blinded active study drug 4-times daily (QID); those participants who were on placebo study drug will receive 1 active tablet and 1 placebo tablet QID (blinded) during the first 2 weeks and increase to 2 active tablets QID (blinded) thereafter. After the first dose, the Investigator may adjust the dose as medically warranted. The maximum dose for this study is 30 microgram (μg) QID with a minimum accepted dose as 15 μg QID. For the first 4 weeks, contact with the participant should occur weekly to ensure up-titration to the fixed dose is tolerated and assess adverse events (AEs). Participants will return to the clinic at Week 4 to be supplied open-label esuberaprost sodium tablets and complete protocol specified procedures. At the Week 4 Visit, participants will be dosed with two 15 μg tablets (30 μg total), administered orally QID (provided the target dose is tolerated), or follow the Investigator's (or designee's) directions if adjustment is needed. Following the Week 4 Visit, each participant will return to the clinic at Months 3, 6, 9, and 12, and quarterly thereafter for assessments. This study is expected to continue until the first of any of the following are reached: the study drug is commercially available, the Sponsor discontinues the study, or the Sponsor offers enrollment in another study (estimated to be up to 2 years). At the conclusion of the study or if a participant discontinues the study prematurely, participants will return to the clinic for an End-of-Study (EOS) Visit. Participants will be provided instructions about down titration off esuberaprost sodium tablets by the Investigator.
Interventions
DRUGEsuberaprost
Sodium tablets
DRUGPlacebo
Placebo tablets, which are identical in size and appearance to those containing Esuberaprost.
Sponsors
Lung Biotechnology PBC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Treatment during the first 4 weeks of this study will be double-blind. The Investigator and study staff, the participants, the monitors, and the Sponsor will remain blinded to the treatment group allocation from BPS-314d-MR-PAH-302 double-blind study (NCT01908699) and to study drug during the first 4 weeks of the OLE study while the participants transition to the OLE treatment. After the 4 weeks, the study will continue as unblinded and open label.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Participant must have been actively participating in the double-blind study, BPS-314d-MR-PAH-302 (NCT01908699), when the Sponsor concluded that study. 2. In the Investigator's opinion, participant must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form (ICF) and must sign the form prior to the initiation of any study procedures. 3. Women of child-bearing potential (defined as less than 1 year post-menopausal and not surgically sterile) must be practicing abstinence or using 2 highly-effective methods of contraception (defined as a method of birth control that results in a low failure rate \[that is, less than 1% per year, such as approved hormonal contraceptives, barrier methods (such as a condom or diaphragm) used with a spermicide or an intrauterine device\]). Participant must have a negative pregnancy test at the BPS-314d-MR-PAH-302 EOS Visit / BPS-314d-MR-PAH-303 Enrollment Visit. 4. Participant must be willing and able to comply with study requirements and restrictions.
Exclusion criteria
1. Participant is pregnant or lactating. 2. Participant is scheduled to receive another investigational drug, device, or therapy during the course of the study. 3. Participant is taking or intends to take any prostacyclin / prostacyclin (IP) analog or IP receptor agonist (except for treprostinil, inhaled \[Tyvaso®\]). 4. Participant has any other clinically significant illness or other reason that, in the opinion of the Investigator, might put the participant at risk of harm during the study or might adversely affect the interpretation of the study data.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Baseline up to Month 7 | A TEAE is any untoward medical occurrence or undesirable event(s) experienced in a participant that begins or worsens following administration of study drug, whether or not considered related to study drug by Investigator. A serious adverse event (SAE) is an adverse event (AE) resulting in any of the following outcomes or deemed significant for any other reason, death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), or persistent or significant disability/incapacity. AEs included both SAEs and non-serious AEs. AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Walked for the 6 Minute Walk Distance (6MWD) Test | Week 4 and then every 3 months until study termination (Month 7) | Area used for the Six Minute Walk Test (6MWT) were to be pre-measured at 30 meters in length. Rest periods were to be allowed if participant could no longer continue. If participant needed to rest, he/she could have stood or sit and then begin again when rested but the clock would continue to run. At the end of 6 minutes, the tester was to call stop while stopping the watch and then measure the distance walked. Distance \<500 meters would have suggested considerable exercise limitation; distance 500-800 meters would have suggested moderate limitation; and distance \>800 meters (with no rests) would have suggested mild or no limitation. This extension study was terminated early due to the pivotal double-blind study failed to demonstrate efficacy. Therefore, efficacy data was not collected or analyzed. |
| Borg Dyspnea Score | Week 4 and then every 3 months until study termination (Month 7) | The modified 0-10 category-ratio Borg scale is one in which the participants were to rate the maximum level of dyspnea they experienced during the 6MWT. Scores would have ranged from 0 (for the best condition) and 10 (for the worst condition). This extension study was terminated early due to the pivotal double-blind study failed to demonstrate efficacy. Therefore, efficacy data was not collected or analyzed. Note, a summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. |
| Number of Participants in Each Category of the World Health Organization (WHO) Functional Class (FC) | Week 4 and then every 3 months until study termination (Month 7) | The WHO Functional Class of pulmonary hypertension is a physical activity rating scale as follows: Class I: No limitation of physical activity. Class II: Slight limitation of physical activity. Class III: Marked limitation of physical activity. Class IV: Inability to carry out any physical activity without symptoms. This extension study was terminated early due to the pivotal double-blind study failed to demonstrate efficacy. Therefore, efficacy data was not collected or analyzed. |
| Number of Participants With a TEAE of N-terminal Pro-brain Natriuretic Peptide (NT-pro-BNP) Increased | Baseline up to Month 7 | A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. |
Countries
Israel, United States
Participant flow
Pre-assignment details
At the Enrollment Visit for this open-label extension (OLE) study, participants began a blinded transition from the pivotal BPS-314d-MR-PAH-302 double-blind study (NCT01908699) to this study over 4 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Esuberaprost Participants who received esuberaprost during the BPS-314d-MR-PAH-302 double-blind study received 2 tablets of 15 μg esuberaprost sodium tablets for oral administration QID for up to 7 months (which included the 4 weeks of blinded transition). | 59 |
| Placebo/Esuberaprost Participants who received placebo during the BPS-314d-MR-PAH-302 double-blind study received 1 esuberaprost tablet and 1 placebo tablet QID for the first 2 weeks of the blinded transition and then received 2 esuberaprost tablets QID for the rest of the study, for up to 7 months (which included the other 2 weeks of the total 4-week blinded transition). | 53 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 |
| Overall Study | Study Terminated by Sponsor | 58 | 49 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo/Esuberaprost | Total | Esuberaprost |
|---|---|---|---|
| Age, Continuous | 62.5 years STANDARD_DEVIATION 9.75 | 60.6 years STANDARD_DEVIATION 10.54 | 59.0 years STANDARD_DEVIATION 11.02 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 10 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 102 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 19 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 44 Participants | 93 Participants | 49 Participants |
| Sex: Female, Male Female | 39 Participants | 82 Participants | 43 Participants |
| Sex: Female, Male Male | 14 Participants | 30 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 53 |
| other Total, other adverse events | 56 / 59 | 52 / 53 |
| serious Total, serious adverse events | 12 / 59 | 8 / 53 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
A TEAE is any untoward medical occurrence or undesirable event(s) experienced in a participant that begins or worsens following administration of study drug, whether or not considered related to study drug by Investigator. A serious adverse event (SAE) is an adverse event (AE) resulting in any of the following outcomes or deemed significant for any other reason, death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), or persistent or significant disability/incapacity. AEs included both SAEs and non-serious AEs. AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Baseline up to Month 7
Population: All participants who receive at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Esuberaprost | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAEs | 56 Participants |
| Esuberaprost | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Treatment-Emergent SAEs | 9 Participants |
| Placebo/Esuberaprost | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAEs | 52 Participants |
| Placebo/Esuberaprost | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Treatment-Emergent SAEs | 8 Participants |
Secondary
Area Walked for the 6 Minute Walk Distance (6MWD) Test
Area used for the Six Minute Walk Test (6MWT) were to be pre-measured at 30 meters in length. Rest periods were to be allowed if participant could no longer continue. If participant needed to rest, he/she could have stood or sit and then begin again when rested but the clock would continue to run. At the end of 6 minutes, the tester was to call stop while stopping the watch and then measure the distance walked. Distance \<500 meters would have suggested considerable exercise limitation; distance 500-800 meters would have suggested moderate limitation; and distance \>800 meters (with no rests) would have suggested mild or no limitation. This extension study was terminated early due to the pivotal double-blind study failed to demonstrate efficacy. Therefore, efficacy data was not collected or analyzed.
Time frame: Week 4 and then every 3 months until study termination (Month 7)
Population: All participants who receive at least 1 dose of study drug. Efficacy data was not collected or analyzed for this extension study.
Secondary
Borg Dyspnea Score
The modified 0-10 category-ratio Borg scale is one in which the participants were to rate the maximum level of dyspnea they experienced during the 6MWT. Scores would have ranged from 0 (for the best condition) and 10 (for the worst condition). This extension study was terminated early due to the pivotal double-blind study failed to demonstrate efficacy. Therefore, efficacy data was not collected or analyzed. Note, a summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Week 4 and then every 3 months until study termination (Month 7)
Population: All participants who receive at least 1 dose of study drug. Efficacy data was not collected or analyzed for this extension study.
Secondary
Number of Participants in Each Category of the World Health Organization (WHO) Functional Class (FC)
The WHO Functional Class of pulmonary hypertension is a physical activity rating scale as follows: Class I: No limitation of physical activity. Class II: Slight limitation of physical activity. Class III: Marked limitation of physical activity. Class IV: Inability to carry out any physical activity without symptoms. This extension study was terminated early due to the pivotal double-blind study failed to demonstrate efficacy. Therefore, efficacy data was not collected or analyzed.
Time frame: Week 4 and then every 3 months until study termination (Month 7)
Population: All participants who receive at least 1 dose of study drug. Efficacy data was not collected or analyzed for this extension study.
Secondary
Number of Participants With a TEAE of N-terminal Pro-brain Natriuretic Peptide (NT-pro-BNP) Increased
A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Baseline up to Month 7
Population: All participants who receive at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Esuberaprost | Number of Participants With a TEAE of N-terminal Pro-brain Natriuretic Peptide (NT-pro-BNP) Increased | 5 Participants |
| Placebo/Esuberaprost | Number of Participants With a TEAE of N-terminal Pro-brain Natriuretic Peptide (NT-pro-BNP) Increased | 2 Participants |