Connective Tissue Disease-Associated Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary Hypertension, Pulmonary Arterial Hypertension, Connective Tissue Disease-Associated Pulmonary Arterial Hypertension, Bardoxolone methyl, PAH, RTA 402, 6-minute walk distance
Brief summary
This study assesses the safety and efficacy of bardoxolone methyl relative to placebo in patients with connective tissue disease-associated pulmonary arterial hypertension to determine the recommended dose range and evaluate the change from baseline in 6-minute walk distance (6MWD) following 24 weeks of study participation.
Detailed description
This double-blind, randomized, placebo-controlled trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with World Health Organization Group I Connective Tissue Disease Pulmonary Arterial Hypertension (WHO Group I CTD-PAH). Qualified patients will be randomized 1:1 to either bardoxolone methyl or placebo to be administered once daily for 24 weeks. Patients randomized to placebo will remain on placebo throughout the study. Patients randomized to bardoxolone methyl will start at 5 mg and will dose-escalate to 10 mg at Week 4 unless contraindicated clinically. Dose de-escalation is permitted during the study if indicated clinically. All patients in the study will follow the same visit and assessment schedule. Following randomization, patients will be scheduled to be assessed in person during treatment at Weeks 1, 2, 4, 6, 8, 16, and 24 and by telephone contact on Days 3, 10, 21, 31, 38, 84, and 140. Patients will also be scheduled to be assessed at an in person follow up visit at Week 28, four weeks after the end of treatment.
Interventions
DRUGPlacebo capsules
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* BMI \> 18.5 kg/m2; * Symptomatic pulmonary hypertension WHO/NYHA FC class II and III; * WHO Group I PAH associated with connective tissue disease; * Had a diagnostic right heart catheterization performed and documented within 36 months prior to Day 1 that confirmed a diagnosis of PAH according to all the following criteria: * Mean pulmonary artery pressure ≥ 25 mm Hg (at rest); * Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg; * Pulmonary vascular resistance \> 240 dyn.sec/cm5 or \> 3 mm Hg/liter (L)/minute; * Has BNP level ≤ 400 pg/mL; * Had an average 6MWD ≥ 150 meters on two consecutive tests performed on different days prior to randomization, with both tests measuring within 15% of one another; * Has been receiving no more than two (2) approved disease-specific PAH therapies. PAH therapy must have been at a stable dose for at least 90 days prior to Day 1. No additions or changes should be made to PAH therapies and doses should remain stable for the duration of the study; * Has maintained a stable dose for 30 days prior to Day 1 if receiving any of the following therapies that may affect PAH: vasodilators (including calcium channel blockers), digoxin, L-arginine supplementation, or oxygen supplementation. No additions or changes should be made to therapies and doses should remain stable for the duration of the study; * If receiving treatment for CTD with prednisone or any other drugs, doses must remain stable for at least 30 days prior to Day 1 and for the duration of the study Had pulmonary function tests (PFTs) within 90 days prior to Day 1 with total lung capacity ≥ 65% (predicted); * Had a ventilation-perfusion (V/Q) lung scan, spiral/helical/electron beam computed tomography (CT), or pulmonary angiogram prior to Day 1 that shows no evidence of thromboembolic disease (i.e., should note normal or low probability for pulmonary embolism). If V/Q scan was abnormal (i.e., results other than normal or low probability), then a confirmatory CT or selective pulmonary angiography must exclude chronic thromboembolic pulmonary hypertension; * Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 as measured by the central lab; * Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures; * Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study prior to initiation of any patient-mandated procedures
Exclusion criteria
* Participation in other investigational clinical studies involving interventional products being tested or used in a way different from the approved form or when used for an unapproved indication within 30 days prior to Day 1; * Initiation of an exercise program for cardio-pulmonary rehabilitation within 90 days prior to Day 1 or planned initiation during the study; * Stopped receiving any PAH chronic therapy within 60 days prior to Day 1; * Received a dose of prednisone \> 20 mg/day (or equivalent dose if other corticosteroid) within 30 days prior to Day 1; * Received intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogues within 90 days prior to Day 1; * Received intravenous inotropes within 30 days prior to Day 1; * Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) \> 160 mm Hg or sitting diastolic BP \> 100 mm Hg during Screening after a period of rest; * Has systolic BP \< 90 mm Hg during Screening after a period of rest; * Has a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following: * Congenital or acquired valvular disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension; * Pericardial constriction; * Restrictive or congestive cardiomyopathy; * Left ventricular ejection fraction \< 40% per echocardiogram (ECHO) within 90 days of Day 1; * Symptomatic coronary artery disease within the last 3 years; * Acutely decompensated heart failure within 30 days prior to Day 1, per investigator assessment; * Has more than two of the following clinical risk factors for left ventricular diastolic dysfunction: * Age \> 65 years; * BMI ≥ 30 kg/m2; * History of systemic hypertension; * History of type 2 diabetes; * History of atrial fibrillation; * History of atrial septostomy within 180 days prior to Day 1; * History of uncontrolled obstructive sleep apnea; * Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to severe hepatic impairment (Child-Pugh Class A-C); * Serum aminotransferase (ALT or AST) levels \> 1.5X the upper limit of normal (ULN) at Screening; * Hemoglobin (Hgb) concentration \< 8.5 g/dL at Screening; * Diagnosis of Down syndrome; * History of malignancy within 5 years prior to screening, with the exception of localized skin or cervical carcinomas; * Untreated or uncontrolled active bacterial, fungal, or viral infection; * Known or suspected active drug or alcohol abuse, per investigator judgment; * Use of Herbalife supplements within 14 days prior to Day 1; * Major surgery within 30 days prior to Day 1 or planned to occur during the course of the study; * Unwilling to practice acceptable methods of birth control (both males who have partners of childbearing potential and females of childbearing potential) during screening, while taking study drug, and for at least 30 days after the last dose of study drug is ingested; * Use of inhaled nitric oxide within 7 days prior to Screening and Day 1 visits, excluding acute vasodilator testing during diagnostic cardiac catheterization; * Women who are pregnant or breastfeeding; * Any disability or impairment that would prohibit performance of the 6MWT; * Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at risk by trial enrollment; * Patient is, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason; * Known hypersensitivity to any component of the study drug; * Unable to communicate or cooperate with the investigator because of language problems, poor mental development, or impaired cerebral function.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Six-minute-walk Distance (6MWD) Relative to Placebo at Week 24 | Baseline through 24 weeks after participant receives the first dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Persistent Clinical Improvement Event | Baseline through the end of the study | At least one of the following four criteria must have been met: 1. Improvement by at least one WHO functional class coupled with no more than a 15% decrease from baseline in 6MWT 2. Increase from baseline in 6MWT by at least 10% and stability or improvement in the WHO functional class 3. Decrease from baseline in creatine kinase (a surrogate biomarker for muscle injury and inflammation) by at least 10% and no worsening in WHO functional class and no more than a 15% decrease from baseline in 6MWT 4. Improvement in estimated glomerular filtration rate eGFR ≥10% of baseline The persistence of the change in WHO functional class, 6MWT, eGFR, or creatine kinase must be confirmed by a subsequent assessment at least 14 days after the initial assessment, or at the next scheduled assessment. If persistent improvement is confirmed, the date of the event was considered the initial assessment of improved WHO functional class, 6MWT, eGFR, or creatine kinase. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Czechia, Germany, Israel, Japan, Mexico, Netherlands, Philippines, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Capsules Placebo capsules administered orally once a day for 24 weeks with sham titration. | 102 |
| Bardoxolone Methyl Capsules Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient was 5 mg and dose-escalated to 10 mg at Week 4, unless contraindicated clinically. | 100 |
| Total | 202 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Rolled over to EAP study | 6 | 4 |
| Overall Study | Terminated by Sponsor | 8 | 5 |
| Overall Study | Withdrawal by Subject | 5 | 6 |
Baseline characteristics
| Characteristic | Placebo Capsules | Bardoxolone Methyl Capsules | Total |
|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 13.17 | 55 years STANDARD_DEVIATION 13.57 | 55.7 years STANDARD_DEVIATION 13.36 |
| Age, Customized Median Age | 60 years | 57 years | 59 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 32 Participants | 27 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 70 Participants | 73 Participants | 143 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 | 10 Participants | 16 Participants | 26 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 6 Participants | 16 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 | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) White | 78 Participants | 76 Participants | 154 Participants |
| Region of Enrollment Argentina | 14 participants | 12 participants | 26 participants |
| Region of Enrollment Australia | 8 participants | 7 participants | 15 participants |
| Region of Enrollment Belgium | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Brazil | 5 participants | 4 participants | 9 participants |
| Region of Enrollment Canada | 5 participants | 5 participants | 10 participants |
| Region of Enrollment Czechia | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Germany | 1 participants | 5 participants | 6 participants |
| Region of Enrollment Israel | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Japan | 7 participants | 9 participants | 16 participants |
| Region of Enrollment Mexico | 4 participants | 8 participants | 12 participants |
| Region of Enrollment Netherlands | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Philippines | 1 participants | 4 participants | 5 participants |
| Region of Enrollment Spain | 5 participants | 3 participants | 8 participants |
| Region of Enrollment United Kingdom | 1 participants | 2 participants | 3 participants |
| Region of Enrollment United States | 45 participants | 35 participants | 80 participants |
| Sex: Female, Male Female | 91 Participants | 88 Participants | 179 Participants |
| Sex: Female, Male Male | 11 Participants | 12 Participants | 23 Participants |
| Six Minute Walk Distance (6MWD) | 380.4 meters STANDARD_DEVIATION 91.19 | 389.1 meters STANDARD_DEVIATION 107.78 | 384.7 meters STANDARD_DEVIATION 99.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 102 | 0 / 100 |
| other Total, other adverse events | 79 / 102 | 85 / 100 |
| serious Total, serious adverse events | 18 / 102 | 16 / 100 |
Outcome results
Primary
Change From Baseline in Six-minute-walk Distance (6MWD) Relative to Placebo at Week 24
Time frame: Baseline through 24 weeks after participant receives the first dose
Population: ITT population (all randomized patients categorized by their assigned treatment group regardless of treatment exposure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Capsules | Change From Baseline in Six-minute-walk Distance (6MWD) Relative to Placebo at Week 24 | 9.25 meters | Standard Error 4.954 |
| Bardoxolone Methyl Capsules | Change From Baseline in Six-minute-walk Distance (6MWD) Relative to Placebo at Week 24 | -3.61 meters | Standard Error 4.952 |
p-value: 0.068395% CI: [-26.69, 0.98]Mixed Models Analysis
Secondary
Time to First Persistent Clinical Improvement Event
At least one of the following four criteria must have been met: 1. Improvement by at least one WHO functional class coupled with no more than a 15% decrease from baseline in 6MWT 2. Increase from baseline in 6MWT by at least 10% and stability or improvement in the WHO functional class 3. Decrease from baseline in creatine kinase (a surrogate biomarker for muscle injury and inflammation) by at least 10% and no worsening in WHO functional class and no more than a 15% decrease from baseline in 6MWT 4. Improvement in estimated glomerular filtration rate eGFR ≥10% of baseline The persistence of the change in WHO functional class, 6MWT, eGFR, or creatine kinase must be confirmed by a subsequent assessment at least 14 days after the initial assessment, or at the next scheduled assessment. If persistent improvement is confirmed, the date of the event was considered the initial assessment of improved WHO functional class, 6MWT, eGFR, or creatine kinase.
Time frame: Baseline through the end of the study
Population: ITT population (all randomized patients categorized by their assigned treatment group regardless of treatment exposure)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Capsules | Time to First Persistent Clinical Improvement Event | 17.9 weeks | Standard Error 1.263 |
| Bardoxolone Methyl Capsules | Time to First Persistent Clinical Improvement Event | 6.62 weeks | Standard Error 0.646 |
p-value: 0.000495% CI: [1.36, 2.895]Chi-squared