Pulmonary Arterial Hypertension
Conditions
Brief summary
The main objective of this study is to evaluate the safety and tolerability of 12-week oral CXA-10 therapy in subjects with pulmonary arterial hypertension, with additional evaluation on the clinical efficacy of oral CXA-10 on changes in hemodynamics, exercise capacity, cardiovascular function and patient reported outcomes.
Detailed description
This is a single-center, one-arm, open-label proof of concept safety study and a phase 2a proof of efficacy pre- and post-assessment study of oral CXA-10 for the treatment of pulmonary arterial hypertension. The investigators hypothesize that administration of CXA-10 for 12 weeks will improves exercise capacity, cardiovascular function and health related quality of life in pulmonary arterial hypertension patients with limited toxicity. Subjects who meet the inclusion criteria and none of the exclusion criteria will be scheduled within 4 weeks of screening to receive oral CXA-10 at the dose of 300 mg once daily followed by 12 weeks of open-label CXA-10 treatment and then a 4-week safety follow-up. Additional follow-up assessments by telephone will occur in between each outpatient clinic visit.
Interventions
DRUGCXA-10
Each subject will receive oral CXA-10 at the dose of 300 mg once daily for 12 weeks
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Complexa, Inc.
Gladwin, Mark, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
One-arm, open-label
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
The following criteria will be required on ALL subjects: * Male or female between 18-80 years of age inclusive at Screening * Weight ≥ 40 kg or 88 lbs * Have a WHO Classification of Functional Status Class II or III * Must meet all of the following hemodynamic criteria by means of a right heart catheterization: mPAP of ≥ 25 mmHg, PVR ≥ 3 wood units, PAWP of ≤ 15 mmHg. A clinical RHC done within 2 months is acceptable to determine eligibility * Meet all of the following pulmonary function test parameters, completed no more than 12 months before Screening or at screening: forced expiratory volume in one second (FEV1) \> 60% of predicted normal and forced vital capacity (FVC) ≥ 60% * A 6 MWD test of ≥ 100 m and ≤ 600 m at Screening * Participants enrolled in an exercise program for pulmonary rehabilitation must be in a stable program 1 month prior to Screening and must agree to maintain their current level of rehabilitation throughout the study. If subjects are not enrolled in an exercise training program for pulmonary rehabilitation they cannot enroll during the Screening/Baseline Period or throughout the study * If receiving 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) subjects must not have changed their dose \< 4 weeks prior to Screening * If receiving simvastatin-containing products: simvastatin (Zocor), Vytorin, or any other combination therapy containing simvastatin, the subject's simvastatin dose should not exceed 20 mg/day Note: Subjects using a simvastatin product at dose \> 20 mg/day may be rescreened if their dose has been adjusted to ≤ 20 mg/day, at least 4 weeks prior to Screening with no dose or regimen changes within 4 weeks prior to Baseline * Subjects must be receiving one or more of the following previously approved PAH therapies: phosphodiesterase type 5 inhibitors (PDE5), endothelin receptor antagonist (ERA), soluble guanylate cyclase (sGC) stimulator, prostanoids, prostacyclin receptor agonists and must be on stable doses ≥ 3 months) with no dose adjustment within 1 month of Screening * Ability to provide written informed consent
Exclusion criteria
Subjects meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-Related Adverse Events as Assessed by CTCAE v4.0 in 12 Weeks | Baseline to 12 Weeks | Numbers of treatment-related adverse events is assessed by CTCAE v4.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Pulmonary Artery Pressure is Measured at Baseline and 12 Weeks by Right Heart Catheterization | Baseline and 12 Weeks | Pulmonary Artery mean pressure will be measured by right heart catheterization |
| Change From Baseline in RV Function as Measured by Tricuspid Annular Plane Systolic Excursion (TAPSE) as Assessed by Echocardiograms at 12 Weeks | at baseline and 12 weeks | Change from baseline in RV function as measured by tricuspid annular plane systolic excursion (TAPSE) as assessed by echocardiograms at 12 weeks |
| Changes From Baseline in Functional Exercise Capacity by Assessing 6 Minute Walk Distance Test | at baseline and 12 weeks | Change from baseline in 6 minute walk distance at 12 weeks |
| Change From Baseline in Pulmonary Vascular Resistance is Measured at Baseline and 12 Weeks by Right Heart Catheterization | Baseline and 12 Weeks | Pulmonary vascular resistance (PVR) will be measured by right heart catheterization; results reported as changed from baseline in Woods units. PVR is calculated as (mean pulmonary artery pressure - pulmonary artery wedge pressure)/cardiac output, where pressures are in units of mm Hg and cardiac output is in units of L/min. Pulmonary hypertension is defined as PVR \> 3 Woods units. A negative change implies a decrease in PVR which would be considered an improvement. |
| Change From Baseline in Functional Status of Patients as Assessed by New York Heart Association Functional Class | at Baseline and 12 Weeks | The New York Heart Association Classification of Functional Status of Patients with pulmonary hypertension will be used to classify disease severity in PAH. It places patients in one of four categories based on how much they are limited during physical activity. Measure Description: Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). Class II: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class III: Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort. Symptoms of dyspnea at rest. If any physical activity is undertaken, discomfort increases. |
| Change From Baseline in Daily Physical Activity as Measured by a Accelerometer | Baseline and 12 Weeks | Continuous physical activity monitoring will be conducted using a noninvasive accelerometer. The device must be worn for a minimum of 7 days at home prior to receiving the first dose of the study drug and prior to the end of the study drug treatment at week 12. |
| Change From Baseline in Levels of Serum N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at 12 Weeks | at Baseline and 12 Weeks | Blood samples will be collected for NT-proBNP analysis |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CXA-10 Oral CXA-10 300 mg once daily for 12 weeks
CXA-10: Each subject will receive oral CXA-10 at the dose of 300 mg once daily for 12 weeks | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | CXA-10 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
Number of Treatment-Related Adverse Events as Assessed by CTCAE v4.0 in 12 Weeks
Numbers of treatment-related adverse events is assessed by CTCAE v4.0
Time frame: Baseline to 12 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-10 | Number of Treatment-Related Adverse Events as Assessed by CTCAE v4.0 in 12 Weeks | 2 Events |
Secondary
Change From Baseline in Daily Physical Activity as Measured by a Accelerometer
Continuous physical activity monitoring will be conducted using a noninvasive accelerometer. The device must be worn for a minimum of 7 days at home prior to receiving the first dose of the study drug and prior to the end of the study drug treatment at week 12.
Time frame: Baseline and 12 Weeks
Population: Drug and funding withdrawn prior to analysis; data were not collected
Secondary
Change From Baseline in Functional Status of Patients as Assessed by New York Heart Association Functional Class
The New York Heart Association Classification of Functional Status of Patients with pulmonary hypertension will be used to classify disease severity in PAH. It places patients in one of four categories based on how much they are limited during physical activity. Measure Description: Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). Class II: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class III: Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort. Symptoms of dyspnea at rest. If any physical activity is undertaken, discomfort increases.
Time frame: at Baseline and 12 Weeks
Population: Drug and funding withdrawn prior to analysis; data were not collected
Secondary
Change From Baseline in Levels of Serum N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at 12 Weeks
Blood samples will be collected for NT-proBNP analysis
Time frame: at Baseline and 12 Weeks
Population: Drug and funding withdrawn; data were not collected
Secondary
Change From Baseline in Mean Pulmonary Artery Pressure is Measured at Baseline and 12 Weeks by Right Heart Catheterization
Pulmonary Artery mean pressure will be measured by right heart catheterization
Time frame: Baseline and 12 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-10 | Change From Baseline in Mean Pulmonary Artery Pressure is Measured at Baseline and 12 Weeks by Right Heart Catheterization | -5 mm Hg |
Secondary
Change From Baseline in Pulmonary Vascular Resistance is Measured at Baseline and 12 Weeks by Right Heart Catheterization
Pulmonary vascular resistance (PVR) will be measured by right heart catheterization; results reported as changed from baseline in Woods units. PVR is calculated as (mean pulmonary artery pressure - pulmonary artery wedge pressure)/cardiac output, where pressures are in units of mm Hg and cardiac output is in units of L/min. Pulmonary hypertension is defined as PVR \> 3 Woods units. A negative change implies a decrease in PVR which would be considered an improvement.
Time frame: Baseline and 12 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-10 | Change From Baseline in Pulmonary Vascular Resistance is Measured at Baseline and 12 Weeks by Right Heart Catheterization | -1.2 Woods units |
Secondary
Change From Baseline in RV Function as Measured by Tricuspid Annular Plane Systolic Excursion (TAPSE) as Assessed by Echocardiograms at 12 Weeks
Change from baseline in RV function as measured by tricuspid annular plane systolic excursion (TAPSE) as assessed by echocardiograms at 12 weeks
Time frame: at baseline and 12 weeks
Population: Drug and funding withdrawn prior to analysis; data were not collected.
Secondary
Changes From Baseline in Functional Exercise Capacity by Assessing 6 Minute Walk Distance Test
Change from baseline in 6 minute walk distance at 12 weeks
Time frame: at baseline and 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-10 | Changes From Baseline in Functional Exercise Capacity by Assessing 6 Minute Walk Distance Test | 23.5 meters |