Pulmonary Arterial Hypertension
Conditions
Keywords
Cardiopulmonary Exercise Test, 6MWT
Brief summary
The objectives of this study are to evaluate the safety of RT234 and the effects of RT234 on exercise capacity as assessed by Cardiopulmonary Exercise Testing (CPET) and six minute walk testing (6MWT) as well as exertional symptoms in patients with pulmonary arterial hypertension (PAH).
Detailed description
PAH results in significant limitations in cardiorespiratory fitness (CRF), exercise capacity, and profound dyspnea with physical exertion. The objective of this study is to assess the ability of a single inhaled dose of RT234 to acutely improve primary CPET measures of CRF and exercise capacity, and to decrease the experience of lower the sensation of dyspnea with physical exertion compared to baseline CPET measures.
Interventions
COMBINATION_PRODUCTDrug: RT234 - vardenafil inhalation powder; Device: Axially Oscillating Sphere dry powder inhaler (AOS DPI)
RT234 capsules of a dry powder formulation containing vardenafil administered via oral inhalation with a non-invasive AOS DPI.
Sponsors
Respira Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Must be between 18 and 80 years of age, inclusive. 2. Must be willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to undergoing any research-related procedures. 3. Must be willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures. 4. Able to exercise during CPET and ambulate independently. 5. Diagnosis documented and confirmed by Right Heart Catheterization (RHC)-confirmed WHO Group 1 PAH in any of the following 3 categories: 1. Idiopathic, primary, or familial pulmonary arterial hypertension (IPAH, PPH, or FPAH) OR 2. PAH associated with one of the following connective tissue diseases: i) Systemic sclerosis (scleroderma) ii) Limited scleroderma iii) Mixed connective tissue disease iv) Systemic lupus erythematosus v) Overlap syndrome vi) Other autoimmune disorders OR c) PAH associated with: i) Human immunodeficiency virus (HIV) infection. ii) Simple, congenital systemic-to-pulmonary shunts at least 1-year post-surgical repair. iii) Exposure to drugs, chemicals, and toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil, or L-tryptophan. 6. Subjects with a diagnosis of HIV must have stable disease, defined by: 1. Unchanged medication treatment regimen for HIV for at least 8 weeks prior to beginning Visit 1 Screen assessments. 2. No active opportunistic infection during the Screening Period. 3. No hospitalizations for HIV for at least 4 weeks prior to beginning Visit 1 Screen assessments. 7. The patient must have adequate, documented test results that exclude chronic thromboembolic pulmonary hypertension (CTEPH). 8. Previous diagnosis of PAH, but with the following conditions: 1. Stable PAH without significant adjustments of disease-specific background PAH therapy, at least 3 months prior to the Baseline CPET procedure. Stable is defined as no change in PAH -specific drug therapy within 3 months of Screening Visit 1, and for the duration of the study, and no change in dose of PAH-specific drug(s) within 1 month of Screening. AND 2. If on corticosteroids, has been receiving a stable dose of ≤ 20 mg/day of prednisone (or equivalent dose of other corticosteroid) for at least 30 days prior to the Baseline CPET. 9. PFT within 6 months prior to signing the Informed Consent Form that fulfills the following criteria: 1. FEV1 ≥ 60% predicted (pre-bronchodilators). 2. FEV1 / FVC ≥ 60% (pre-bronchodilators). 3. FVC ≥ 60% predicted. 10. Has had RHC performed and documented prior to Screening that meets the following hemodynamic criteria: 1. mPAP ≥ 20 mmHg. 2. PVR ≥ 300 dyn·s/cm5. 3. PCWP or LVEDP of ≤ 12 mmHg if PVR ≥ 300 to \< 500 dyn∙s/cm5, or PCWP or LVEDP ≤ 15 mmHg if PVR ≥ 500 dyn∙s/cm5. 11. Has WHO/New York Heart Association (WHO/NYHA) functional class II-IV symptomatology. 12. On stable oral PAH disease-specific background therapy of oral or inhaled therapies (any combination of an endothelin receptor antagonist, phosphodiesterase type 5 inhibitor, and/or a prostacyclin or prostacyclin receptor agonist). Stable is defined as no change in PAH-specific drug therapy within 3 months of Screening Visit 1, and for the duration of the study, and no change in dose of PAH-specific drug(s) within 1 month of Screening. Parenteral prostacyclin subjects will be limited to up to 20% of a particular cohort with approval of Sponsor Medical Monitor. Sotatercept subjects should have been on sotatercept for a minimum of 6 months at the time of screening. Sotatercept subjects will be limited to 20% of a particular cohort with approval of the Sponsor Medical Monitor. 13. Must be able to walk a distance of ≥ 150 meters in the Baseline 6MWTs. This will be determined using the mean of the two 6MWT results done during Screening. If tolerable by the subject, the 2 Baseline 6MWTs will be conducted at Visit 1 with a minimum of 2 hours of rest between the first and second tests. 14. Has a VE/VCO2 slope ≥ 36 during the Baseline CPET as assessed by the study CPET Core Laboratory. 15. Evidence of good effort on the Baseline CPET reaching a peak RER \> 1.0 as assessed by the study CPET Core Laboratory. 16. Peak VO2 ≤ 20 ml/min/kg during the Baseline CPET as assessed by the study CPET Core Laboratory. 17. If the subject is taking the following concomitant medications which may affect PAH, the subject must be on a stable therapeutic dose for at least 1 month prior to the start of Screening and the dosage maintained throughout the study. 1. Vasodilators (including calcium channel blockers - specify the indication e.g., PAH, hypertension, Raynaud's disease), digoxin, or L-arginine supplement. 2. If the subject is taking a vitamin K antagonist anticoagulant, then anticoagulation status should be maintained/stable in the therapeutic range for at least 1 month before the start of Screening. 18. Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study through the 30-day post-treatment safety follow-up telephone call. Acceptable methods of contraception include hormonal birth control (oral, intravaginal, transdermal, implantable, or intrauterine device/system \[IUD/IUS\]), IUDs (non-hormonal), vasectomy (in male partner), or any double-barrier methods (combination of male condom and spermicide with either cap, diaphragm, or sponge). 19. Female subjects of childbearing potential must have a negative pregnancy test (urine or serum) at Screening and must agree to additional urine pregnancy tests prior to each dose of study medication while participating in the study. 20. Female subjects considered not of childbearing potential include those who are post-menopausal (defined as cessation of regular menstrual periods for at least 1 year) or have documented evidence of surgical sterilization at least 6 months prior to Screening. 21. No evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinically, by polymerase chain reaction (PCR) test, or antigen test as required by local site infection control policies at the Screening Visit. Subjects with previous coronavirus disease 2019 (COVID-19) infection must have returned to functional baseline prior to entering Screening for this study.
Exclusion criteria
Individuals who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Peak Oxygen Uptake at Peak Exercise During CPET (Peak VO2) | Comparison of measure between baseline and treatment CPETs, typically ~14 days apart | The primary efficacy endpoint was the change from Baseline in peak V̇ O2 measured during CPET after RT234 dosing. |
| Median Change in Peak Oxygen Uptake at Peak Exercise During CPET (Peak VO2) | Comparison of measure between baseline and treatment CPETs, typically ~14 days apart | The primary efficacy endpoint was the change from Baseline in peak V̇ O2 measured during CPET after RT234 dosing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Ventilatory Efficiency up to Peak Exercise During CPET | Comparison of measure between baseline and treatment CPETs, typically ~14 days apart | Change from Baseline to postdose in the V̇E/V̇CO2 slope, a recognized measure of ventilatory efficiency, measured up to peak during CPET. VE/VCO2 tracks the ratio between total air breathed in per minute (VE) and the amount of carbon dioxide exhaled (VCO2) during a cardiopulmonary exercise test (CPET). A reduction in the ratio is favorable, as it indicates that less breathed air is required to clear out the same amount of CO2. |
| Median Change in Ventilatory Efficiency up to Peak Exercise During CPET | Comparison of measure between baseline and treatment CPETs, typically ~14 days apart | Change from Baseline to postdose in the V̇E/V̇CO2 slope, a recognized measure of ventilatory efficiency, measured up to peak during CPET. VE/VCO2 tracks the ratio between total air breathed in per minute (VE) and the amount of carbon dioxide exhaled (VCO2) during a cardiopulmonary exercise test (CPET). A reduction in the ratio is favorable, as it indicates that less breathed air is required to clear out the same amount of CO2. |
| Change in Perceived Dyspnea at Peak Exercise During CPET | Comparison of measure between baseline and treatment CPETs, typically ~14 days apart | Self-reported by subjects. Change in perceived dyspnea at peak exercise during CPET as assessed by the Modified Borg Dyspnea Scale Score. (Minimum score: 0 representing no dyspnea; maximum score: 10 representing maximal dyspnea; a reduction in score represents a favorable outcome.) |
| Change in Perceived Exertion at Peak Exercise During CPET | Comparison of measure between baseline and treatment CPETs, typically ~14 days apart | Self-reported by subjects. Change in perceived exertion at peak exercise during CPET as assessed by the Borg Rating of Perceived Exertion (RPE) Scale score, which rates exertion from a scale of 6 (no exertion) to 20 (maximum effort). A decrease in score is favorable. |
| Change in Partial Pressure of End-tidal CO2 (PETCO2) | Comparison of measure between baseline and treatment CPETs, typically ~14 days apart | Change in partial pressure of end-tidal CO2 (PETCO2) apex response to exercise, i.e., highest level during CPET |
| Change in Ramp-incremental Duration of CPET | Comparison of measure between baseline and treatment CPETs, typically ~14 days apart | — |
| Change in 6-minute Walk Distance (6MWD) | Baseline 6MWD at baseline (during screening visit) and 6MWD measured ~ 30 minutes following RT234 dosing at visit 4, which typically occurred 4-6 weeks following the screening visit | Change from 6MWD at baseline (during screening visit) to 6MWD following RT234 dosing |
Countries
United States
Contacts
STUDY_DIRECTOREd Parsley, DO
Respira Therapeutics
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 9.83 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Peak VO2 relative to actual weight | 14.61 mL/min/kg STANDARD_DEVIATION 4.002 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 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 | 31 Participants |
| Region of Enrollment Serbia | 0 participants |
| Region of Enrollment United States | 37 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 21 | 0 / 14 | 0 / 42 |
| other Total, other adverse events | 1 / 7 | 11 / 21 | 5 / 14 | 17 / 42 |
| serious Total, serious adverse events | 0 / 7 | 0 / 21 | 0 / 14 | 0 / 42 |
Outcome results
None listed