AIR001-CS05 A PHASE 2, MULTI-CENTER, OPEN-LABEL, RANDOMIZED, PARALLEL-DOSE STUDY TO DETERMINE THE SAFETY AND EFFICACY OF AIR001 IN SUBJECTS WITH WHO GROUP 1 PULMONARY ARTERIAL HYPERTENSION
This protocol describes a Phase 2, multi-center, open-label, randomized (1:1:1), parallel-dose study to determine the safety and efficacy of inhaled nebulized AIR001 in subjects with WHO Group 1 PAH. A screening evaluation will be conducted over a period of 30 days prior to Baseline/Day 1 to confirm the PAH diagnosis, assess the disease state, and determine the eligibility of each potential subject. Following the screening period, subjects approved for randomization will have onsite clinic assessments performed at Baseline/Day 1 and Weeks 2, 4, 8, 12, and 16 (End of Study (EOS)) visit. The length of the treatment phase for all randomized subjects will be 16 weeks, unless the subject is terminated from the study. Subjects will be randomized to 1 of 3 dosing groups: 80 milligrams (mg) 4 times daily, 46 mg 4 times daily, or 80 mg once daily which they will receive during the Targeted-Dose Period. The Targeted-Dose Period will be preceded by a 2-week Run-In Period in which all subjects receive 46 mg of nebulized AIR001 utilizing the same dosing schedule (either once or 4 times daily) as in the Targeted-Dose Period.
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study prior to initiation of any subject-mandated procedures.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Has a current diagnosis of symptomatic PAH classified by one of the following:
a. Idiopathic (IPAH) or heritable pulmonary arterial hypertension (HPAH); or
b. PAH associated with one of the following CTD:
i. Systemic sclerosis (scleroderma);
ii. Limited scleroderma;
iii. Mixed connective tissue disease;
iv. Systemic lupus erythematosus;
v. Overlap syndrome.
c. PAH associated with:
i. HIV infection;
ii. Simple, congenital systemic-to-pulmonary shunts at least one year post surgical repair.
iii. Exposure to legal drugs, chemicals and toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil or L-tryptophan. Subjects with PAH associated with illegal drug use, such as methamphetamine, are excluded.
4. Has a cardiac catheterization prior to Screening that is consistent with the diagnosis of PAH meeting all of the following criteria:
a. mPAP >= 25 mmHg (at rest);
b. PCWP <= 15 mmHg
o If PCWP is not available, then mean left atrial pressure (mLAP) or left ventricular-end diastolic pressure (LVEDP) <= 15 mmHg in the absence of left atrial obstruction;
c. PVR > 3 mmHg/Liter (L)/minute (min) or 240 dyn.sec/cm5.
5. A qualification cardiac catheterization is required, to confirm the persistence and severity of PAH, if the diagnostic catheterization was performed more than 1 month (30 days) prior to Baseline/Day 1 (see criteria in Inclusion Criteria #4). This catheterization will serve to provide Baseline hemodynamic values for further efficacy analysis. A cardiac catheterization performed within 1 month (30 days) prior to Baseline/Day 1, per the subject standard medical care (not for the purposes of this study) can be used in lieu of repeating the test, if all the following criteria are met:
a. Confirms diagnosis as per the required data points (PVR, CO, CI, mPAP, mRAP, PCWP, SVR, and SvO2);
b. The subject has a PVR above 300 dyn.sec/cm5 on the catheterization used to qualify the subject for the study (to demonstrate the persistence and severity of PAH)
c. No change in disease-specific PAH therapy has occurred since the catheterization used to qualify the subject for the study.
6. Newly diagnosed PAH on no disease-specific PAH therapy or previously diagnosed with PAH on stable (i.e. 3 months (90 days) prior to the Baseline qualification cardiac catheterization) oral disease-specific PAH therapy with either an ETRA and/or PDE-5i at stable doses. Every attempt should be made to maintain the dose of these agents throughout the study. The use of PDE-5i as needed for erectile dysfunction (ED) is permitted as long as the subject has not taken a dose within 48-hours of any Baseline or study related efficacy assessment. In addition, the subject must not take more than 8 sildenafil tablets, 6 vardenafil, or 4 tadalafil tablets per month for ED.
7. Has PFTs within 6 months (180 days) prior to Baseline/Day 1 with no evidence of significant parenchymal lung disease. Parenchymal lung disease is defined as:
* Forced expiratory volume in 1 second (FEV1 ) <= 70% (predicted) (pre-bronchodilators);
* Forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC) <= 70% (pre-bronchodilators); or
* Total lung capacity (TLC) < 70% (predicted).
8. Has WHO/NYHA functional class II- IV symptomatology.
9. Male or female >=18 and <= 75 years of age at Screening.
10. Has a body weight >= 40 kg at Screening.
11. Has a 6MWT distance >= 50 meters at Screening. If the distance walked is not within the required range, the test may be repeated 1 time. The distance walked during the 2nd assessment must be in the required range, with the test conducted on a separate day, and must be within 15% of the first distance walked.
12. Had a ventilation-perfusion (V/Q) lung scan or pulmonary angiogram prior to Screening that shows no evidence of thromboembolic disease (i.e. should note
* low probability
* for pulmonary embolism). V/Q scanning is preferred, but if unavailable, spiral/helical/electron beam computed tomography (CT) angiography is acceptable in subjects with NO history of venous thromboembolic disease. If V/Q scan is unavailable and subject has a prior history of venous thromboembolic disease, then selective pulmonary angiography is required to exclude chronic thromboembolic disease. If a V/Q scan is abnormal (i.e. anything other than
* low probability
* ), then a selective pulmonary angiography must be conducted to exclude chronic thromboembolic disease. All required tests must be performed prior to Screening or such tests may be requested if clinically indicated to exclude chronic thromboembolic pulmonary hypertension.
13. If on the following therapies, which may affect PAH: vasodilators (including calcium channel blockers), digoxin, spironolactone, or L-Arginine supplementation; the subject must be on a stable dose for at least 1 month (30 days) prior to Baseline/Day 1 and the dosage maintained throughout the study.
14. If on corticosteroids, has been receiving a stable dose of <= 20 mg/day of prednisone (or equivalent dose, if other corticosteroid) for at least 1 month (30 days) prior to study Baseline/Day 1. If receiving treatment for CTD with any other drugs, doses should remain stable for the duration of the study.
15. Women of childbearing potential must be using at least one form of medically acceptable contraception (i.e. either oral, topical, implanted hormonal contraceptives, or an intrauterine device) or two barrier methods; have a negative pregnancy test at Screening and Baseline/Day 1 and agree to use reliable methods of contraception until at least 24-hours after the last dose of study drug. Women who are surgically sterile (i.e. hysterectomy, bilateral oophorectomy, or tubal ligation) or those who are post-menopausal for at least 2 years are not considered to be of childbearing potential. Men who are not sterile (i.e. have not had a vasectomy) must also agree to use contraception until at least 24-hours after last dose of study drug.