Safety and Efficacy of Inhaled Treprostinil in Adult PH With ILD Including CPFE

This is a multicenter, randomized (1:1 inhaled treprostinil: placebo), double-blinded,
placebo-controlled trial to evaluate the safety and efficacy of inhaled treprostinil in
subjects with pre-capillary pulmonary hypertension (PH) associated with interstitial lung
disease (ILD) including combined pulmonary fibrosis and emphysema (CPFE). The study will
include about 314 patients at approximately 100 clinical trial centers. The treatment phase
of the study will last approximately 16 weeks. Patients who complete all required
assessments will also be eligible to enter an open-label, extension study (RIN-PH-202).

Eligibility Criteria

Inclusion Criteria:

1. Subject voluntarily gives informed consent to participate in the study.

2. Males and females aged 18 - 79 years at the time of informed consent.

a. Females of reproductive potential must be non-pregnant (as confirmed by a urine
pregnancy test at screening) and non-lactating, and will: i. Either abstain from
intercourse (when it is in line with their preferred and usual lifestyle), or ii. Use
two medically acceptable, highly-effective forms of contraception for the duration of
study, and at least 30 days after discontinuing study drug.

b. Males must use a condom for the duration of treatment and for at least 48 hours
after discontinuing study drug.

3. The subject has a confirmed diagnosis (based on computed tomography [CT] imaging and
pulmonary function tests [PFTs] performed within six months prior to randomization)
of World Health Organization (WHO) Group 3 PH associated with one of the following:

a. Idiopathic interstitial pneumonia (IIP) including: i. Idiopathic pulmonary
fibrosis (IPF) ii. Idiopathic nonspecific interstitial pneumonia iii. Respiratory
bronchiolitis-associated interstitial lung disease (RB-ILD) iv. Desquamative
interstitial pneumonia (DIP) v. Cryptogenic organizing pneumonia (COP) vi. Acute
interstitial pneumonitis (AIP) vii. Idiopathic lymphoid interstitial pneumonia viii.
Idiopathic pleuroparenchymal fibroelastosis iix. Unclassifiable idiopathic
interstitial pneumonia b. Chronic hypersensitivity pneumonitis (CHP) c. Occupational
or environmental lung disease (drug or radiation-induced) d. Combined pulmonary
fibrosis and emphysema (CPFE)

4. Subjects are required to have a right heart catheterization (RHC) within one year
prior to randomization with the following documented parameters:

1. Pulmonary vascular resistance (PVR) ≥ 4 Wood Units (WU) and

2. A left ventricular end diastolic pressure (LVEDP) or pulmonary capillary wedge
pressure (PCWP) of ≤ 12 mmHg if PVR ≥ 4 WU to < 6.25 WU or ≤ 15 mmHg if PVR ≥
6.25 WU and

3. A mean pulmonary arterial pressure (mPAP) of ≥ 30 mmHg

5. A baseline diffusing capacity of the lungs for carbon monoxide (DLCO) of < 50%

6. Baseline 6MWD ≥ 100 meters

7. The subject has not received any PAH approved therapy including: prostacyclin therapy
(i.e., epoprostenol, treprostinil, iloprost, or beraprost; except for acute
vasoreactivity testing), IP receptor agonist (selexipag), endothelin receptor
antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE-5I), or soluble guanylate
cyclase stimulator (sGC) within 60 days of randomization.

8. Subjects on a chronic medication for underlying lung disease must be on a stable and
optimized dose for ≥ 30 days prior to randomization. Subjects receiving pirfenidone
or nintedanib must have been receiving treatment for at least 90 days and on a stable
dose for at least 30 days prior to randomization.

9. Subjects on a supportive medication therapy (e.g., anticoagulants, diuretics, oxygen,
etc.) must be on a stable and optimized dose for ≥ 30 days prior to randomization.
Exceptions are the discontinuation or dose changes of anticoagulants and / or dose
change of diuretics.

10. In the opinion of the Investigator, the subject is able to communicate effectively
with study personnel, and is considered reliable, willing and likely to be
cooperative with protocol requirements, including attending all study visits.

Exclusion criteria:

1. The subject has a diagnosis of pulmonary arterial hypertension (PAH) or PH for
reasons other than ILD as outlined in inclusion criterion 3. This would include, but
is not limited to, the concomitant presence of thromboembolic disease (acute or
chronic), untreated or inadequately treated obstructive sleep apnea (OSA), connective
tissue disease (including but not limited to systemic sclerosis, scleroderma, or
systemic lupus erythematosus [SLE]), sarcoidosis, human immunodeficiency virus
(HIV)-1 infection, portopulmonary hypertension, and other conditions of the WHO Group
I, II, IV, and V classification.

2. The subject has shown intolerance or significant lack of efficacy to a prostacyclin
or prostacyclin analogue that resulted in discontinuation or inability to effectively
titrate that therapy.

3. The subject has received any PAH approved therapy including: prostacyclin therapy
(i.e., epoprostenol, treprostinil, iloprost, or beraprost; except for acute
vasoreactivity testing), IP receptor agonist (selexipag), ERA, PDE-5I, or sGC within
60 days of randomization.

4. The subject has evidence of clinically significant left-sided heart disease as
defined by:

1. LVEDP or PCWP > 15 mmHg (or > 12 mmHg if PVR ≥ 4 to < 6.25 WU)

2. Left ventricular ejection fraction < 40% as assessed by either multigated
angiogram (MUGA), angiography or echocardiography.

Note: Subjects with abnormal left ventricular function attributable entirely to
impaired left ventricular filling due to the effects of right ventricular overload
(i.e., right ventricular hypertrophy and/or dilatation) will not be excluded.

5. Subjects must not have three or more of the following left ventricular
disease/dysfunction risk factors:

1. Body Mass Index (BMI) ≥ 30 kg/m2

2. History of Essential Hypertension

3. Diabetes Mellitus - any type

4. Historical evidence of significant coronary disease established by any one of
the following:

i. history of myocardial infarction or percutaneous coronary intervention or
angiographic, or ii. evidence of coronary artery disease (> 50% stenosis in at least
one coronary artery), or iii. positive stress test with imaging, or previous coronary
artery bypass graft, or stable angina

6. The subject is receiving > 10 L/min of oxygen supplementation by any mode of delivery
at rest at Baseline.

7. Use of any inhaled tobacco/marijuana products or significant history of drug abuse
within six months prior to randomization.

8. Exacerbation of underlying lung disease or active pulmonary or upper respiratory
infection within 30 days of randomization.

9. Initiation of pulmonary rehabilitation within 12 weeks prior to the randomization.

10. The subject has uncontrolled systemic hypertension as evidenced by systolic blood
pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.

11. The subject has any form of congenital heart disease or congenital heart defect
(repaired or unrepaired) other than a patent foramen ovale (PFO).

12. The subject has anemia as defined by a screening hemoglobin value < 9.0 g/dL, active
infection, or any other condition that would interfere with the interpretation of
study assessments.

13. The subject has a Body Mass Index ≥ 40 kg/m2.

14. The subject has any musculoskeletal disorder (i.e., arthritis affecting the lower
limbs, recent hip or knee joint replacement, artificial leg), is using a device to
assist walking (i.e., cane or walker), or has any other condition that would limit
ambulation.

15. Use of any investigational drug/device, or participation in any investigational study
within 30 days prior to randomization.

Principal Investigator

Leslie Spikes, MD

Study Contact

Mia Zou, mzou@kumc.edu, 913-588-7117

Estimated Completion Date

Monday, October 1, 2018

ClinicalTrials.gov #

NCT02630316
01/12/2017