STUDY OVERVIEW

INCREASE was designed to assess the efficacy and safety of TYVASO® in patients with PH-ILD1

The INCREASE trial was a 16-week phase 3, multicenter, randomized, double-blind, placebo-controlled study of 326 patients1-3

INCREASE study 6MWD primary endpointINCREASE study 6MWD primary endpoint

The starting dose was 3 breaths, 4x daily (during waking hours). Dose escalations (1 breath, 4x daily) could occur up to every 3 days, with a target maintenance dose of 9 breaths, 4x daily and a maximum of 12 breaths, as clinically tolerated.1,2

TYVASO was evaluated across multiple clinical endpoints

Primary Endpoint2

Change in 6MWD measured at peak exposure from baseline to week 16 (between 10 and 60 minutes after most recent dose)

Secondary Endpoints1,4

Change in NT-proBNP from baseline to week 16

Time to first clinical worsening event—from time of randomization until study discontinuation (1 of the following criteria met):

  • Hospitalization due to a cardiopulmonary indication
  • Decrease in 6MWD >15% from baseline directly related to disease under study at 2 consecutive visits and ≥24 hours apart
  • Death (all causes)
  • Lung transplantation

Change in peak 6MWD at week 12

Change in trough 6MWD at week 15

  • ≥4 hours after the most recent study drug dose and ≥24 hours prior to week 16 6MWD

Select Safety Endpoints4*

AEs

Oxygenation:

  • Pulse oximetry (SpO2)
  • Supplemental oxygen requirement (L/min)

PFTs:

  • Forced vital capacity (FVC)
  • Forced expiratory volume in 1 second (FEV1)
  • Total lung capacity (TLC)
  • Lung diffusion capacity (DLCO)

Exacerbations of underlying lung disease

Based on a concern that treating WHO Group 3 pulmonary hypertension with pulmonary vasodilators could worsen V/Q matching in patients, PFTs (including FVC) and exacerbations were included as safety endpoints due to the potential risk of V/Q mismatch.5

Key Inclusion Criteria4

Patients aged ≥18 were eligible to enroll if they had:

A confirmed diagnosis of WHO Group 3 PH based on CT imaging within 6 months prior to randomization and demonstrated evidence of any form of ILD or CPFE

Right heart catheterization within 1 year prior to randomization, with the following documented parameters:

  • Pulmonary vascular resistance (PVR) >3 WU
  • Pulmonary capillary wedge pressure (PCWP) of ≤15 mm Hg
  • Mean pulmonary arterial pressure (mPAP) of ≥25 mm Hg 

Baseline 6MWD ≥100 m

A stable and optimized dose for ≥30 days prior to randomization if on a chronic medication for underlying lung disease (ie, pirfenidone, nintedanib)

Baseline FVC of <70% in patients with connective tissue disease

Key Exclusion Criteria4

Patients were not eligible to enroll if they had:

Diagnosis of PAH or PH for reasons other than WHO Group 3 PH-ILD

Received any PAH-approved therapy within 60 days of randomization

Evidence of clinically significant left-sided heart disease (PCWP >15 mm Hg and LVEF <40%)

Received >10 L/min oxygen supplementation by any mode of delivery at baseline

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

Initiation of pulmonary rehabilitation within 12 weeks prior to randomization

Acute pulmonary embolism within 90 days of randomization

Baseline characteristics of the INCREASE study population (N=326)1,2,4

INCREASE study baseline characteristicsINCREASE study baseline characteristics
Time since PH-ILD diagnosis 6.5 months (mean)
Supplemental oxygen 71.5%

Chronic medication for underlying lung disease

  • 77.3% none
  • 13.5% pirfenidone only
  • 9.2% nintedanib only
6MWD 259.6 m (mean)
NT-proBNP 503.9 pg/mL (median)
FVC (% predicted) TYVASO group: 62.5% (mean)
Placebo group: 63.8% (mean)
DLCO (% predicted) TYVASO group: 30.0% (mean)
Placebo group: 28.1% (mean)

*Additional safety endpoints included clinical laboratory parameters, vital signs, electrocardiograms, and hospitalizations due to a cardiopulmonary indication.4
PFTs were prespecified as safety assessments; however, based on study results, exploratory post hoc efficacy analyses were conducted.1,3
An acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality determined by the investigator.1
§Patients with IPF represented 28.2% of the total study population.1

6MWD=6-minute walk distance; AE=adverse event; CHP=chronic hypersensitivity pneumonitis; CPFE=combined pulmonary fibrosis and emphysema; CT=computed tomography; CTD=connective tissue disease; DLCO=diffusing capacity of the lung for carbon monoxide; IIP=idiopathic interstitial pneumonia; ILD=interstitial lung disease; IPF=idiopathic pulmonary fibrosis; LVEF=left ventricular ejection fraction; NT-proBNP=N-terminal pro−B-type natriuretic peptide; PAH=pulmonary arterial hypertension; PFT=pulmonary function test; PH=pulmonary hypertension; PH-ILD=pulmonary hypertension associated with interstitial lung disease; SpO2=saturation of peripheral capillary oxygenation; V/Q=ventilation/perfusion; WHO=World Health Organization; WU=Wood units.