Increase 1.

The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
Inhaled Treprostinil in Pulmonary Hypertension

Due to Interstitial Lung Disease
Aaron Waxman, M.D., Ph.D., Ricardo Restrepo‑Jaramillo, M.D.,
Thenappan Thenappan, M.D., Ashwin Ravichandran, M.D., Peter Engel, M.D.,
Abubakr Bajwa, M.D., Roblee Allen, M.D., Jeremy Feldman, M.D.,
Rahul Argula, M.D., Peter Smith, Pharm.D., Kristan Rollins, Pharm.D.,
Chunqin Deng, M.D., Ph.D., Leigh Peterson, Ph.D., Heidi Bell, M.D.,
Victor Tapson, M.D., and Steven D. Nathan, M.D.
A BS T R AC T
BACKGROUND
No therapies are currently approved for the treatment of pulmonary hypertension in From Brigham and Women’s Hospital,
patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil Boston (A.W.); the University of South
Florida, Tampa (R.R.-J.), and St. Vin-
for patients with this condition are unclear. cent’s Lung, Sleep, and Critical Care Spe-
cialists, Jacksonville (A.B.) — both in FL;
METHODS the University of Minnesota, Minneapo-
We enrolled patients with interstitial lung disease and pulmonary hypertension lis (T.T.); St. Vincent Medical Group, In-
dianapolis (A.R.); the Carl and Edyth
(documented by right heart catheterization) in a multicenter, randomized, double- Lindner Research Center at the Christ
blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to Hospital, Cincinnati (P.E.); University of
receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery California Davis Medical Center, Sacra-
mento (R. Allen), and Cedars–Sinai, Los
nebulizer in up to 12 breaths (total, 72 μg) four times daily, or placebo. The pri- Angeles (V.T.); Arizona Pulmonary Spe-
mary efficacy end point was the difference between the two groups in the change cialists, Phoenix (J.F.); the Medical Uni-
in peak 6-minute walk distance from baseline to week 16. Secondary end points versity of South Carolina, Charleston (R.
Argula); United Therapeutics Corporation,
included the change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) Silver Spring, MD (P.S., K.R., C.D., L.P.,
level at week 16 and the time to clinical worsening. H.B.); and Inova Fairfax Hospital, Falls
Church, VA (S.D.N.). Address reprint re-
RESULTS quests to Dr. Nathan at the Advanced
Lung Disease and Lung Transplant Pro-
A total of 326 patients underwent randomization, with 163 assigned to inhaled gram, Inova Heart and Vascular Institute,
treprostinil and 163 to placebo. Baseline characteristics were similar in the two 3300 Gallows Rd., Falls Church, VA
groups. At week 16, the least-squares mean difference between the treprostinil 22042, or at steven.nathan@inova.org.
group and the placebo group in the change from baseline in the 6-minute walk This article was published on January 13,
distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). 2021, at NEJM.org.
There was a reduction of 15% in NT-proBNP levels from baseline with inhaled N Engl J Med 2021;384:325-34.
treprostinil as compared with an increase of 46% with placebo (treatment ratio, DOI: 10.1056/NEJMoa2008470
Copyright © 2021 Massachusetts Medical Society.
0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients
(22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the
placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank
test). The most frequently reported adverse events were cough, headache, dyspnea,
dizziness, nausea, fatigue, and diarrhea.
CONCLUSIONS
In patients with pulmonary hypertension due to interstitial lung disease, inhaled
treprostinil improved exercise capacity from baseline, assessed with the use of a
6-minute walk test, as compared with placebo. (Funded by United Therapeutics;
INCREASE ClinicalTrials.gov number, NCT02630316.)
n engl j med 384;4 nejm.org January 28, 2021 325

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P
recapillary pulmonary hyperten- collaboration with the trial sponsor (United Ther-
sion is defined as an elevation in mean apeutics), designed the trial and oversaw its con-
pulmonary arterial pressure and pulmo- duct. The trial protocol (available with the full
nary vascular resistance.1 In the World Health text of this article at NEJM.org) was approved by
Organization (WHO) classification of pulmonary the institutional review board at each participat-
hypertension, precapillary pulmonary hyperten- ing site. The trial was monitored by an indepen-
sion due to lung disease is classified as group 3. dent data and safety monitoring committee and
The most common lung diseases associated with was conducted in accordance with Good Clinical
group 3 pulmonary hypertension are chronic ob- Practice guidelines. A full list of trial personnel,
structive pulmonary disease and interstitial lung including the investigators and trial committees,
disease. is provided in Section S1 in the Supplementary
Pulmonary hypertension has been reported in Appendix, available at NEJM.org.
up to 86% of patients with interstitial lung dis- The collection, management, and analysis of
ease and is associated with reduced exercise ca- the data were performed by the sponsor according
pacity, greater need for supplemental oxygen, de- to a prespecified statistical analysis plan (provid-
creased quality of life, and earlier death.2-4 Despite ed in the protocol). An independent academic
the global prevalence and poor clinical course of statistician reviewed the statistical analysis plan
pulmonary hypertension due to interstitial lung and confirmed the primary efficacy analyses.
disease, there are currently no approved therapies Authors had independent access to the data and
for these patients. Although data are limited, authority to conduct and confirm statistical anal-
therapies approved for group 1 pulmonary hyper- yses. All manuscript drafts were written by the
tension (pulmonary arterial hypertension) have steering committee and authors affiliated with
been used to treat group 3 pulmonary hyperten- the sponsor and were reviewed and approved by
sion.5 Previous studies of vasodilator therapies all the authors. The authors assume responsibility
have shown conflicting results. The largest trial for the accuracy and completeness of the data, as
to date evaluated the soluble guanylate cyclase well as for the fidelity of the trial to the protocol.
stimulator riociguat in a patient population with
group 3 pulmonary hypertension and was stopped Trial Population
early owing to serious harm.6 The trial population consisted of patients 18 years
Treprostinil is a stable analogue of prostacyclin,
of age or older in whom interstitial lung disease
which promotes direct vasodilation of pulmonary was diagnosed on the basis of evidence of diffuse
and systemic arterial vascular beds and inhibits parenchymal lung disease on computed tomogra-
platelet aggregation.7 An inhaled formulation of phy of the chest (not centrally adjudicated) per-
treprostinil was previously shown to improve ex- formed within 6 months before randomization.
ercise capacity after 12 weeks of therapy in pa- Confirmation of group 3 pulmonary hypertension
tients with group 1 pulmonary hypertension.8 by right heart catheterization within 1 year be-
Data from previously completed pilot studies sug- fore randomization was required. Group 3 pul-
gest that inhaled treprostinil can improve hemo- monary hypertension was defined by pulmonary
dynamics and functional capacity in patients with vascular resistance of more than 3 Wood units,
group 3 pulmonary hypertension.9-12 Therefore, pulmonary capillary wedge pressure of 15 mm
the objective of the INCREASE trial was to evalu- Hg or lower, and mean pulmonary arterial pres-
ate the safety and efficacy of inhaled treprostinilsure of 25 mm Hg or higher. Patients with group
in patients with pulmonary hypertension due to 3 pulmonary hypertension due to connective tis-
interstitial lung disease. sue disease were also required to have a baseline
forced vital capacity of less than 70%. Eligible pa-
tients also had to walk at least 100 m during a
Me thods
6-minute walk test. Patients receiving drug treat-
Trial Design and Oversight ment (i.e., pirfenidone or nintedanib) for their
INCREASE was a multicenter, randomized, double- underlying lung disease were required to have
blind, placebo-controlled trial. The steering com- been receiving a stable dose for at least 30 days
mittee (the first author and last two authors), in before undergoing randomization. Patients re-
326 n engl j med 384;4 nejm.org January 28, 2021

ceiving approved therapy for pulmonary arterial weeks 8 and 16 (or at early discontinuation) after
hypertension within 60 days before randomiza- the patients recovered from the 6-minute walk
tion were not eligible for enrollment. A complete test. The St. George’s Respiratory Questionnaire
list of trial enrollment criteria is provided in Sec- (SGRQ), a quality-of-life measure, was completed
tion S2. Written informed consent was obtained at baseline and week 16 or at the time of early
from all the patients. discontinuation.
Trial Procedures Outcome Measures

Within 30 days after screening, eligible patients The primary end point of the trial was the dif-
were randomly assigned in a 1:1 ratio to receive ference between the two groups in the change in
inhaled treprostinil (Tyvaso, United Therapeutics) peak 6-minute walk distance from baseline to
or placebo in a double-blind manner. Random- week 16. Secondary efficacy end points were
ization, based on permuted blocks, was stratified analyzed in the following hierarchical testing
by baseline 6-minute walk distance (≤350 m vs. order: the change in NT-proBNP level from base-
>350 m) and was implemented through an inter- line to week 16, the time to clinical worsening,
active Web-response system. the change in 6-minute walk distance at peak
Inhaled treprostinil (0.6 mg per milliliter) was plasma treprostinil level at week 12, and the
administered by means of an ultrasonic, pulsed- change in 6-minute walk distance at trough
delivery nebulizer at 6 μg per breath. Placebo treprostinil level at week 15. The time to clinical
was administered similarly as a visually identical worsening was evaluated from the time of ran-
solution. The first dose of trial drug (3 breaths) domization until the patient’s withdrawal from
was administered in the clinic, followed by at the trial and was defined as the time until the
least a 1-hour observation period. The dose of occurrence of any one of the following events:
treprostinil or placebo was adjusted, with dose hospitalization for a cardiopulmonary indication,
escalation (an additional 1 breath four times daily) a decrease in 6-minute walk distance greater
occurring as often as every 3 days, with a target than 15% from baseline that was directly related
dose of 9 breaths four times daily and a maxi- to the disease under study at two consecutive
mum dose of 12 breaths four times daily. Investi- visits and at least 24 hours apart, death from any
gators adjusted the dose on an individual patient cause, or lung transplantation.
basis to achieve the maximum tolerated dose Exploratory end points were the changes in
leading to functional improvement. peak 6-minute walk distance at weeks 4 and 8,
quality of life as measured with the use of the
Trial Assessments SGRQ at week 16, and the distance–saturation
The 6-minute walk test was performed and labo- product (calculated by multiplying the total dis-
ratory data were obtained at baseline and at tance walked by the lowest oxygen saturation
weeks 4, 8, 12, and 16, or at the time of early measurement during the 6-minute walk) at
discontinuation of treprostinil or placebo. Each week 16. Safety end points included adverse
6-minute walk test was performed 10 to 60 min- events, abnormal laboratory results, oxygenation
utes after the most recent dose of active drug or as measured by pulse oximetry (Spo2) and sup-
placebo, which is the time of peak plasma plemental oxygen requirement, changes in pul-
treprostinil exposure. (A description of the pro- monary function test results, hospitalization for
cedure for the 6-minute walk test is provided in a cardiopulmonary indication, and investigator-
Section S3.) A trough test was performed at reported exacerbations of underlying lung disease,
week 15 at least 4 hours after the participant defined as acute, clinically significant respiratory
received a dose of treprostinil or placebo and at deterioration characterized by evidence of new
least 24 hours before the week 16 test. Pulse widespread alveolar abnormality. A full list of
oximetry was performed immediately before, trial end points is provided in Section S4.
during, and after each 6-minute walk test. Mea-
surement of N-terminal pro–B-type natriuretic Statistical Analysis
peptide (NT-proBNP) levels and pulmonary func- Original estimates suggested that with 266 pa-
tion tests were performed at baseline and at tients randomly assigned in a 1:1 ratio to receive

inhaled treprostinil or placebo, the trial would was 6.2 Wood units, and the mean NT-proBNP
have at least 90% power at a significance level of level was 1832.9 pg per milliliter.
0.05 (two-sided) to detect a between-group differ-
ence of 30 m in the change in peak 6-minute Exposure and Follow-up
walk distance from baseline at week 16, assuming Patients in the treprostinil group took a median
a standard deviation of 75 m. To account for ap- of 11 breaths from the inhaler (66 μg) at each of
proximately 15% of participants discontinuing the four daily sessions at week 12 and 12 breaths (72
trial, 314 patients would need to be enrolled. μg) per session at week 16. The percentage of
For the primary efficacy analysis, the change patients in this group who took 10 to 12 breaths
in 6-minute walk distance was analyzed by mixed- (60 to 72 μg) per session was 57.0% at week 12
model repeated-measures methods, under the and 57.8% at week 16. Patients in the placebo
assumption that missing data were missing at group took a median of 12 breaths from the
random. The model included the change from inhaler per session at weeks 12 and 16.
baseline to peak 6-minute walk distance as the The date of the database lock was February 18,
dependent variable, with treatment, week, and 2020. Forty patients assigned to receive inhaled
treatment-by-week interaction as fixed effects, treprostinil (24.5%) and 38 assigned to placebo
and the baseline 6-minute walk distance as a (23.3%) discontinued the assigned regimen pre-
covariate. A sensitivity analysis for the primary maturely. These patients were encouraged to re-
end point was performed by means of a multiple main in the trial and complete assessments
imputation approach with a multivariate normal through week 16; 33 patients in the treprostinil
imputation model according to the Markov group and 35 in the placebo group discontinued
chain Monte Carlo method. The imputation mod- participation in the trial. The reasons for discon-
el included treatment group, all scheduled visits, tinuation are shown in Figure 1.
the patient’s sex, and the patient’s age at ran-
domization. If the result for the primary efficacy Primary End Point
end point was significant, secondary efficacy end Mean within-group changes in the 6-minute walk
points were to be evaluated according to a hier- distance are shown in Figure 2. Mixed-model
archical testing procedure. Confidence intervals repeated-measures analysis showed that the least-
have not been adjusted for multiplicity and can- squares mean difference between the treprostinil
not be used to infer definitive treatment effects group and the placebo group in the change from
for secondary efficacy end points. Additional de- baseline in peak 6-minute walk distance was
tails of the statistical methods are provided in 31.12 m (95% confidence interval [CI], 16.85 to
Section S5. 45.39; P<0.001) (Table 2 and Fig. S1). Similar ef-
fects were observed across subgroups, including
subgroups defined by disease cause and severity
R e sult s
(as measured by baseline 6-minute walk distance),
Patients baseline hemodynamics, and dose group (Fig. S2).
Of 462 patients screened for eligibility, 326 were In addition, the between-group difference in the
enrolled at 93 centers from February 3, 2017, change from baseline in peak 6-minute walk
through August 30, 2019, and were randomly as- distance at week 16 was significant when ana-
signed to receive placebo (163 patients) or inhaled lyzed with multiple imputation according to the
treprostinil (163 patients) (Fig. 1). Reasons for Markov chain Monte Carlo method (30.97 m;
screening failure for the 136 patients who were 95% CI, 16.53 to 45.41; P<0.001) (Fig. S3).
excluded are shown in Table S1. Baseline charac-
teristics were similar in the two groups (Table 1). Secondary and Exploratory End Points
The mean age of the patients was 66.5 years, Patients assigned to inhaled treprostinil, as
46.9% were female, and the most common diag- compared with those assigned to placebo,
nosis was idiopathic interstitial pneumonia (in showed significant improvements in each of the
44.8%). Baseline test data are provided in Table S2. secondary end points (Table 2). The NT-proBNP
At baseline, the mean 6-minute walk distance was level decreased 15% from baseline with inhaled
259.6 m, the mean pulmonary vascular resistance treprostinil and increased 46% from baseline with

462 Patients were assessed for eligibility
136 Failed screening
326 Underwent randomization
163 Were assigned to receive inhaled

163 Were assigned to receive placebo
treprostinil
40 Discontinued treprostinil prematurely 38 Discontinued placebo prematurely

16 Had an adverse event 13 Had an adverse event
6 Died 5 Died
6 Had progressive disease 10 Had progressive disease
3 Had protocol violation 9 Withdrew
7 Withdrew 1 Had other reason
2 Had other reason
35 Discontinued study
33 Discontinued study
participation
participation
3 Had an adverse event
7 Had an adverse event
10 Died
8 Died
1 Was lost to follow-up
4 Had progressive disease
7 Had progressive disease
2 Had protocol violation
13 Withdrew consent
10 Withdrew consent
1 Had other reason
2 Had other reason
130 Completed week 16 of study 128 Completed week 16 of study

assessment assessment
Figure 1. Screening, Randomization, and Follow-up.

Of 462 patients screened for eligibility, 326 patients underwent randomization and received at least one dose of
the assigned treprostinil or placebo (included in the intention-to-treat and safety populations). Reasons for screen-
ing failure (136 patients) are shown in Table S1. Of the patients who underwent randomization, 40 patients in the
treprostinil group and 38 in the placebo group discontinued the assigned regimen prematurely. These patients were
not withdrawn from the trial but were encouraged to remain and complete assessments through week 16; 33 patients
in the treprostinil group and 35 in the placebo group discontinued trial participation before week 16.
placebo, as assessed by the least-squares mean from baseline to week 15 in trough 6-minute
for the log-transformed ratio to the baseline level walk distance was 21.99 m greater in the trepro-
at week 16 (treatment ratio, 0.58; 95% CI, 0.47 to stinil group (P = 0.004). There was no significant
0.72; P<0.001) (Fig. S4). Clinical worsening oc- between-group difference in patient-reported qual-
curred in 37 patients (22.7%) in the treprostinil ity of life as assessed with the SGRQ or in the
group, as compared with 54 patients (33.1%) in distance–saturation product at week 16 (Tables
the placebo group (hazard ratio, 0.61; 95% CI, S3 and S4).
0.40 to 0.92; P = 0.04 by the log-rank test) (Fig. S5).
The least-squares mean change from baseline to Safety End Points
week 12 in peak 6-minute walk distance was The most frequently reported adverse events were
31.29 m greater in the treprostinil group than in cough, headache, dyspnea, dizziness, nausea,
the placebo group (P<0.001), and the change fatigue, and diarrhea (Table 3). Most of these

Table 1. Characteristics of the Patients at Baseline.*
Inhaled Treprostinil Placebo All Patients

Characteristic (N = 163) (N = 163) (N = 326)
Female sex — no. (%) 85 (52.1) 68 (41.7) 153 (46.9)
Mean age at randomization (range) — yr 65.6 (26–90) 67.4 (36–85) 66.5 (26–90)
Age distribution — no. (%)
<65 yr 64 (39.3) 48 (29.4) 112 (34.4)
65 to <80 yr 83 (50.9) 100 (61.3) 183 (56.1)
≥80 yr 16 (9.8) 15 (9.2) 31 (9.5)
Race or ethnic group — no. (%)†
White 112 (68.7) 126 (77.3) 238 (73.0)
Black or African American 41 (25.2) 30 (18.4) 71 (21.8)
American Indian or Alaska Native 2 (1.2) 1 (0.6) 3 (0.9)
Asian 7 (4.3) 5 (3.1) 12 (3.7)
Multiple 0 1 (0.6) 1 (0.3)
Unknown 1 (0.6) 0 1 (0.3)
Hispanic or Latino ethnic group — no. (%)†
Yes 11 (6.7) 16 (9.8) 27 (8.3)
No 152 (93.3) 146 (89.6) 298 (91.4)
Data missing 0 1 (0.6) 1 (0.3)
Mean time since diagnosis — yr 0.54±1.16 0.54±1.31 0.54±1.23
Cause of lung disease — no. (%)
Idiopathic interstitial pneumonia 65 (39.9) 81 (49.7) 146 (44.8)
Chronic hypersensitivity pneumonitis 10 (6.1) 9 (5.5) 19 (5.8)
Occupational lung disease 5 (3.1) 1 (0.6) 6 (1.8)
Combined pulmonary fibrosis and emphysema 42 (25.8) 40 (24.5) 82 (25.2)
Connective tissue disease 40 (24.5) 32 (19.6) 72 (22.1)
Other 1 (0.6) 0 1 (0.3)
Idiopathic interstitial pneumonia subcategory — no. (%)
Idiopathic pulmonary fibrosis 37 (22.7) 55 (33.7) 92 (28.2)
Idiopathic nonspecific interstitial pneumonia 21 (12.9) 16 (9.8) 37 (11.3)
Respiratory bronchiolitis associated with interstitial lung 2 (1.2) 0 2 (0.6)
disease
Desquamative interstitial pneumonia 0 1 (0.6) 1 (0.3)
Acute interstitial pneumonia 0 1 (0.6) 1 (0.3)
Unclassified idiopathic interstitial pneumonia 5 (3.1) 8 (4.9) 13 (4.0)
Use of supplemental oxygen — no. (%) 119 (73.0) 114 (69.9) 233 (71.5)
Background therapy — no. (%)
None 133 (81.6) 119 (73.0) 252 (77.3)
Pirfenidone only 19 (11.7) 25 (15.3) 44 (13.5)
Nintedanib only 11 (6.7) 19 (11.7) 30 (9.2)
* Plus–minus values are means ±SD. Additional patient characteristics at baseline are provided in Table S2 in the
Supplementary Appendix. Percentages may not total 100 because of rounding.
† Race and ethnic group were reported by the patient.

events were of mild-to-moderate intensity. Seri-

ous adverse events occurred in 23.3% of the pa- Observed MMRM MCMC
tients who received inhaled treprostinil and in 30 125

Inhaled 121
treprostinil
25.8% of those who received placebo (Table S5). 25
132
Change from Baseline (m)

No serious adverse events were reported signifi- 20
cantly more frequently in the treprostinil group 15
than in the placebo group. A full list of serious 10 148
adverse events is provided in Table S5. 5
120
0 121
Significantly fewer patients in the treprostinil 131
−5
group than in the placebo group had exacerba- 148
−10 Placebo
tions of underlying lung disease (43 [26.4%] vs.
−15
63 [38.7%]; P = 0.02 by Fisher’s exact test). Fewer
−20
patients in the treprostinil group than in the 0 4 8 12 16
placebo group had a first occurrence of clinical Week
worsening that involved hospitalization for a
cardiopulmonary indication (18 [11.0%] vs. 24 Figure 2. Mean Change from Baseline in Peak 6-Minute Walk Distance
[14.7%]; P = 0.41). Inhaled treprostinil had no through Week 16.
deleterious effect on any pulmonary function Shown are mean (±SE) changes from baseline (dashed line) in peak 6-min-
ute walk distance over the 16-week trial period. The data shown are for pa-
test variable during the trial (Table S6). There
tients with available data (observed) as well as for the results of two analy-
were no significant treatment-related changes in sis methods used to account for missing data. The values shown at each
pulse oximetry or supplemental oxygen use in ei- data point indicate the number of patients assessed at that time point.
ther group over the trial period (Tables S7 and S8). The primary analysis used mixed-model repeat-measurement (MMRM)
methods, with the assumption that missing data were missing at random.
The model included the change from baseline to peak 6-minute walk dis-
Discussion tance as the dependent variable, with treatment, week, and treatment-by-
week interaction as fixed effects, and the baseline 6-minute walk distance
Pulmonary hypertension frequently complicates as a covariate. A sensitivity analysis for the primary end point was per-
the treatment of patients with interstitial lung formed with the use of a multiple imputation approach with a multivariate
disease and is associated with worse functional normal imputation model using the Markov chain Monte Carlo (MCMC)
method. The imputation model included treatment group, all scheduled
status, greater need for supplemental oxygen, and
visits, patient’s sex, and patient’s age at randomization. The confidence
worse outcomes.3,13 In the INCREASE trial, pa- intervals have not been adjusted for multiplicity and cannot be used to infer
tients treated with inhaled treprostinil had sig- definitive treatment effects.
nificant improvements in exercise capacity, as
evidenced by changes in the 6-minute walk dis-
tance. Treatment with inhaled treprostinil was could worsen ventilation–perfusion matching in
also associated with a lower risk of clinical wors- patients with group 3 pulmonary hypertension.
ening than that in patients who received placebo, Inhaled agents have the advantage of preferen-
as well as reductions in NT-proBNP levels and tially redirecting blood flow to the best-ventilated
fewer exacerbations of underlying lung disease, lung units, thus reducing the risk of ventilation–
over the 16-week treatment period. The safety perfusion mismatching.9,14 Indeed, a retrospec-
profile of inhaled treprostinil observed in this tive study of inhaled treprostinil in patients with
vulnerable patient population was similar to that group 3 pulmonary hypertension showed that
reported in previous studies. The most frequent- such patients had improvements in functional
ly reported adverse events were cough, headache, class and 6-minute walk distance without any ad-
dyspnea, dizziness, nausea, fatigue, and diarrhea. verse effect on peripheral oxygen saturation, rein-
The use of inhaled treprostinil was not associated forcing the concept of unchanged or even im-
with any decrement in lung function. proved ventilation–perfusion matching with
Patients with group 3 pulmonary hyperten- inhaled treprostinil.10 Similarly, in the current
sion are often treated with systemic pulmonary trial, we found no evidence of worsened oxygen-
vasodilators, which are currently approved only ation, which further allays concerns about venti-
for treatment of group 1 pulmonary hyperten- lation–perfusion mismatching.
sion. However, there is concern that such agents The INCREASE trial was not without its limi-

Table 2. Summary of Primary and Secondary End Points.*
Inhaled Treprostinil Placebo Treatment Effect P

End Point (N = 163) (N = 163) (95% CI) Value
Primary end point
Change in peak 6-minute walk distance from baseline 21.08±5.12 −10.04±5.12 31.12±7.25 <0.001
to wk 16 — m† (16.85 to 45.39)‡
Secondary end points§
Change in plasma concentration of NT-proBNP from
baseline to wk 16¶
Mean (±SD) change — pg/ml −396.35±1904.90 1453.95±7296.20
Median — pg/ml −22.65 20.65
Range — pg/ml −11,433.0 to 5373.1 −5483.3 to 87,148.3
Ratio to baseline 0.85±0.06 1.46±0.11 0.58±0.06 (0.47 to 0.72)‖ <0.001
Occurrence of clinical worsening — no. (%) 0.61 (0.4 to 0.92)** 0.04
Any event 37 (22.7) 54 (33.1)
Hospitalization for cardiopulmonary indication 18 (11.0) 24 (14.7)
Decrease in 6-minute walk distance of >15% from 13 (8.0) 26 (16.0)
baseline
Death from any cause 4 (2.5) 4 (2.5)
Lung transplantation 2 (1.2) 0
Least-squares mean change in peak 6-minute walk 18.77±4.99 −12.52±5.01 31.29±7.07 <0.001
distance from baseline to wk 12 — m† (17.37 to 45.21)‡
Least-squares mean change in trough 6-minute walk 9.3±5.5 −12.7±5.5 21.99±7.7 0.005††
distance from baseline to wk 15 — m (6.85 to 37.14)‡
* Plus–minus values are means ±SE, unless otherwise indicated. For secondary end points, the confidence intervals (CIs) have not been
adjusted for multiplicity and cannot be used to infer definitive treatment effects. NT-proBNP denotes N-terminal pro–B-type natriuretic
peptide.
† The effect of inhaled treprostinil as compared with placebo on the change in 6-minute walk distance was evaluated with the use of a
mixed-model repeat measurement with the change from baseline in peak 6-minute walk distance as the dependent variable; treatment,
week, and treatment-by-week interaction as the fixed effects; baseline 6-minute walk distance as the covariate; and subject as the random
effect. Results are shown in Figures S1 and S3.
‡ This is a least-squares mean difference between the groups.
§ The effect of inhaled treprostinil as compared with placebo on the change in log-transformed NT-proBNP was evaluated with the use of
a mixed-model repeat measurement with the change from baseline in log-transformed NT-proBNP as the dependent variable; treatment,
week, and treatment-by-week interaction as the fixed effects; and log-transformed baseline NT-proBNP as the covariate. Ratio to baseline
is the least-squares mean of the change from baseline in log-transformed data.
¶ The change in plasma concentration of NT-proBNP from baseline to week 16 was assessed in 156 patients in the treprostinil group and
160 in the placebo group.
‖ This is the treatment ratio, which is the ratio of ratios between two treatment groups.
** This is a hazard ratio, calculated from a Cox proportional-hazards model. The P value was calculated with the use of a log-rank test strati-
fied by the baseline 6-minute walk distance category.
†† The P value was obtained from 100 multiple imputations with Markov chain Monte Carlo estimation with the use of analysis of covariance
(ANCOVA) modeling, with the change from baseline in peak 6-minute walk distance as the dependent variable, treatment as a fixed effect,
and baseline 6-minute walk distance as a covariate.
tations. The trial was of short duration, and 21% on the 6-minute walk distance with inhaled
of the patients discontinued the trial prematurely treprostinil is similar to estimates of the mini-
(before week 16). In addition, events of clinical mum clinically important difference for this test
worsening and exacerbation of underlying lung in patients with pulmonary disease (21.7 to 37 m
disease were investigator-reported and not adju- in a study by Nathan et al., and 24 to 45 m in a
dicated by an independent review committee. study by du Bois et al.).15,16
Finally, the size of the favorable treatment effect This study showed that among patients with

Table 3. Summary of Adverse Events.
Inhaled
Treprostinil Placebo
Variable (N = 163) (N = 163) P Value*
Total no. of adverse events 890 793
Patients with ≥1 adverse event — no. (%) 152 (93.3) 149 (91.4) 0.68
Total no. of serious adverse events† 53 89
Patients with ≥1 serious adverse event — no. (%) 38 (23.3) 42 (25.8) 0.70
Total no. of adverse events leading to withdrawal of treprostinil 47 38
or placebo
Most frequently occurring adverse events — no. of patients
(%)‡
Cough 71 (43.6) 54 (33.1) 0.07
Headache 45 (27.6) 32 (19.6) 0.12
Dyspnea 41 (25.2) 51 (31.3) 0.27
Dizziness 30 (18.4) 23 (14.1) 0.37
Nausea 25 (15.3) 26 (16.0) >0.99
Fatigue 23 (14.1) 23 (14.1) >0.99
Diarrhea 22 (13.5) 19 (11.7) 0.74
Throat irritation 20 (12.3) 6 (3.7) 0.007
Oropharyngeal pain 18 (11.0) 4 (2.5) 0.003
NT-proBNP increased 9 (5.5) 25 (15.3) 0.006
* P values were calculated with the use of Fisher’s exact test.

† A list of serious adverse events is shown in Table S5.
‡ Shown are the most frequently occurring adverse events occurring in more than 10% of patients in either group in the
safety population, which comprised all patients who underwent randomization and received at least one dose of trepro-
stinil or placebo.
pulmonary hypertension due to interstitial lung Supported by United Therapeutics.

disease, treatment with inhaled treprostinil im- Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
proved exercise capacity as shown by improvement A data sharing statement provided by the authors is available
in the 6-minute walk distance through the end with the full text of this article at NEJM.org.
of the 16-week treatment period. In addition, treat- We thank Lisa Edwards, Ph.D. (United Therapeutics), for sta-
tistical expertise and support provided in the conduct of the
ment with inhaled treprostinil was associated trial; and Eric Shen, Pharm.D. (United Therapeutics), and April
with a lower risk of clinical worsening than that Ingram (Upstart Medical Communications) for editorial sup-
with placebo, a reduction in NT-proBNP levels, and port with an earlier version of the manuscript, funded by United
Therapeutics.
fewer exacerbations of underlying lung disease.
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The n e w e ng l a n d j o u r na l of m e dic i n e

Inhaled Treprostinil in Pulmonary Hypertension

n engl j med 384;4 nejm.org January 28, 2021 325

326 n engl j med 384;4 nejm.org January 28, 2021

The New England Journal of Medicine

Trial Procedures Outcome Measures

n engl j med 384;4 nejm.org January 28, 2021 327

328 n engl j med 384;4 nejm.org January 28, 2021

The New England Journal of Medicine

462 Patients were assessed for eligibility

136 Failed screening

326 Underwent randomization

163 Were assigned to receive inhaled

40 Discontinued treprostinil prematurely 38 Discontinued placebo prematurely

130 Completed week 16 of study 128 Completed week 16 of study

Figure 1. Screening, Randomization, and Follow-up.

n engl j med 384;4 nejm.org January 28, 2021 329

Table 1. Characteristics of the Patients at Baseline.*

Inhaled Treprostinil Placebo All Patients

330 n engl j med 384;4 nejm.org January 28, 2021

The New England Journal of Medicine

events were of mild-to-moderate intensity. Seri-

tients who received inhaled treprostinil and in 30 125

Change from Baseline (m)

n engl j med 384;4 nejm.org January 28, 2021 331

Table 2. Summary of Primary and Secondary End Points.*

Inhaled Treprostinil Placebo Treatment Effect P

332 n engl j med 384;4 nejm.org January 28, 2021

The New England Journal of Medicine

Table 3. Summary of Adverse Events.

* P values were calculated with the use of Fisher’s exact test.

pulmonary hypertension due to interstitial lung Supported by United Therapeutics.

n engl j med 384;4 nejm.org January 28, 2021 333

receive immediate notification when an article

To be notified by email when Journal articles

334 n engl j med 384;4 nejm.org January 28, 2021

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* P values were calculated with the use of Fisher’s exact test.