Abstract
Introduction
The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD.
Methods
Of 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded.
Results
At INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and −19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL−1 at RCT baseline to 359 pg·mL−1 at week 64; and the absolute (% predicted) mean forced vital capacity change from RCT baseline to week 64 was 51 mL (2.8%). Patients who received inhaled treprostinil versus placebo in the RCT had a 31% lower relative risk of exacerbation of underlying lung disease in the OLE (hazard ratio 0.69 (95% CI 0.49–0.97); p=0.03). Adverse events leading to drug discontinuation occurred in 54 (22.3%) patients.
Conclusions
These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT.
Short abstract
The INCREASE open-label extension supports the safety and efficacy of long-term treatment with inhaled treprostinil in patients with interstitial lung disease and associated pulmonary hypertension http://bit.ly/3KiEClA
Introduction
Pulmonary hypertension (PH) frequently complicates the course of most fibrosing interstitial lung diseases (ILDs) [1]. Between 15% and 86% of patients with ILD may develop PH, which is then associated with further impaired exercise tolerance, decreased quality of life and a poor prognosis [2, 3]. Prior to March 2021, no therapies were approved for treating PH due to ILD (PH-ILD). Vasodilators used for pulmonary arterial hypertension (PAH) have been utilised off-label with mixed success, sometimes even causing harm [4, 5].
The INCREASE study was a randomised, double-blind, placebo-controlled, phase 3 trial (RCT) that evaluated the effectiveness of inhaled treprostinil, a prostacyclin analogue, on exercise tolerance in patients with PH-ILD [6]. In INCREASE, 326 patients were randomised to inhaled treprostinil or placebo for 16 weeks. Inhaled treprostinil was associated with a significant placebo-corrected improvement in the primary end-point of 6-min walk distance (6MWD) of 31.1 m (95% CI 16.9–45.4 m; p<0.001) at week 16. Inhaled treprostinil led to improvements compared with placebo in important secondary end-points, including decreased plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) and decreased occurrence of clinical worsening. Additionally, in post-hoc analyses, inhaled treprostinil was associated with placebo-corrected improvement in forced vital capacity (FVC) [7] with fewer disease progression events [8]. Based on the INCREASE results, the US Food and Drug Administration (FDA) approved inhaled treprostinil as the first treatment for PH-ILD.
The chronicity of ILD necessitates long-term treatment; therefore, understanding the safety of prolonged administration of inhaled treprostinil is of paramount importance. Patients from the INCREASE RCT were eligible to enrol in an open-label extension (OLE) to evaluate the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD. Herein we present the results of the INCREASE OLE. A graphical abstract is provided in the supplementary material.
Methods
The INCREASE OLE (ClinicalTrials.gov: NCT02633293) was a multicentre study. All patients received inhaled treprostinil (figure 1). The primary objective was to provide inhaled treprostinil to eligible patients who participated in the INCREASE RCT. The secondary objectives were to assess the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD. The study protocol was approved by the institutional review board at each trial site. The study was conducted in accordance with the International Council for Harmonisation and Good Clinical Practice guidelines, and was monitored for safety by an independent data monitoring committee. All participants provided written informed consent. The planned study duration was until all patients were in the OLE for 108 weeks after the 16-week parent trial (i.e. a total of 124 weeks) or until inhaled treprostinil was approved by the FDA for the treatment of patients with PH-ILD, upon which the study would be discontinued.
FIGURE 1.
Study schema: INCREASE randomised controlled trial (RCT) and open-label extension (OLE). #: two additional patients entered the OLE who were excluded from the RCT due to a labelling issue; ¶: patients receiving >3 breaths per session four times daily at week 16 of the RCT had their dose reduced to 3 breaths per session four times daily at the start of the OLE.
Patients
Eligible patients 1) had received study drug treatment for the duration of the 16-week INCREASE RCT and completed all scheduled study visits; or 2) had discontinued study drug due to clinical worsening during the RCT and completed all remaining scheduled study visits; or 3) were enrolled in the RCT and their participation was discontinued by the sponsor. Briefly, patients eligible for INCREASE were adults with ILD and Group 3 PH diagnosed by right heart catheterisation within 1 year before randomisation and who had a 6MWD of ≥100 m. Patients with underlying connective tissue disease were required to have a baseline FVC of <70%. No approved therapy for PAH was permitted within 60 days of randomisation [6]. New medications were allowed, but if a patient required infused prostacyclin lasting ≥29 days, they were discontinued from the OLE.
Treatment
In the OLE, all patients discontinued the treatment received during the RCT and received inhaled treprostinil at 0.6 mg·mL−1 via an ultrasonic pulsed-delivery nebuliser at 6 µg per breath regardless of their assigned treatment arm in the RCT. To preserve prior blinding, all OLE patients initiated inhaled treprostinil at 3 breaths per session (18 µg) four times daily. Recommended dose escalations were an additional 1 breath per session four times daily every 3 days, per the investigator's discretion, to a maximum of 15 breaths per session (90 µg) four times daily as tolerated.
Assessments
In the OLE, patients were assessed at week 20 (i.e. 4 weeks into the OLE), week 28 and then every 12 weeks up to week 124. Initial assessments for the OLE were collected at the RCT study termination visit (week 16) prior to the initiation of inhaled treprostinil. These assessments included a physical examination, 6-min walk test, pulse oximetry, pulmonary function tests (PFTs), St George's Respiratory Questionnaire (SGRQ) [9], supplemental oxygen requirement, clinical laboratory assessments (serum electrolyte, chemistry and haematology panels), serum NT-proBNP, urine pregnancy test and adverse events (AEs). Hospitalisations, exacerbations of underlying lung disease and death were recorded from the time of informed consent until study termination. Clinical worsening was assessed in the RCT but not recorded in the OLE as a prespecified end-point. The SGRQ and NT-proBNP were assessed at weeks 64 and 124 or study termination. PFTs were assessed at weeks 28, 64 and 124 or study termination. AEs were coded using MedDRA version 24.0.
End-points
There were no prespecified analyses as the objective of the OLE was to provide inhaled treprostinil to study patients and capture observational long-term safety and efficacy data in the open-label setting. The observational efficacy data captured included 6MWD, NT-proBNP, quality of life as measured by the SGRQ and change in distance-saturation product (DSP) [10] from baseline to week 64 (or study discontinuation if earlier). The safety data collected included AEs; pulse oximetry and supplemental oxygen requirements; PFTs including FVC, forced expiratory volume in 1 s, total lung capacity (TLC) and diffusing capacity of the lung for carbon monoxide (DLCO); clinical laboratory parameters; vital signs; hospitalisations due to a cardiopulmonary indication; exacerbations of underlying lung disease, defined as an acute, clinically significant, respiratory deterioration characterised by evidence of new widespread alveolar infiltrates on chest imaging; and death.
Statistical methods
All analyses were performed on the safety population, defined as all patients who received inhaled treprostinil during the OLE. Descriptive statistics were used to summarise results. All new AEs with an onset date on or after the first dose of inhaled treprostinil in the OLE were tabulated. Time to exacerbation of lung disease, cardiopulmonary hospitalisation and death from the beginning of the OLE was analysed using the Kaplan–Meier method and log-rank test comparing patients by prior treatment assignment in the RCT. A Cox regression model was used to obtain hazard ratios (HRs) with prior treatment as an explanatory variable.
Results
A total of 243 patients enrolled in the INCREASE OLE (figure 2), of whom 242 received at least one dose of study drug and were included in the safety population. Two patients were excluded from the INCREASE RCT analysis due to a study drug labelling issue and enrolled directly into the OLE as allowed by the study protocol; the remaining 240 patients were previously enrolled and analysed in the RCT, representing 73.6% of the total RCT population (n=326) and 93.0% of the eligible analysed RCT population (n=258). Baseline characteristics of patients at the start of the OLE reflected the differential treatment received during the RCT, with a mean 6MWD of 281.8 m in the inhaled treprostinil group and 266.3 m in the placebo group and a median NT-proBNP of 1312.9 pg·mL−1 in the inhaled treprostinil group and 3115.2 pg·mL−1 in the placebo group (table 1). Overall, patients had a median of 0.9 years since the diagnosis of PH-ILD and the most common ILD was idiopathic interstitial pneumonia (44.6%).
FIGURE 2.
Patient disposition diagram: INCREASE randomised controlled trial (RCT) and open-label extension (OLE). #: completed 16 weeks of assessment in the RCT; ¶: includes two patients who were excluded from the RCT due to a labelling issue; +: one patient was inadvertently enrolled in the OLE after not meeting eligibility criteria but withdrew from the OLE before receiving study drug.
TABLE 1.
Baseline characteristics for subjects in the INCREASE open-label extension (OLE)#
| Received inhaled treprostinil in RCT (n=119) | Received placebo in RCT (n=121) | Overall (n=242) ¶ | |
| Age (years) | 70.0 (27–90) | 71.0 (36–86) | 70.0 (27–90) |
| Female | 63 (52.9) | 52 (43.0) | 116 (47.9) |
| Race or ethnicity | |||
| White | 78 (65.5) | 98 (81.0) | 178 (73.6) |
| Black or African American | 33 (27.7) | 20 (16.5) | 53 (21.9) |
| American Indian or Alaska Native | 2 (1.7) | 1 (0.8) | 3 (1.2) |
| Asian | 6 (5.0) | 2 (1.7) | 8 (3.3) |
| Hispanic or Latino | 7 (5.9) | 10 (8.3) | 17 (7.0) |
| Time since PH-ILD diagnosis (years) | 0.9±1.1 | 0.9±1.5 | 0.9±1.3 |
| Current ILD diagnosis | |||
| Idiopathic interstitial pneumonia | 47 (39.5) | 61 (50.4) | 108 (44.6) |
| Combined pulmonary fibrosis and emphysema | 29 (24.4) | 29 (24.0) | 59 (24.4) |
| Connective tissue disease | 33 (27.7) | 24 (19.8) | 57 (23.6) |
| Chronic hypersensitivity pneumonitis | 7 (5.9) | 6 (5.0) | 13 (5.4) |
| Occupational lung disease | 3 (2.5) | 1 (0.8) | 5 (2.1) |
| Idiopathic interstitial pneumonia subcategory | |||
| Idiopathic pulmonary fibrosis | 25 (21.0) | 42 (34.7) | 67 (27.7) |
| Idiopathic nonspecific interstitial pneumonia | 16 (13.4) | 13 (10.7) | 29 (12.0) |
| Respiratory bronchiolitis associated with ILD | 2 (1.7) | 0 | 2 (0.8) |
| Desquamative interstitial pneumonia | 0 | 1 (0.8) | 1 (0.4) |
| Acute interstitial pneumonia | 0 | 1 (0.8) | 1 (0.4) |
| Unclassified idiopathic interstitial pneumonia | 4 (3.4) | 4 (3.3) | 8 (3.3) |
| 6MWD (m) | 281.8±99.6 | 266.3±113.2 | 274.2±106.3 |
| 6MWD at the start of the 16-week RCT (m) | 256.2±101.3 | 269.5±90.1 | 262.0±95.9 |
| FVC (% pred) | 64.7±22.3 | 63.4±19.7 | 64.3±21.1 |
| NT-proBNP (pg·mL−1) | 1312.9±2242.8 | 3115.2±9461.4 | 2231.9±6943.0 |
| Antifibrotic therapy | |||
| None | 100 (84.0) | 88 (72.7) | 190 (78.5) |
| Pirfenidone only | 12 (10.1) | 18 (14.9) | 30 (12.4) |
| Nintedanib only | 7 (5.9) | 15 (12.4) | 22 (9.1) |
Data are presented as median (range), n (%) or mean±sd. RCT: randomised controlled trial; PH: pulmonary hypertension; ILD: interstitial lung disease; 6MWD: 6-min walk distance; FVC: forced vital capacity; NT-proBNP: N-terminal pro-brain natriuretic peptide. #: baseline is defined as the last measurement prior to the first dose of inhaled treprostinil in the OLE unless otherwise specified (baseline data from the RCT have been previously published [6]); ¶: two patients were not previously enrolled in the RCT.
Exposure
Total median inhaled treprostinil exposure duration in the OLE was 62.1 weeks (77.3 and 47.0 weeks in patients from the inhaled treprostinil group and placebo group of the RCT, respectively). The reduced exposure in the prior placebo group likely reflected a higher number of patients who discontinued study drug due to an AE in this group compared with the prior inhaled treprostinil group (table 2). Study drug dosing is summarised in supplementary figure S1. From week 28 to week 76, the median number of breaths per session was 12 at all time-points for both groups. Overall, 80.6%, 60.7% and 26.9% of patients had achieved a maximum dose of ≥9, ≥12 and ≥15 breaths per session four times daily, respectively, by the end of the study.
TABLE 2.
Adverse events (AEs) during the INCREASE open-label extension (OLE)
| Received inhaled treprostinil in RCT (n=119) | Received placebo in RCT (n=121) | Overall (n=242)# | |
| Patients with ≥1 AEs | 112 (94.1) | 115 (95.0) | 229 (94.6) |
| Total AEs (AE rate) ¶ | 1085 (6.7) | 993 (7.9) | 2091 (7.2) |
| Patients with ≥1 SAEs | 66 (55.5) | 65 (53.7) | 133 (55.0) |
| Patients with ≥1 AEs leading to discontinuation of inhaled treprostinil | 20 (16.8) | 34 (28.1) | 54 (22.3) |
| AEs occurring in >10% of all patients | |||
| Cough | 22 (18.5) | 43 (35.5) | 65 (26.9) |
| Dyspnoea | 30 (25.2) | 33 (27.3) | 63 (26.0) |
| Headache | 12 (10.1) | 33 (27.3) | 45 (18.6) |
| Diarrhoea | 20 (16.8) | 17 (14.0) | 37 (15.3) |
| Dizziness | 18 (15.1) | 18 (14.9) | 36 (14.9) |
| Upper respiratory tract infection | 20 (16.8) | 14 (11.6) | 34 (14.0) |
| Nausea | 18 (15.1) | 14 (11.6) | 32 (13.2) |
| Fatigue | 18 (15.1) | 14 (11.6) | 32 (13.2) |
| Pneumonia | 14 (11.8) | 15 (12.4) | 30 (12.4) |
| Acute respiratory failure | 16 (13.4) | 14 (11.6) | 30 (12.4) |
| Urinary tract infection | 10 (8.4) | 15 (12.4) | 27 (11.2) |
| Back pain | 16 (13.4) | 10 (8.3) | 26 (10.7) |
| Productive cough | 8 (6.7) | 16 (13.2) | 25 (10.3) |
Data are presented as n (%). RCT: randomised controlled trial; SAE: serious adverse event. #: two patients were not previously enrolled in the RCT; ¶: AE rate calculated as the number of AEs divided by the total number of patient-years per treatment group (total patient-years were 160.91 years for patients previously treated with inhaled treprostinil, 126.46 years for previously treated with placebo and 289.84 years overall).
Efficacy
The mean±sd 6MWD at week 52 was 279.1±114.8 m for the overall population, 286.2±119.2 m in the former inhaled treprostinil arm and 270.3±109.5 m in the former placebo arm. Mean 6MWD results by study visit (figure 3a) demonstrated that among patients who received inhaled treprostinil in the RCT, mean 6MWD increased from RCT baseline to week 16 and then during the OLE remained greater than RCT baseline through week 52. Patients who received placebo in the RCT experienced an increase in mean 6MWD at weeks 28 and 40 of the OLE after initiating inhaled treprostinil, and then a decrease in mean 6MWD from week 40 to week 52. When 6MWD was analysed as change from baseline of the RCT (figure 3b), the mean±sd change at week 52 was 3.5±70.7 m for the overall population, 22.1±66.3 m in the former inhaled treprostinil arm and −19.5±69.8 m in the former placebo arm.
FIGURE 3.
Results for 6-min walk distance (6MWD). a) Mean 6MWD by study visit starting from baseline of the 16-week INCREASE randomised controlled trial (RCT). Data are mean observed values. b) Mean change from baseline in 6MWD by study visit starting at baseline of the 16-week RCT. Note: time 0 for the open-label extension (OLE) is also week 16 for the RCT; all available data at each time-point are included in the figure. Errors bars indicate the sem.
For the overall population, the median (interquartile range) NT-proBNP decreased from 389 (159–1763) pg·mL−1 at RCT baseline to 359 (135–1551) pg·mL−1 at week 64. Results for each prior treatment arm are shown in figure 4.
FIGURE 4.
Median serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels during the INCREASE randomised controlled trial (RCT) and open-label extension (OLE) in patients who received inhaled treprostinil or placebo during the RCT. The interquartile range is given in parentheses.
No deterioration in the SGRQ or DSP was observed during the OLE (supplementary tables S1 and S2, respectively).
Safety
AEs occurred in 229 patients (94.6%) during the OLE (table 2). Serious AEs occurred in 133 patients (55.0%). AEs leading to drug discontinuation occurred in 54 patients (22.3%), with a higher incidence occurring in patients who had previously received placebo rather than inhaled treprostinil (28.1% versus 16.8%, respectively). Consistent with the RCT, the most common AEs were cough, dyspnoea and headache. Patients previously on placebo were more likely than patients previously on inhaled treprostinil to experience cough and headache.
For the overall population, the mean change from RCT baseline in FVC at week 64 was 51 mL, corresponding to a mean±sd increase of 2.8±8.6% in FVC % predicted. Results for each prior treatment arm are shown in figure 5. FVC changes for the four most common ILD subtypes are shown in supplementary figure S2. No other changes in PFTs were observed during the OLE (supplementary table S3) and no clinically relevant treatment-related changes in blood oxygen saturation (supplementary table S4) or supplemental oxygen use occurred (supplementary table S5).
FIGURE 5.
Mean change from baseline in forced vital capacity (FVC) in a) millilitres and as b) % predicted in the INCREASE randomised controlled trial (RCT) and open-label extension (OLE). Note: time 0 for the OLE is also week 16 for the RCT; all available data at each time-point are included in the figure. Errors bars indicate the sem.
Overall, 133 (55.0%) patients experienced at least one exacerbation of underlying lung disease during the OLE. The Kaplan–Meier estimate of time to first exacerbation of underlying lung disease from the start of the OLE was significantly prolonged among patients who previously received inhaled treprostinil compared with patients who previously received placebo (HR 0.69 (95% CI 0.49–0.97); p=0.0321; median 67.0 versus 32.9 weeks) (figure 6a). This translates to a 31% reduction in acute exacerbations for the former inhaled treprostinil group compared with the former placebo arm. In a Cox regression analysis incorporating adjustments for sex, age and baseline pulmonary vascular resistance, patients formerly on inhaled treprostinil had a significantly reduced risk for exacerbation (HR 0.70 (95% CI 0.49–0.99); p=0.0437). Time to first exacerbation from the start of the RCT is shown in figure 6b.
FIGURE 6.
Kaplan–Meier estimates of time to exacerbation of lung disease from a) INCREASE open-label extension (OLE) baseline (week 16) in all patients and b) INCREASE randomised controlled trial (RCT) baseline (week 0) in all patients. In a) the Kaplan–Meier plot includes only exacerbations taking place in the OLE; therefore, all patients in both the prior inhaled treprostinil arm and the prior placebo arm are represented without an event at week 16. Hazard ratios, 95% confidence intervals and p-values were calculated from a Cox proportional hazards model with the parent study treatment group as an explanatory variable.
During the OLE, 76 patients (31.4%) experienced a cardiopulmonary hospitalisation. There was no significant difference in time to cardiopulmonary hospitalisation between the prior active arm compared with the prior placebo arm (HR 0.90 (95% CI 0.57–1.41); p=0.64). 62 patients (25.6%) died during the OLE. Patients in the prior active arm had a numerically reduced risk of death compared with the prior placebo arm, but the difference was not statistically significant (HR 0.67 (95% CI 0.41–1.11); p=0.12). Among the patients who died, 29 patients (24.4%) who had previously received inhaled treprostinil had a median time to death of 62.0 weeks compared with 31.3 weeks in the 33 patients (27.3%) who had previously received placebo. Kaplan–Meier estimates of median time to event for cardiopulmonary hospitalisations and deaths could not be calculated due to the low number of events.
Discussion
The development of PH in patients with ILD portends a poor prognosis. The COMPERA registry reported estimated 5-year survival rates of 14.0% in patients with PH-ILD compared with 51.8% in patients with idiopathic PAH [11]. Data from a Danish centre demonstrated an eightfold increased risk of death among ILD patients who developed PH compared with those who did not [12]. Prior to INCREASE, data with vasodilators led to conflicting results [5]. The largest RCT in patients with PH-ILD prior to INCREASE, the RISE-IIP trial of riociguat, demonstrated a lack of clinical benefit and had increased serious AEs and deaths in the active treatment arm [4].
In the INCREASE RCT, 16 weeks of inhaled treprostinil therapy was associated with improvements in 6MWD, NT-proBNP and time to clinical worsening, demonstrating a substantial advance in treating this challenging disease [6]. The INCREASE OLE demonstrated minimal decline in exercise capacity for up to 52 weeks. Levels of NT-proBNP, a biomarker associated with morbidity and mortality in PH [13], as well as clinical status and pulmonary haemodynamics in patients with ILD [14], decreased in patients transitioning from placebo to inhaled treprostinil and remained stable in patients previously assigned to active treatment in the parent trial. Lastly, oxygenation data continued to demonstrate that ventilation/perfusion mismatch is not a significant concern even with long-term inhaled treprostinil use in patients with PH-ILD.
Upon further assessment of the 6MWD results by prior treatment arm, it is encouraging to observe the stabilisation of 6MWD in patients formerly randomised to inhaled treprostinil. However, the 6MWD results for the patients formerly on placebo are mixed: mean 6MWD improved at weeks 28 and 40, suggesting that patients derived benefit once they started inhaled treprostinil, but this improvement was not sustained at week 52 (figure 3a). When analysing 6MWD as change from baseline of the RCT (figure 3b), there is only a slight deterioration observed during the OLE during which patients are receiving inhaled treprostinil. From the RCT baseline, the mean change at week 52 was 22.1 m in the former inhaled treprostinil arm and −19.5 m in the former placebo arm. By comparison, data from other studies in similar ILD patient populations suggest that 6MWD decreases quite dramatically when patients are left untreated on placebo, with mean declines of 45.2 m (12 weeks) and 53.1 m (16 weeks) [15, 16]. Therefore, the lack of significant deterioration observed in the OLE could be considered a marker of efficacy in the context of the progressive nature of PH-ILD.
One possible interpretation of these two methods of evaluating 6MWD is that earlier intervention impacts 6MWD improvement; patients who received placebo in the RCT and thus had a 16-week delay in treatment did not achieve the same benefit at week 52 as the group originally randomised to inhaled treprostinil. However, real-world application of this finding may be difficult in light of the varied course of ILD progression and PH onset. As there is no true comparator group in the OLE, and no follow-up pulmonary haemodynamic data, the impact of earlier treatment in PH-ILD remains a topic of future research.
The increase in FVC among patients who had previously received inhaled treprostinil in the RCT demonstrated durability during the OLE with no substantial changes observed. For patients who had received placebo in the RCT, a numerical increase in FVC was demonstrated once starting inhaled treprostinil in the OLE. This finding is notable in that clinical studies of other ILD therapies have generally shown a slowing of the decline in lung function, with FVC loss being numerically greater in the placebo group compared with active therapy [17, 18]. By contrast, in both the INCREASE RCT and OLE, there is an overall increase in mean FVC after initiating inhaled treprostinil. The FVC increase in the former placebo arm is intriguing as it replicates the change seen in the active arm of the parent study. This observation lends support to the study of the antifibrotic properties of treprostinil [19]. Other potential, albeit speculative, hypotheses that could explain this FVC increase might be improved pulmonary vascular compliance or improved blood flow and respiratory muscle strength. Regarding other PFTs, there was no clinically significant change in DLCO or TLC (supplementary table S3).
At present, it is unclear why the FVC increase seen in the OLE is not accompanied by a similarly strong improvement in exercise capacity. The 6MWD results could reflect the deconditioning associated with the 16-week treatment delay that is not reflected in lung function. For instance, the treatment delay may have impacted muscle physiology, muscle perfusion and perfusion/metabolism matching; the incomplete transition to 6MWD benefit could possibly be due to a treatment delay adversely affecting the patients’ ability to exercise. Furthermore, this trial was conducted during coronavirus disease 2019 (COVID-19) restrictions. Many pulmonary rehabilitation programmes were inaccessible and patients may have been unable to exercise. Randomised trials have demonstrated the benefit of exercise training in patients with both ILD [20, 21] and PAH [22, 23], and a lack of ongoing access to programmes may have impacted the 6MWD results.
Earlier treatment with inhaled treprostinil may have led to benefits in clinical outcomes in the INCREASE OLE as well. Prior treatment with inhaled treprostinil was associated with a significant 31% reduction in the risk of exacerbations when compared with prior treatment with placebo. One post-hoc analysis of the OLE showed that treatment with inhaled treprostinil in the RCT resulted in improved event-free survival, defined as the composite of time to first hospitalisation, exacerbation or death when compared with placebo [24]. These results suggest that early screening and diagnosis of PH in patients with ILD need to be studied systematically. A Delphi consensus study has been recently published that can aid clinicians in screening for PH in patients with ILD [25] and there is an ongoing prospective clinical trial to elucidate PH screening strategies in this patient population (PHINDER; ClinicalTrials.gov: NCT05776225).
The safety of inhaled treprostinil in the OLE is consistent with the 16-week trial [6], with the encouraging finding of improvement in tolerability over time. Patients in the inhaled treprostinil arm of the RCT experienced reduced rates of cough (18.5% versus 35.5%) and headache (10.1% versus 27.3%) during the OLE compared with those who initiated inhaled treprostinil in the OLE. This finding attests to the possible attenuation of these AEs over time and, together with the outcomes data, supports persistence with the medication while trying to manage AEs. Indeed, one post-hoc analysis of the OLE safety data shows that the majority of patients reported recovery or resolution of the most common AEs in the study [26].
The primary strength of the current trial was its extended duration, providing information on long-term treatment with inhaled treprostinil. Limitations of the OLE were the open-label design which limits data interpretation; without a placebo arm, the varying degree of responses between different end-points (e.g. 6MWD versus FVC) can be challenging to interpret. In addition, analysis of the results is limited by the small number of subjects with evaluable data at the end of the OLE period, and patients have varying periods of follow-up. There is a high probability of deteriorating patients being among those who discontinued the study early and no imputation was employed to account for this.
In conclusion, the INCREASE OLE demonstrated the safety of long-term inhaled treprostinil in patients with PH-ILD. No new safety signals were observed and the rate of cough decreased with a longer treatment duration. The safety profile was accompanied by maintained exercise capacity and increased FVC, despite challenges associated with the COVID-19 pandemic. Overall, these long-term results are consistent with the findings from the parent INCREASE study and lend further support to the study of the potential antifibrotic effects of inhaled treprostinil.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material ERJ-02414-2022.Supplement (702.5KB, pdf)
Graphical abstract ERJ-02414-2022.Graphical_abstract (164.7KB, pdf)
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Acknowledgements
The authors would like to thank Laura Evans (Twist Medical, Burlingame, CA, USA) for assistance with manuscript preparation and editing that was funded by United Therapeutics. We would also like to thank all INCREASE study centres, research staff and patients for participating in this trial.
Footnotes
This clinical trial was prospectively registered at ClinicalTrials.gov with identifier number NCT02633293. Data may be made available to bona fide researchers who agree to comply with patient informed consent and submit a research proposal form via www.utcrequests.com. Proposals will be evaluated by the sponsor and data will be made available once the research proposal has been approved and the data sharing agreement between sponsor and investigator signed.
This article has an editorial commentary: https://doi.org/10.1183/13993003.00944-2023
Conflict of interest: A. Waxman reports that the present manuscript was funded by United Therapeutics; and reports grants or contracts with payments to his institution from United Therapeutics, Gossamer, Acceleron/Merck, ARIA CV and NIH/NHLBI, patents with Johnson & Johnson, and participation on a data safety monitoring board or advisory board for INSMED. R. Restrepo-Jaramillo reports research grants from Merck, United Therapeutics, Bayer and J&J Actelion, payment of honoraria for speakers bureaus from United Therapeutics, Bayer and J&J Actelion, and participation on advisory boards for Merck, United Therapeutics and Bayer. T. Thenappan reports grants for clinical research studies from United Therapeutics, Tenax Therapeutics, Aria CV and Merck, and consulting fees from United Therapeutics and Acceleron Pharma. P. Engel reports no disclosures. A. Bajwa reports a grant from United Therapeutics for study procedures, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics, Bayer, Johnson & Johnson, Boehringer Ingelheim, and Intuitive. A. Ravichandran reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics, Bayer, Abbott, Medtronic and Janssen. J. Feldman reports consulting fees from United Therapeutics, Aerovate, Altavant and Liquidia, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen and United Therapeutics, and participation on a data safety monitoring board or advisory board for Liquidia, Altavant and Aerovate. A. Hajari Case reports that the present manuscript is funded by United Therapeutics; and reports clinical research contracts to institution from United Therapeutics, and serving as Senior Medical Advisor for the Pulmonary Fibrosis Foundation. R.G. Argula reports consulting fees from Liquidia Corporation, United Therapeutics, Merck Pharma Inc., Janssen Inc. and CVS Health, and payment or honoraria for lectures and educational events from United Therapeutics. V. Tapson reports research grants paid to institution from Boston Scientific Corporation, Bristol Myers Squibb and Genentech, speaker and consulting fees from Janssen, fees from Boston Scientific Corporation for participating in an executive committee for a clinical trial, that he serves as President for PE Response Team Consortium (unpaid), owns stock in Thrombolex and Inari Medical, and that he is employed as VP of Medical Affairs at Inari Medical. P. Smith reports that he is an employee of the study sponsor, United Therapeutics. C. Deng and E. Shen report that they are employees of and hold stock in United Therapeutics, the study sponsor. S.D. Nathan reports that the present manuscript is funded by United Therapeutics; and reports consulting fees from United Therapeutics, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics.
Support statement: Funding for the study was provided by United Therapeutics. Funding information for this article has been deposited with the Crossref Funder Registry.
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