Inhaled Treprostinil Dosage in Pulmonary Hypertension Associated With Interstitial Lung Disease and Its Effects on Clinical Outcomes

Abstract

BackgroundPulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve functional ability and to delay clinical worsening in patients with PH resulting from ILD.Research QuestionDo higher dosages of iTre have greater benefits in preventing clinical worsening and achieving clinical improvement?Study Design and MethodsPost hoc analysis of the INCREASE study, a 16-week double-blind, randomized, placebo-controlled trial of iTre in patients with PH resulting from ILD. Four groups were identified based on the number of breaths per session (bps; < 9 and ≥ 9 bps) of active drug or placebo attained at 4 weeks. Patients were evaluated for clinical worsening (15% decrease in 6-min walkdistance, cardiopulmonary hospitalization, lung transplantation, or death) or clinical improvement (15% increase in the six-minute walk distance with a concomitant 30% reduction in N-terminal prohormone of brain natriuretic peptide without any clinical worsening event).ResultsAt 4 weeks, 70 patients were at a dose of ≥ 9 bps (high-dosage group) and 79 patients were at a dose of < 9 bps (low-dosage group) in the iTre arm vs 86 patients in the high-dose group and 67 patients in the low-dose group in the placebo arm. Between weeks 4 and 16, 17.1% of patients in the high-dose treprostinil group and 22.8% in the low-dose treatment group experienced a clinical worsening event vs 33.7% and 34.3% of patients in the two placebo arms, respectively (P = .006). By week 16, 15.7% and 12.7% of patients in the high- and low-dose iTre groups, respectively, demonstrated clinical improvement vs 7% and 1.5% patients in the placebo arms (P = .003)InterpretationHigher dosages of iTre overall show greater benefit in terms of preventing clinical worsening and achieving clinical improvement. These data support the early initiation and uptitration of therapy to a dosage of at least 9 bps four times daily in patients with PH resulting from ILD.Trial RegistryClinicalTrials.gov; No.: NCT02630316; URL: www.clinicaltrials.gov Pulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve functional ability and to delay clinical worsening in patients with PH resulting from ILD. Do higher dosages of iTre have greater benefits in preventing clinical worsening and achieving clinical improvement? Post hoc analysis of the INCREASE study, a 16-week double-blind, randomized, placebo-controlled trial of iTre in patients with PH resulting from ILD. Four groups were identified based on the number of breaths per session (bps; < 9 and ≥ 9 bps) of active drug or placebo attained at 4 weeks. Patients were evaluated for clinical worsening (15% decrease in 6-min walkdistance, cardiopulmonary hospitalization, lung transplantation, or death) or clinical improvement (15% increase in the six-minute walk distance with a concomitant 30% reduction in N-terminal prohormone of brain natriuretic peptide without any clinical worsening event). At 4 weeks, 70 patients were at a dose of ≥ 9 bps (high-dosage group) and 79 patients were at a dose of < 9 bps (low-dosage group) in the iTre arm vs 86 patients in the high-dose group and 67 patients in the low-dose group in the placebo arm. Between weeks 4 and 16, 17.1% of patients in the high-dose treprostinil group and 22.8% in the low-dose treatment group experienced a clinical worsening event vs 33.7% and 34.3% of patients in the two placebo arms, respectively (P = .006). By week 16, 15.7% and 12.7% of patients in the high- and low-dose iTre groups, respectively, demonstrated clinical improvement vs 7% and 1.5% patients in the placebo arms (P = .003) Higher dosages of iTre overall show greater benefit in terms of preventing clinical worsening and achieving clinical improvement. These data support the early initiation and uptitration of therapy to a dosage of at least 9 bps four times daily in patients with PH resulting from ILD. ClinicalTrials.gov; No.: NCT02630316; URL: www.clinicaltrials.gov Take-home PointsStudy Question: What is the impact of higher dosages of inhaled treprostinil on clinical outcomes in patients with pulmonary hypertension (PH) resulting from interstitial lung disease (ILD)?Results: After 4 weeks, inhaled treprostinil (iTre) at a dose of ≥ 9 breaths per session (bps) four times daily resulted in less clinical worsening and more clinical improvement during the subsequent 3 months.Interpretation: The treatment of patients with PH resulting from ILD with iTre at a dose of ≥ 9 bps results in fewer clinical worsening events and greater clinical improvement. Study Question: What is the impact of higher dosages of inhaled treprostinil on clinical outcomes in patients with pulmonary hypertension (PH) resulting from interstitial lung disease (ILD)? Results: After 4 weeks, inhaled treprostinil (iTre) at a dose of ≥ 9 breaths per session (bps) four times daily resulted in less clinical worsening and more clinical improvement during the subsequent 3 months. Interpretation: The treatment of patients with PH resulting from ILD with iTre at a dose of ≥ 9 bps results in fewer clinical worsening events and greater clinical improvement. Pulmonary hypertension (PH) commonly complicates the course of patients with various forms of fibrotic interstitial lung disease (ILD). When it does occur, it is associated with significant functional impairment, worse quality of life, and increased mortality.1King C.K. Shlobin O.A. The trouble with group 3 pulmonary hypertension in interstitial lung disease: dilemmas in diagnosis and the conundrum of treatment.Chest. 2020; 158: 1651-1664Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Whether to treat PH associated with ILD has been a controversial issue.1King C.K. Shlobin O.A. The trouble with group 3 pulmonary hypertension in interstitial lung disease: dilemmas in diagnosis and the conundrum of treatment.Chest. 2020; 158: 1651-1664Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar,2Nathan S.D. Barbera J.A. Gaine S.P. et al.Pulmonary hypertension in chronic lung disease.Eur Respir J. 2019; 531801914Crossref PubMed Scopus (335) Google Scholar Which patients might benefit from therapy, and what defines these phenotypic patients, has been a topic of much debate. Numerous case reports and retrospective series have been reported, but few randomized clinical trials have addressed this issue.2Nathan S.D. Barbera J.A. Gaine S.P. et al.Pulmonary hypertension in chronic lung disease.Eur Respir J. 2019; 531801914Crossref PubMed Scopus (335) Google Scholar Until recently, the few randomized clinical studies have been equivocal at best, and in some cases even harmful.3Nathan S.D. Behr J. Collard H.R. et al.Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study.Lancet Respir Med. 2019; 7: 780-790Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar,4Corte T.J. Keir G.J. Dimopoulos K. et al.Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia.Am J Respir Crit Care Med. 2014; 190: 208-217Crossref PubMed Scopus (155) Google Scholar The INCREASE study, a phase 3 double-blind placebo-controlled trial of inhaled treprostinil (iTre), is the largest study to date in patients with PH resulting from ILD.5Waxman A. Restrepo R. Thenappan T. al t Inhaled treprostinil in patients with pulmonary hypertension due to interstitial lung disease.N Engl J Med. 2021; 384: 325-334Crossref PubMed Scopus (186) Google Scholar This 16-week trial included patients with the diagnosis of PH resulting from ILD confirmed by right heart catheterization and CT imaging. Patient were treated with iTre or placebo initially at 3 breaths per session (bps) four times daily and titrating up to 9 to 12 bps four times daily. The study met its primary end point of change in 6-min walk distance (6MWD) at week 16. Additionally, patients receiving iTre showed a lower risk of clinical worsening than patients receiving placebo as defined by either cardiopulmonary hospitalization, 6MWD decrease of > 15% from baseline, lung transplantation, or death. In the INCREASE study, higher doses of iTre were associated with greater improvements in 6MWD. However, it is unknown whether higher doses of iTre in patients with PH resulting from ILD are associated with other benefits such as decreased rates of clinical worsening. The goal of this post hoc analysis therefore was to evaluate whether patients achieving higher doses did indeed demonstrate better outcomes based on the end points of clinical worsening or clinical improvement. Details of the INCREASE study procedures and end points have been reported previously.5Waxman A. Restrepo R. Thenappan T. al t Inhaled treprostinil in patients with pulmonary hypertension due to interstitial lung disease.N Engl J Med. 2021; 384: 325-334Crossref PubMed Scopus (186) Google Scholar Patients were started on iTre or placebo at a dose of 3 bps four times daily. ITre (0.6 mg/mL) or placebo was administered by an ultrasonic, pulsed-delivery nebulizer at 6 μg/breath. The dosage was escalated by an additional 1 bps as often as every 3 days, with a target dose of 9 bps four times daily and a maximum dose of 12 bps four times daily. Investigators adjusted the dose on an individual patient basis to achieve the maximum tolerated dosage. Therefore, the earliest patients could achieve the lowest target dose of 9 bps was 21 days. To allow for sufficient time to uptitrate the dose of iTre, the week 4 dose was used to stratify patients by dosage: < 9 bps (< 54 μg) and ≥ 9 bps (≥ 54 μg). The decision to analyze patients for clinical events only after week 4 was intended to avoid any biases imposed by the early uptitration period. Four groups of patients were analyzed independently for outcomes: iTre ≥ 9 bps at 4 weeks, iTre < 9 bps at 4 weeks, placebo ≥ 9 bps at 4 weeks, and placebo < 9 bps at 4 weeks. If patients continued to increase the dosage beyond 4 weeks to ≥ 9 bps or the dosage was decreased from ≥ 9 to < 9 bps, then they were still analyzed in the original groups similar to that of an intention-to-treat analysis. Dosing of individual patients was tracked closely through a study diary and the reconciliation of used and unused study drug ampules at each study visit. Those who did not reach the week 4 study visit were not included in this analysis. The coprimary end points of this study were the proportion of patients who experienced a clinical worsening event or who demonstrated clinical improvement between weeks 4 and 16 in each group. Clinical worsening was defined by one of four events: a 15% decrease in the 6MWD, hospitalization for cardiopulmonary cause, lung transplantation, or death. Clinical improvement was defined by a 15% increase in the 6MWD by 16 weeks accompanied by a 30% reduction in N-terminal prohormone of brain natriuretic peptide in the absence of any clinical worsening events. The Cochran-Mantel-Haenszel Pearson χ 2Nathan S.D. Barbera J.A. Gaine S.P. et al.Pulmonary hypertension in chronic lung disease.Eur Respir J. 2019; 531801914Crossref PubMed Scopus (335) Google Scholar test was used to compare overall rates of clinical worsening and overall rates of clinical improvement between treatment groups adjusted for the dosage groups and for baseline 6MWD category (≤ 350 m vs > 350 m). The baseline demographics, hemodynamics, and lung function among the four groups was compared using Cochran-Mantel-Haenszel test for categorical variables and the Wilcoxon (van Elteren) test for continuous variables. The INCREASE study enrolled 326 patients with PH resulting from ILD who were randomized equally to receive iTre or placebo in a double-blind fashion. The baseline characteristics of the study cohort have been described previously.3Nathan S.D. Behr J. Collard H.R. et al.Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study.Lancet Respir Med. 2019; 7: 780-790Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Figure 1 provides a Consolidated Standards of Reporting Trials diagram depicting patient disposition based on dosage. Fourteen patients in the iTre arm dropped out before week 4 vs 10 patients in the placebo arm. Of these, seven patients in the iTre group experienced a clinical worsening episode compared with two patients in the placebo arm before week 4. At 4 weeks, 149 patients were in the iTre group and 153 patients were in the placebo group. Of these, 70 patients receiving iTre had achieved a dosage of > 9 bps vs 86 patients in the placebo group. Seventy-nine patients receiving iTre and 67 patients receiving placebo remained at < 9 bps at 4 weeks. The median dosages in the iTre < 9 bps and ≥ 9 bps groups were 6 and 12 bps, respectively. The patients categorized into these four groups formed the primary cohort for this analysis. The demographics, hemodynamics, and lung function at baseline of the four groups at week 4 are shown in Table 1. The four groups were well balanced with regard to baseline demographics and clinical variables. Baseline values for diffusing capacity for carbon monoxide % predicted and mean pulmonary arterial pressure were higher in the iTre ≥ 9 bps group and the iTre < 9 bps group, respectively, but did not reach significance. The distribution of dosages at week 4 is shown in Figure 2.Table 1Baseline Demographics, Hemodynamics, and Lung Function of the Four Groups at the Start of the INCREASE StudyCharacteristiciTre ≥ 9 bps (≥ 54 μg; n = 70)Placebo ≥ 9 bps (n = 86)iTre < 9 bps (< 54 μg; n = 79)Placebo < 9 bps (n = 67)P ValueaCochran-Mantel-Haenszel test for categorical variables and stratified Wilcoxon (van Elteren) test for continuous variables.Female sex32 (45.7)35 (40.7)45 (57)28 (41.8).287Age, y70 (26-89)71 (37-85)68 (31-88)70 (36-85).224ILD type.648 IIP32 (45.7)41 (47.7)29 (36.7)36 (53.7) Chronic HP5 (7.1)6 (7)4 (5)1 (1.5) CPFE16 (22.9)25 (29.1)23 (29.1)13 (19.4) CTD-related ILD15 (21.4)13 (15.1)22 (27.9)17 (25.4) Other2 (2.9)1 (1.2)1 (1.3)0Oxygen, L/min3 (0-8)2 (0-8)3 (0-10)2 (0-6).346FVC % predicted60 (27-130)61 (25-130)60 (24-112)60.5 (20-134).600FEV1 % predicted63 (23-120)62 (25-117)62.5 (27-103)66 (22-145).796Dlco % predicted30 (5-54)25 (8-71)26.5 (7-86)27 (1-86).1736MWD, m268.5 (100-533)249 (30-491)232 (101-538)285 (105-505).147NT-proBNP, pg/mL488 (10-21,942)476 (41,16297)551 (10-12,848)321 (23-14,331).568mPAP, mm Hg34.5 (25-66)35 (25-61)37 (25-74)33 (25-57).081PVR, Wood units5.4 (3.1-16.1)5.3 (3-17.6)5.55 (3.2-18)4.7 (3.1-11.2).198Data are presented as No. (%) or median (range), unless 6MWD = 6-min walk bps = breaths per = pulmonary and = = diffusing capacity for carbon = = idiopathic interstitial ILD = interstitial lung = idiopathic pulmonary iTre = inhaled = mean pulmonary = N-terminal prohormone of brain natriuretic = pulmonary Cochran-Mantel-Haenszel test for categorical variables and stratified Wilcoxon (van Elteren) test for continuous variables. in a Figure the distribution of dosages at week Figure are presented as No. (%) or median (range), unless 6MWD = 6-min walk bps = breaths per = pulmonary and = = diffusing capacity for carbon = = idiopathic interstitial ILD = interstitial lung = idiopathic pulmonary iTre = inhaled = mean pulmonary = N-terminal prohormone of brain natriuretic = pulmonary patients in the iTre < 9 bps group to iTre ≥ 9 bps between weeks 4 and 16, four patients from iTre ≥ 9 bps to iTre < 9 during this period. the placebo and 3 patients, respectively, groups At week 16, patients the study at iTre ≥ 9 bps four times daily and patients the study at iTre < 9 bps, in the placebo groups, patients the study at placebo at ≥ 9 bps and patients the study at placebo < 9 Figure 1 the disposition of the patients between weeks 4 and 16. of 70 patients in the iTre ≥ 9 bps group experienced a clinical worsening event between weeks 4 and 16 vs of 79 patients in the iTre < 9 bps group vs of 86 patients and of 67 patients in the placebo ≥ 9 bps and < 9 bps groups, respectively (P = .006). the other end of the of 70 patients and of 79 patients in the high- and iTre groups experienced clinical improvement by week 16 vs 6 of 86 patients and 1 of 67 patients in the placebo > 9 bps and < 9 bps groups, respectively (P = .003) and Clinical in the Four Groups of Patients at at > 9 bps (n = 70)Placebo > 9 bps (n = 86)iTre < 9 bps (n = 79)Placebo < 9 bps (n = 67)P ValueaCochran-Mantel-Haenszel test adjusted for baseline 6MWD for cardiopulmonary ≥ 15% decrease in Lung by a 15% increase in 6MWD accompanied by a 30% decrease in N-terminal prohormone of brain natriuretic peptide in the absence of any clinical are presented as No. unless 6MWD = 6-min walk bps = breaths per iTre = inhaled Cochran-Mantel-Haenszel test adjusted for baseline 6MWD by a 15% increase in 6MWD accompanied by a 30% decrease in N-terminal prohormone of brain natriuretic peptide in the absence of any clinical worsening. in a are presented as No. unless 6MWD = 6-min walk bps = breaths per iTre = inhaled a analyzed patients for any clinical worsening event or improvement by dosage this included only patients who it to week 4 for with the primary analysis The results of this were with fewer patients in the iTre > 9 bps group clinical worsening compared with the other groups < 9 bps, placebo ≥ 9 bps, placebo < 9 bps, In more patients in the iTre > 9 bps group achieved clinical improvement compared with the other groups and and Clinical After 4 by Groups by the ≥ 9 bps (≥ 54 μg; n = ≥ 9 bps (n = < 9 bps (< 54 μg; n = < 9 bps (n = ValueaCochran-Mantel-Haenszel test adjusted for baseline 6MWD for cardiopulmonary ≥ 15% decrease in Lung by a 15% increase in 6MWD accompanied by a 30% decrease in N-terminal prohormone of brain natriuretic peptide in the absence of any clinical are presented as No. unless 6MWD = 6-min walk bps = breaths per iTre = inhaled Cochran-Mantel-Haenszel test adjusted for baseline 6MWD by a 15% increase in 6MWD accompanied by a 30% decrease in N-terminal prohormone of brain natriuretic peptide in the absence of any clinical worsening. in a are presented as No. unless 6MWD = 6-min walk bps = breaths per iTre = inhaled This post hoc analysis of the INCREASE trial provides of a higher for clinical benefit using iTre, at higher compared with placebo in patients with PH resulting from ILD. analysis evaluated clinical change 4 weeks after study to allow sufficient time for drug The benefit was on of the clinical with lower rates of clinical worsening and higher rates of clinical improvement experienced in the iTre group compared with the placebo arm during the 16-week These benefits with higher dosages of of patients were to achieve a dosage of ≥ 9 bps four times that titrating to higher dosages of iTre is in patients a with event This analysis that iTre clinical worsening and in that iTre is associated with more patients clinical improvement compared with receiving analysis that iTre is more than in achieving these The results from this analysis in patients with PH resulting from ILD are with reports in group 1 pulmonary arterial hypertension that higher doses of iTre have on and time to R. et and drug in patients receiving inhaled treprostinil at doses greater than 54 four times 2021; Scopus Google Scholar However, analysis from studies in that evaluated patients for clinical worsening and clinical improvement. to the of iTre is to evaluate the number to treat either to one clinical worsening event or to one clinical improvement This is by the of the between the treatment and placebo arms for clinical worsening and clinical improvement. the risk reduction for the iTre ≥ 9 bps group vs the placebo group for clinical worsening was at 16 weeks the in clinical improvement at 16 weeks was Therefore, the in outcomes was to a number to treat of four by either to one clinical worsening event or to clinical improvement by week 16. To clinical improvement has not been evaluated in any ILD study and is in clinical The study evaluated the of therapy to with clinical improvement as the primary end et to therapy with in patients with pulmonary arterial hypertension a Respir Med. 2021; Full Text Full Text PDF PubMed Scopus Google Scholar This was defined as an absence of clinical worsening accompanied by at least two of the 6MWD increase of ≥ functional 1 or or N-terminal prohormone of brain natriuretic peptide reduction of ≥ of clinical improvement was used a higher but did not the functional this was not in the INCREASE that any PH resulting from ILD studies have clinical improvement as an end point this is an The ability to patients a therapy that in improvement than one that only delay worsening better with patients and This as a more treatment than only by preventing worsening. similar has in the treatment of in the goal of therapy is to improve overall risk than preventing from et and therapy of pulmonary arterial Respir J. 2019; Scopus Google Scholar the of clinical improvement in PH resulting from ILD is what as improvement is to debate. a 15% increase in the 6MWD, for patients in the of the that has been to from to m in patients with the of the et walk test pulmonary and J Respir Crit Care Med. S.D. et of test characteristics and of the walk test in patients with idiopathic pulmonary Med. Full Text Full Text PDF PubMed Scopus Google Scholar This is similar to the in The in the walk test for patients with pulmonary arterial J Respir Crit Care Med. PubMed Scopus Google Scholar However, of the 6MWD in PH resulting from ILD has been a similar as To this 15% increase as imposed the additional of a 30% decrease in the N-terminal prohormone of brain natriuretic that this of right to a in that the increase in the 6MWD indeed was the of a treatment than a In to as patients could not any worsening any cardiopulmonary this is the only worsening event after patients could still show improvement. The decision to analyze patients for clinical events only after week 4 was to avoid any biases imposed by the early uptitration period. had analyzed patients for events in the 4 weeks, then the have been more clinical worsening events in the group, the patients were in the uptitration phase during this period. However, the that a group of patients did show clinical worsening during this early phase of the study does the for the early of the to 16-week of patients of However, group clinical worsening to they and then experienced an event this that the analysis was to the of an intention-to-treat based on the at week 4. this to a analysis of clinical events of the four based on the dosage This analysis demonstrated similar results and the of primary analysis. have been to an analysis based on the to iTre by using the dose of iTre for each patient through the 16-week trial and then to the median dose to the for the high- and However, in a analysis using any patient who the study early or during the study to the low-dose group. This the results to the high-dose group, and not it an of the for of this analysis the of patients groups between 4 and 16 weeks and the in clinical event However, that addressed this between the primary and of showed similar The of the study is it is that have more events with a of to the analysis at 4 weeks this time for patients to uptitrate and with a study visit. any clinical worsening events during this have been to the lower dosage group, have an the group. The that a number of clinical worsening events during this early of dose the of and for pulmonary hypertension in patients with ILD with the goal of early drug out that of higher dosages could a for disease patients who are to up have clinical at higher risk of the iTre < 9 bps group showed a lower baseline 6MWD compared with the iTre ≥ 9 bps group. This provides support for the initiation of clinical worsening events were not but the of this end point are This post hoc analysis demonstrated that a higher doses of iTre is associated with an overall greater benefit in patients with PH resulting from not only in with but in with lower doses of This benefit is one the of clinical worsening and the of clinical improvement. These results support the of early initiation and uptitration of iTre therapy to ≥ 9 bps four times daily. analysis the for an improvement end point in clinical trials of PH resulting from the to what patients with PH resulting from ILD for and The INCREASE study was by but this was not by any R. is by the and the of and the R. is by the of and the and T. is by the of

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