Effectiveness of inhaled treprostinil versus standard of care for the treatment of pulmonary hypertension associated with interstitial lung disease: A propensity score-weighted study of the INCREASE trial and registry data from Europe

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Effectiveness study (incl. comparative)
• Data collection methods:
  Combined primary data collection and secondary use of data

Non-interventional study

• Non-interventional study design:
  Other
• Non-interventional study design, other:
  External comparator arm study

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  AMBRISENTAN

  BOSENTAN MONOHYDRATE

  MACITENTAN

  RIOCIGUAT

  SILDENAFIL

  TADALAFIL

  TREPROSTINIL SODIUM
• Anatomical Therapeutic Chemical (ATC) code:
  (B01AC) Platelet aggregation inhibitors excl. heparin

  Platelet aggregation inhibitors excl. heparin
• Medical condition to be studied:
  Pulmonary hypertension

  Interstitial lung disease

  Combined pulmonary fibrosis and emphysema
• Additional medical condition(s):
  PH WHO Group 3.2 and 3.3

Population studied

• Short description of the study population:
  This study will include adult patients (aged more or equal to 18 years at index date) diagnosed with pulmonary hypertension associated with interstitial lung disease of various aetiologies, documented by right heart catheterisation.; The exposure (inhaled treprostinil) is captured in the INCREASE trial (RIN-PH-201), a multicentre, randomised, doubleblind, placebo-controlled, 16-week Phase III trial, and its open-label extension (RIN-PH-202), with an additional follow-up of up to 108 weeks. The real-world comparator group will be derived from European disease specific data sources: Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and Royal Brompton Hospital National Pulmonary Hypertension Service research ready dataset (UKRB). Exposure to inhaled treprostinil will be compared to 2 different comparator groups derived from real-world data in Europe: (1) off-label PDE5i treated patients from UKRB and COMPERA; (2) treatment naïve patients from UKRB; (3) RW patients (off-label PAH treated and treatment naive) from UKRB.
• Age groups:
  Adult and elderly population (≥18 years)
• Estimated number of subjects:
  500

Study design details

• Study design:
  This is an external comparator arm (ECA) study using data from the INCREASE and INCREASE OLE clinical trials (treatment group) and COMPERA and UKRB registries (external comparator) to generate evidence on the comparative effectiveness of inhaled treprostinil versus SOC in Europe.
• Main study objective:
  By emulating a target trial utilising data from INCREASE (RIN-PH-201) and INCREASE OLE (RINPH-202) clinical trials with an external comparator group of RW patients from PH registries in Europe, this study aims to generate evidence of long-term comparative effectiveness of inhaled treprostinil in adult patients with PH-ILD.; ; Research Question: What is the comparative effectiveness of inhaled treprostinil in the treatment of PH-ILD, between adult patients enrolled in INCREASE and INCREASE OLE clinical trials and RW patients from Europe treated with current SOC (3 comparator groups will be considered as SOC: off-label phosphodiesterase type-5 inhibitor (PDE5i) treated patients from UKRB and COMPERA, treatment naïve patients from UKRB, and RW patients [off-label PAH treated and treatment naive] from UKRB)?; ; Primary objective:; 1. To estimate the effect associated with exposure to inhaled treprostinil versus SOC3 on all-cause mortality up to 28 weeks, 52 weeks, and 124 weeks, among adult patients with PH-ILD.; ; Secondary objectives:; 1. To estimate the effect associated with exposure to inhaled treprostinil versus SOC3 on cardiopulmonary hospitalisation up to 28 weeks, 52 weeks, and 124 weeks, among adult patients with PH-ILD.; 2. To estimate the effect associated with exposure to inhaled treprostinil versus SOC3 on six-minute walk distance (6MWD) from baseline to 28 weeks, 52 weeks, and 124 weeks, among adult patients with PHILD.; 3. To estimate the effect associated with exposure to inhaled treprostinil versus SOC3 on forced vital capacity (FVC) from baseline to 28 weeks, 64 weeks, and 124 weeks, among adult patients with PHILD.
• Comparators:
  Standard of Care: 3 separate comparator groups, treatment naïve and treated with off-label pulmonary arterial hypertension therapy (excluding prostanoids), will be considered as standard of care
• Data analysis plan:
  A statistical analysis plan will be developed prior to the statistical analysis and will describe all planned analysis. In short, descriptive statistics for baseline demographic data, clinical characteristics, and duration of exposure will be presented for inhaled treprostinil group and standard of care group in Europe.; IRs together with 95% CIs will be calculated for each event of interest over the entire observation period and at different follow-up timepoints. Kaplan Meier curves will be plotted for all-cause mortality and all-cause hospitalisation and presented for the entire period at risk.; IPTW based on propensity scores will be implemented to account for observed differences in patient characteristics between the treprostinil and standard of care comparator group, estimating the average treatment effect in the treated population.; To estimate the treatment effect for survival outcomes, Royston-Parmar models with zero (Weibull distribution) or more knots will be applied as a primary analysis and estimates with the respective 95% CIs and p-values will be presented. Additionally, Restricted Mean Survival Time (RMST) will be estimated as a supplementary analysis, by utilising the Kaplan-Meier curve to estimate RMSTs, RMST differences and 95% CIs of inhaled treprostinil versus SOC in PH patients. Weighted RMSTs may be estimated by utilising weighted Kaplan-Meier curves.;